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1
Ito, Ichiaki, Abdelrahman M. G. Yousef, Princess A. Dickson, Keith F. Fournier, Natalie Wall Fowlkes, and John Paul Y. C. Shen. "Antitumor activity of intraperitoneal (IP) paclitaxel to mucinous appendiceal adenocarcinoma in orthotopic patient-derived xenograft model." Journal of Clinical Oncology 41, no. 4_suppl (February 1, 2023): 151. http://dx.doi.org/10.1200/jco.2023.41.4_suppl.151.
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151 Background: Appendiceal adenocarcinomas (AAs) are a rare and heterogeneous mix of tumors for which only few preclinical models exist for drug discovery. These tumors are commonly treated with chemotherapy like those for colorectal cancer despite clear evidence that the two cancers are distinctly different in their clinical behavior and molecular profiles. Taxanes such as paclitaxel (PTX) and docetaxel have been used in the systemic treatment of gastric cancer with peritoneal metastases. IP administration of PTX has been considered a promising treatment for eliminating peritoneal metastasis, as IP delivery of PTX can attain a higher drug exposure in the peritoneal cavity with reduced systemic toxicity because of high local concentrations over a long period of time due to its hydrophobic property. The purpose of this study was to test the efficacy of IP PTX treatment in orthotopic AA PDX models. Methods: AA tumors TM00351, PMP-2 and PMCA-3 were implanted in the peritoneal cavity of NSG mice. PDX models were treated with PTX (6.25, 12.5 or 25.0 mg/kg, IP) with weekly (3 weekly treatments and 1 week off, for two cycles) or biweekly (biweekly treatments for up to 12 weeks) schedule. The peritoneal tumor burden was monitored by MRI. Solid tumor size was evaluated by modified peritoneal Response Evaluation Criteria In Solid Tumors (mpRECIST) method using ImageJ software and mucinous tumor volume was quantified by OsiriX Lite software. Results: TM00351, taken from a high-grade tumor (Grade 3), formed mucin-rich solid tumors with mucinous ascites. PDX models PMP-2 (Grade 2) and PMCA-3 (Grade 3), both with GNASR201C mutation, had a mucinous phenotype similar to GNAS mutant appendiceal tumors in humans. Weekly 25.0 mg/kg of IP PTX treatment reduced AA tumor growth of TM00351 (77.9% reduction vs. control), PMP-2 (98.6% reduction vs. control), and PMCA-3 (85.6% reduction vs. control). Similarly, biweekly 25.0 mg/kg of IP PTX treatment was effective on PMCA-3 (66.2% reduction vs. control). Survival of PMCA-3 PDX mice was significantly improved by 12.5 mg/kg (p=0.0254, log-rank test) and 25.0 mg/kg (p=0.0038) of IP PTX. At 25.0 mg/kg IP PTX treatment induced 12.0% body weight loss of PMCA-3 PDX mice 1 week after the treatment. Lower doses of IP PTX treatment, 6.25 and 12.5 mg/kg, did not induce significant body weight loss or any noticeable adverse effects on mice. Comparing the efficacy of IV to IP administration, neither 6.25 or 12.5 mg/kg of IV PTX reduced growth of PMCA-3, 25.0 mg/kg of IV PTX was lethal to mice shortly after administration. Conclusions: IP PTX is a therapeutically active for mucinous AA tumors.
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Kim, Gunzung, Imran Ashraf, Jeongsook Eom, and Yongwan Park. "Optimal Path Configuration with Coded Laser Pilots for Charging Electric Vehicles Using High Intensity Laser Power Beams." Applied Sciences 11, no. 9 (April 23, 2021): 3826. http://dx.doi.org/10.3390/app11093826.
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Wireless power transmission (WPT) for wireless charging has been gaining wide attention as a promising approach to miniaturizing the battery size and increasing the maximal total range of an electric vehicle (EV). With an appropriate charging infrastructure, WPT holds great potential to accelerate the acceptance of EVs through users’ higher satisfaction, reducing EV cost, and increasing the driving range and capability. A WPT system based on high-intensity laser power beaming (HILPB) provides an optimal solution for wirelessly charging electric vehicles from a distance of several meters. Despite a large number of WPT approaches, the problem of optimal path configuration for charging EV remains an unexplored area. This paper proposes a method to determine the optimal power transmission path in environments where multiple power transmitters (PTXs) and power receivers (PRXs) are operated simultaneously. To this end, we modeled the HILPB power that reaches a PRX equipped with a photovoltaic (PV) array and validated the model by simulating the WPT process in an environment with multiple PTXs and PRXs using a direct-sequence optical code division multiple access (DS-OCDMA) system. In the simulation environment, upon receiving a request from a PRX, a PTX sent its power channel information through optically encoded laser pulses using each available wireless power channel (WPC). The PRX calculated the maximum deliverable power of a PTX and WPC based on the received channel power indicator of the incident laser beam. Based on the calculation results, it selected the optimal PTX and WPC for its maximum power requirement (MPQ). The MPQ of each PRX was satisfied by applying the algorithm for selecting the PTX according to the alignment and characteristics of the PTXs and PRXs. We modeled a power reception model of the PRX based on a PV array using coded laser pilots and validated it through experimentation. We discussed some algorithms that select the most suitable PTX among several PTXs for which several EVs receive the power it needs.
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Borghese, Cinzia, Naike Casagrande, Giuseppe Corona, and Donatella Aldinucci. "Adipose-Derived Stem Cells Primed with Paclitaxel Inhibit Ovarian Cancer Spheroid Growth and Overcome Paclitaxel Resistance." Pharmaceutics 12, no. 5 (April 27, 2020): 401. http://dx.doi.org/10.3390/pharmaceutics12050401.
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Adipose-derived stem cells (ADSCs) primed with paclitaxel (PTX) are now hypothesized to represent a potential Trojan horse to vehicle and deliver PTX into tumors. We analyzed the anticancer activity of PTX released by ADSCs primed with PTX (PTX-ADSCs) (~20 ng/mL) in a panel of ovarian cancer (OvCa) cells sensitive or resistant to PTX. We used two (2D) and three dimensional (3D) in vitro models (multicellular tumor spheroids, MCTSs, and heterospheroids) to mimic tumor growth in ascites. The coculture of OvCa cells with PTX-ADSCs inhibited cell viability in 2D models and in 3D heterospheroids (SKOV3-MCTSs plus PTX-ADSCs) and counteracted PTX-resistance in Kuramochi cells. The cytotoxic effects of free PTX and of equivalent amounts of PTX secreted in PTX-ADSC-conditioned medium (CM) were compared. PTX-ADSC-CM decreased OvCa cell proliferation, was more active than free PTX and counteracted PTX-resistance in Kuramochi cells (6.0-fold decrease in the IC50 values). Cells cultivated as 3D aggregated MCTSs were more resistant to PTX than 2D cultivation. PTX-ADSC-CM (equivalent-PTX) was more active than PTX in MCTSs and counteracted PTX-resistance in all cell lines. PTX-ADSC-CM also inhibited OvCa-MCTS dissemination on collagen-coated wells. In conclusion, PTX-ADSCs and PTX-MSCs-CM may represent a new option with which to overcome PTX-resistance in OvCa.
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Lippton, H. L., Q. Hao, T. Hauth, and A. Hyman. "Mechanisms of signal transduction for adenosine and ATP in pulmonary vascular bed." American Journal of Physiology-Heart and Circulatory Physiology 262, no. 3 (March 1, 1992): H926—H929. http://dx.doi.org/10.1152/ajpheart.1992.262.3.h926.
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The purpose of the present study was to investigate the contribution of pertussis toxin (PTX)-sensitive guanine nucleotide (G) proteins in the pulmonary vascular response to adenosine and ATP in the intact cat under conditions of controlled pulmonary blood flow and left atrial pressure. Adenosine, ATP, and beta-tau-ATP increased lobar arterial pressure in a dose-dependent manner. The pulmonary vasoconstrictor response to adenosine was abolished by BW 1433U, a specific purinergic receptor (P1) inhibitor, PTX pretreatment, indomethacin, and ONO 3708, a thromboxane A2 (TxA2) receptor antagonist. These data suggest that the pulmonary vasoconstrictor response to adenosine depends on activation of P1 purinergic receptors coupled to PTX-sensitive G proteins and subsequent metabolism of liberated arachidonic acid to form TxA2. Because each blocking agent studied produced similar reductions in the pulmonary vasoconstrictor response to ATP without altering the pulmonary vasoconstrictor response to beta-tau-ATP, the present data suggest that ATP constricts the pulmonary vascular bed, in part, by hydrolysis to adenosine. Moreover, the present study suggests that both A1 purinoceptors that are linked to PTX-sensitive G proteins as well as P2x purinoceptors receptors that are independent of PTX-insensitive G proteins mediate the pulmonary vasoconstrictor response to ATP in vivo.
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Melloni, Elisabetta, Elena Marchesi, Lorenzo Preti, Fabio Casciano, Erika Rimondi, Arianna Romani, Paola Secchiero, Maria Luisa Navacchia, and Daniela Perrone. "Synthesis and Biological Investigation of Bile Acid-Paclitaxel Hybrids." Molecules 27, no. 2 (January 12, 2022): 471. http://dx.doi.org/10.3390/molecules27020471.
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Chenodeoxycholic acid and ursodeoxycholic acid (CDCA and UDCA, respectively) have been conjugated with paclitaxel (PTX) anticancer drugs through a high-yield condensation reaction. Bile acid-PTX hybrids (BA-PTX) have been investigated for their pro-apoptotic activity towards a selection of cancer cell lines as well as healthy fibroblast cells. Chenodeoxycholic-PTX hybrid (CDC-PTX) displayed cytotoxicity and cytoselectivity similar to PTX, whereas ursodeoxycholic-PTX hybrid (UDC-PTX) displayed some anticancer activity only towards HCT116 colon carcinoma cells. Pacific Blue (PB) conjugated derivatives of CDC-PTX and UDC-PTX (CDC-PTX-PB and UDC-PTX-PB, respectively) were also prepared via a multistep synthesis for evaluating their ability to enter tumor cells. CDC-PTX-PB and UDC-PTX-PB flow cytometry clearly showed that both CDCA and UDCA conjugation to PTX improved its incoming into HCT116 cells, allowing the derivatives to enter the cells up to 99.9%, respect to 35% in the case of PTX. Mean fluorescence intensity analysis of cell populations treated with CDC-PTX-PB and UDC-PTX-PB also suggested that CDC-PTX-PB could have a greater ability to pass the plasmatic membrane than UDC-PTX-PB. Both hybrids showed significant lower toxicity with respect to PTX on the NIH-3T3 cell line.
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Koeda, Keisuke, Kohei Shitara, Atsuo Takashima, Kazumasa Fujitani, Hironori Tsujimoto, Akihito Tsuji, Eiji Oki, et al. "ABSOLUTE: A phase 3 trial of nanoparticle albumin-bound paclitaxel (nab-PTX) versus solvent-based paclitaxel (sb-PTX) in patients with pre-treated advanced gastric cancer (AGC)—Efficacy and QOL results." Journal of Clinical Oncology 35, no. 15_suppl (May 20, 2017): 4010. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.4010.
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4010 Background: Sb-PTX is a standard second-line treatment for patients (pts) with AGC. Nab-PTX was developed to avoid the toxicities with use of solvents in sb-PTX and potentially improve efficacy. Based on ABSOLUTE trial, we conducted the additional analysis to evaluate the efficacy and QOL of nab-PTX and sb-PTX. Methods: Pts who were refractory to a fluoropyrimidine-containing first-line treatment were randomly assigned (1:1:1) to receive intravenous q3w nab-PTX (260 mg/m2) on day 1 of a 21-day cycle, and q1w nab-PTX (100 mg/m2) or q1w sb-PTX (80 mg/m2) on days 1, 8, and 15 of a 28-day cycle. The primary objective was to evaluate whether q3w nab-PTX and q1w nab-PTX were non-inferior to q1w sb-PTX in terms of overall survival (OS). Tumor shrinkage at 8 weeks and at the time of the best response were also investigated. For the QOL analysis, EQ-5D score were collected at baseline and every 8 weeks during the first 24 weeks, and thereafter at every 24 weeks. Time to deterioration of EQ-5D score was compared between each arm as a minimally important difference of 0.05. Results: 741 pts were randomly assigned to q3w nab-PTX, q1w nab-PTX, or q1w sb-PTX. Median OS (months) were 10.3, 11.1, and 10.9, respectively. Q1w nab-PTX was non-inferior to q1w sb-PTX (hazard ratio 0.97, 97.5% CI 0.76-1.23; non-inferiority one-sided p = 0.0085), whereas q3w nab-PTX was not non-inferior to q1w sb-PTX (1.06, 95% CI 0.87-1.31; non-inferiority one-sided p = 0.062).The response rate of target lesions at 8 weeks and at the time of the best response (%) were 22.1 and 27.7 for q3w nab-PTX, 28.2 and 34.9 for q1w nab-PTX, and 18.0 and 25.6 for q1w sb-PTX. Median time to deterioration of EQ-5D score (months) were 2.1 in q3w nab-PTX, 3.8 in q1w nab-PTX, and 3.7 in q1w sb-PTX. Conclusions: Q1w nab-PTX was non-inferior to q1w sb-PTX in terms of OS. In addition, q1w nab-PTX showed favorable effect in comparison with q1w sb-PTX in terms of response rate of target lesions and time at best response. QOL was similar between q1w nab-PTX and q1w sb-PTX. These results suggest that q1w nab-PTX is a useful second-line treatment for pts with AGC. Clinical trial information: 132059.
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Hyun, Hoon, Min Park, Gayoung Jo, So Kim, Heung Chun, and Dae Yang. "Photo-Cured Glycol Chitosan Hydrogel for Ovarian Cancer Drug Delivery." Marine Drugs 17, no. 1 (January 10, 2019): 41. http://dx.doi.org/10.3390/md17010041.
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In this study, we prepared an injectable drug delivery depot system based on a visible light-cured glycol chitosan (GC) hydrogel containing paclitaxel (PTX)-complexed beta-cyclodextrin (β-CD) (GC/CD/PTX) for ovarian cancer (OC) therapy using a tumor-bearing mouse model. The hydrogel depot system had a 23.8 Pa of storage modulus at 100 rad/s after visible light irradiation for 10 s. In addition, GC was swollen as a function of time. However, GC had no degradation with the time change. Eventually, the swollen GC matrix affected the releases of PTX and CD/PTX. GC/PTX and GC/CD/PTX exhibited a controlled release of PTX for 7 days. In addition, GC/CD/PTX had a rapid PTX release for 7 days due to improved water solubility of PTX through CD/PTX complex. In vitro cell viability tests showed that GC/CD/PTX had a lower cell viability percentage than the free PTX solution and GC/PTX. Additionally, GC/CD/PTX resulted in a superior antitumor effect against OC. Consequently, we suggest that the GC/CD system might have clinical potential for OC therapy by improving the water solubility of PTX, as PTX is included into the cavity of β-CD.
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Wang, Longkun, Chunqian Zhao, Lu Lu, Honglei Jiang, Fengshan Wang, and Xinke Zhang. "Transcytosable Peptide-Paclitaxel Prodrug Nanoparticle for Targeted Treatment of Triple-Negative Breast Cancer." International Journal of Molecular Sciences 24, no. 5 (February 28, 2023): 4646. http://dx.doi.org/10.3390/ijms24054646.
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Triple-negative breast cancer (TNBC) is an extremely aggressive subtype associated with a poor prognosis. At present, the treatment for TNBC mainly relies on surgery and traditional chemotherapy. As a key component in the standard treatment of TNBC, paclitaxel (PTX) effectively inhibits the growth and proliferation of tumor cells. However, the application of PTX in clinical treatment is limited due to its inherent hydrophobicity, weak penetrability, nonspecific accumulation, and side effects. To counter these problems, we constructed a novel PTX conjugate based on the peptide-drug conjugates (PDCs) strategy. In this PTX conjugate, a novel fused peptide TAR consisting of a tumor-targeting peptide, A7R, and a cell-penetrating peptide, TAT, is used to modify PTX. After modification, this conjugate is named PTX-SM-TAR, which is expected to improve the specificity and penetrability of PTX at the tumor site. Depending on hydrophilic TAR peptide and hydrophobic PTX, PTX-SM-TAR can self-assemble into nanoparticles and improve the water solubility of PTX. In terms of linkage, the acid- and esterase-sensitive ester bond was used as the linking bond, with which PTX-SM-TAR NPs could remain stable in the physiological environment, whereas PTX-SM-TAR NPs could be broken and PTX be released at the tumor site. A cell uptake assay showed that PTX-SM-TAR NPs were receptor-targeting and could mediate endocytosis by binding to NRP-1. The vascular barrier, transcellular migration, and tumor spheroids experiments showed that PTX-SM-TAR NPs exhibit great transvascular transport and tumor penetration ability. In vivo experiments, PTX-SM-TAR NPs showed higher antitumor effects than PTX. As a result, PTX-SM-TAR NPs may overcome the shortcomings of PTX and present a new transcytosable and targeted delivery system for PTX in TNBC treatment.
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Mao, Yukang, Yili Zhang, Zheng Luo, Ruoting Zhan, Hui Xu, Weiwen Chen, and Huicai Huang. "Synthesis, Biological Evaluation and Low-Toxic Formulation Development of Glycosylated Paclitaxel Prodrugs." Molecules 23, no. 12 (December 5, 2018): 3211. http://dx.doi.org/10.3390/molecules23123211.
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Paclitaxel (PTX) is a famous anti-cancer drug with poor aqueous solubility. In clinical practices, Cremophor EL (polyethoxylated castor oil), a toxic surfactant, is used for dissolution of PTX, which accounts for serious side effects. In the present study, a single glucose-conjugated PTX prodrug (SG-PTX) and a double glucose-conjugated PTX prodrug (DG-PTX) were synthesized with a glycosylated strategy via succinate linkers. Both of the two prodrugs presented significant solubility improvement and drug-like lipophilicities. Compared to DG-PTX, SG-PTX manifested more promising release of the parent drug in serum. A high percentage of PTX released from SG-PTX could be detected after enzymatic hydrolysis of β-glucuronidase. Besides, both of the two prodrugs exhibited effective cytotoxicity against breast cancer cells and ovarian cancer cells, but presented reduced cytotoxicity against normal breast cells. Moreover, SG-PTX manifested impressive solubility in a low toxic formulation (without ethanol) with a different percentage of Cremophor EL. These results indicated that glycosylation is a promising strategy for PTX modification and SG-PTX may be a feasible and potential type of PTX prodrug. In addition, ethanol-free formulation with a low percentage of Cremophor EL might have the potential to develop a safer formulation for further studies of glycosylated PTX prodrugs.
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Tang, Bo, Yu Qian, Yi Gou, Gang Cheng, and Guihua Fang. "VE-Albumin Core-Shell Nanoparticles for Paclitaxel Delivery to Treat MDR Breast Cancer." Molecules 23, no. 11 (October 25, 2018): 2760. http://dx.doi.org/10.3390/molecules23112760.
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Multi-drug resistance (MDR) presents a serious problem in cancer chemotherapy. In this study, Vitamin E (VE)-Albumin core-shell nanoparticles were developed for paclitaxel (PTX) delivery to improve the chemotherapy efficacy in an MDR breast cancer model. The PTX-loaded VE-Albumin core-shell nanoparticles (PTX-VE NPs) had small particle sizes (about 100 nm), high drug entrapment efficiency (95.7%) and loading capacity (12.5%), and showed sustained release profiles, in vitro. Docking studies indicated that the hydrophobic interaction and hydrogen bonds play a significant role in the formation of the PTX-VE NPs. The results of confocal laser scanning microscopy analysis demonstrated that the cell uptake of PTX was significantly increased by the PTX-VE NPs, compared with the NPs without VE (PTX NPs). The PTX-VE NPs also exhibited stronger cytotoxicity, compared with PTX NPs with an increased accumulation of PTX in the MCF-7/ADR cells. Importantly, the PTX-VE NPs showed a higher anti-cancer efficacy in MCF-7/ADR tumor xenograft model than the PTX NPs and the PTX solutions. Overall, the VE-Albumin core-shell nanoparticles could be a promising nanocarrier for PTX delivery to improve the chemotherapeutic efficacy of MDR cancer.
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Wang, Ying, Ke-Chun Wu, Bing-Xiang Zhao, Xin Zhao, Xin Wang, Su Chen, Shu-Fang Nie, Wei-San Pan, Xuan Zhang, and Qiang Zhang. "A Novel Paclitaxel Microemulsion Containing a Reduced Amount of Cremophor EL: Pharmacokinetics, Biodistribution, andIn VivoAntitumor Efficacy and Safety." Journal of Biomedicine and Biotechnology 2011 (2011): 1–10. http://dx.doi.org/10.1155/2011/854872.
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The purpose of this study was to prepare a novel paclitaxel (PTX) microemulsion containing a reduced amount of Cremophor EL (CrEL) which had similar pharmacokinetics and antitumor efficacy as the commercially available PTX injection, but a significantly reduced allergic effect due to the CrEL. The pharmacokinetics, biodistribution,in vivoantitumor activity and safety of PTX microemulsion was evaluated. The results of pharmacokinetic and distribution properties of PTX in the microemulsion were similar to those of the PTX injection. The antitumor efficacy of the PTX microemulsion in OVCRA-3 and A 549 tumor-bearing animals was similar to that of PTX injection. The PTX microemulsion did not cause haemolysis, erythrocyte agglutination or simulative reaction. The incidence and degree of allergic reactions exhibited by the PTX microemulsion group, with or without premedication, were significantly lower than those in the PTX injection group (P<.01). In conclusion, the PTX microemulsion had similar pharmacokinetics and anti-tumor efficacy to the PTX injection, but a significantly reduced allergic effect due to CrEL, indicating that the PTX microemulsion overcomes the disadvantages of the conventional PTX injection and is one way of avoiding the limitations of current injection product while providing suitable therapeutic efficacy.
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Nakasya, Akio, Yuya Hagiwara, Tatsuki Ikoma, Yusuke Kurioka, Toshihiko Matsumoto, Yoshiyuki Yamamoto, Takao Tsuduki, et al. "Nanoparticle albumin-bound paclitaxel and ramucirumab versus paclitaxel and ramucirumab as second-line chemotherapy for unresectable advanced or recurrent gastric cancer: a multicenter, propensity score-matched analysis (CROSS SELL study)." International Journal of Clinical Oncology 27, no. 4 (January 28, 2022): 684–94. http://dx.doi.org/10.1007/s10147-022-02114-y.
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Abstract Background Paclitaxel plus ramucirumab (PTX + RAM) is the standard second-line chemotherapy for unresectable advanced or recurrent gastric cancer (AGC). Nanoparticle albumin-bound paclitaxel (nab-PTX) is an improved, more convenient form of PTX and is non-inferior to PTX. Although some retrospective and single-arm phase II studies regarding nab-PTX + RAM have been reported, comparative studies are lacking. Here, we compared the efficacy and toxicity of nab-PTX + RAM and PTX + RAM using propensity score matching. Methods Clinical data of 265 patients treated for AGC with nab-PTX + RAM or PTX + RAM were retrospectively collected. Nab-PTX was administered at dosages of 100 mg/m2, replacing PTX in the standard PTX + RAM regimen. Progression-free survival (PFS), overall survival (OS), and toxicity were compared using 1:1 propensity score matching. Results In total, 190 (72%) patients were matched. The median PFS was 5.3 [95% confidence interval (CI) 4.4–6.3] and 4.7 (95% CI 3.2–5.3) months in the nab-PTX + RAM and PTX + RAM groups, respectively [hazard ratio (HR) = 0.76, 95% CI 0.56–1.03, p = 0.07]. The median OS was 11.5 (95% CI 9.2–15.0) and 9.9 (95% CI 8.0–12.7) months, respectively (HR = 0.78, 95% CI 0.56–1.07, p = 0.12). Grade 3 and 4 neutropenia was observed more frequently in the nab-PTX + RAM group (72% vs. 56%, p = 0.03). No treatment-related deaths occurred. Conclusions Nab-PTX + RAM exhibited more favorable trends in terms of PFS and OS but was more myelosuppressive than PTX + RAM. As neutropenia is commonly manageable toxicity, nab-PTX + RAM presents a treatment alternative for AGC. Further studies including randomized, controlled studies are warranted.
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Yu, Na, Jun Li, Pankaj Kumar Singh, Dan Ding, Weihao Sun, Qiyun Tang, and Huae Xu. "The Superior Anticancer Effect of Reactive Oxygen Species-Responsive Paclitaxel Nanoparticles is Mediated Through Autophagic Cell Death." Journal of Biomedical Nanotechnology 15, no. 11 (November 1, 2019): 2251–61. http://dx.doi.org/10.1166/jbn.2019.2847.
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Paclitaxel (Ptx) is a first-line chemotherapeutic drug for advanced gastric cancer. However, the poor solubility of Ptx still limits its clinical application. Here, we designed a methoxy poly(ethylene glycol)/poly(epsilon-caprolactone) (DSPE-PEG2000-TK-Ptx) nanoparticle loaded with "ROS sensitive" groups—thioketal (TK) to improve Ptx release in high ROS areas in cells. We evaluated the anticancer effect of the DSPE-PEG2000-TK-Ptx nanoparticles (Ptx-NPs) in the SGC-7901 gastric tumor cell line. The Ptx-NPs-treated group showed superior cytotoxicity to the same dose of free Ptx by MTT test and clonogenic assay. Autophagy inhibitor 3-MA protected cells from the cytotoxicity of Ptx in tumor cells. More autophagic cells were identified in the Ptx-NPs group via MDC/EB dual staining. NAC, an ROS inhibitor, inhibited cell autophagy induced by free Ptx or Ptx-NPs. SGC-7901 cells transfected with mCherry-EGFP-LC3II showed much brighter fluorescence in the Ptx-NPs group, while 3-MA markedly suppressed the fluorescence. Western blot verified the protein expression of autophagy, such as P62, Beclin 1 and LC3II. In this study, "ROS sensitive" conjugated DSPE-PEG2000-TK-Ptx nanoparticles with enhanced cancer-suppressive efficacy were produced. Ptx-NPs could be a promising antitumor agent for gastric cancer treatment with more efficiency and fewer side effects.
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Kimura, Michio, Eiseki Usami, Hitomi Teramachi, and Tomoaki Yoshimura. "Cost-effectiveness and safety of ramucirumab plus paclitaxel chemotherapy in the treatment of advanced and recurrent gastric cancer." Journal of Oncology Pharmacy Practice 24, no. 6 (April 24, 2017): 403–11. http://dx.doi.org/10.1177/1078155217707335.
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Introduction Weekly paclitaxel (PTX), irinotecan (CPT-11) and ramucirumab plus paclitaxel (Ram + PTX) are currently recommended as the standard second-line or later chemotherapies for advanced and recurrent gastric cancer. This study aims to compare the cost-effectiveness of using Ram + PTX vs. PTX or CPT-11. Furthermore, we investigated the safety and treatment continuity of Ram + PTX in Japan. Methods Expected costs were calculated based on data from patients with advanced and recurrent gastric cancer who were treated with PTX, CPT-11 and Ram + PTX. A literature review was performed to obtain clinical information so that the probability of the efficacy of each chemotherapy could be calculated. The cost-effectiveness ratio of each chemotherapy agent was calculated by dividing the expected cost by the median survival time (MST). Results The cost-effectiveness ratio per month was JPY 85,395.8/MST for the PTX regimen, JPY 132,735.4/MST for the CPT-11 regimen and JPY 657,175.4/MST for the Ram + PTX regimen (p < 0.001). The incremental cost-effectiveness ratio per month of the Ram + PTX regimen to the PTX regimen was JPY 2,780,432.4/MST. The incremental cost-effectiveness ratio of the Ram + PTX regimen to the CPT-11 regimen was JPY 2,185,179.0/MST. With regard to the reasons for discontinuation of treatment, the Ram + PTX regimen had only one case of being discontinued owing to adverse events, and had a profile similar to that of the PTX and CPT-11 regimens. Conclusion These findings show that the Ram + PTX regimen is less cost-effective compared to both the PTX and CPT-11 regimen, but the Ram + PTX regimen is a well-tolerated regimen with sufficient efficacy.
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Hirata, Kenro, Yasuo Hamamoto, Hirokazu Shoji, Hiroki Hara, Chihiro Kondoh, Hisateru Yasui, Takeshi Kajiwara, et al. "A randomized phase II trial of paclitaxel plus ramucirumab versus nab-paclitaxel plus ramucirumab for gastric cancer with peritoneal dissemination refractory to first-line therapy (WJOG10617G/P-SELECT)." Journal of Clinical Oncology 40, no. 4_suppl (February 1, 2022): 280. http://dx.doi.org/10.1200/jco.2022.40.4_suppl.280.
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280 Background: Combination of ramucirumab (RAM) + weekly paclitaxel (PTX) is recommended as a standard second-line therapy for unresectable or recurrent gastric cancer (GC). A recent phase II trial evaluating nab-PTX and RAM combination showed that nab-PTX+RAM is promising efficacy and tolerability as well as PTX+RAM. In subgroup analysis of another phase III trial (ABSOLUTE) comparing different nab-PTX scheduling with PTX, weekly nab-PTX was especially effective for the patients with peritoneal dissemination compared to PTX without RAM combination. Therefore, we hypothesized that nab-PTX+RAM would be more effective than PTX+RAM for patients with peritoneal dissemination. Methods: The P-SELECT trial (WJOG10617G) is an open-label randomized phase II study evaluating the safety and efficacy of PTX+RAM and nab-PTX+RAM in GC patients with peritoneal metastasis. Key eligibility criteria were: 1) histologically proven adenocarcinoma, 2) unresectable or recurrent gastric cancer, 3) peritoneal dissemination, 4) intolerance or refractory to first-line therapy including fluoropyrimidines, 5) PS 0–2. Peritoneal dissemination was confirmed by either contrast enema/enterography, CT scan, clinical signs, or operative findings (including exploratory laparoscopy). The primary endpoint was overall survival (OS), and the secondary endpoints were progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), ascites control rate, safety, and neuropathy-specific quality of life. 105 subjects were required to maintain the power of ≥70% expecting the hazard ratio (HR) of 0.90 in OS. The study was conducted in 58 centers of the West Japan Oncology Group. Results: A total of 105 patients (median age 67; M:F 66:39) were randomized (53 patients in PTX+RAM and 52 in nab-PTX+RAM). Moderate and massive amount of ascites was observed in 39.0% of patients. Median OS was 8.1 months in PTX+RAM and 7.2 months in nab-PTX+RAM (HR 1.04, 95% confidence interval [CI] 0.67–1.61, P = 0.63). Median PFS was 5.1 months in PTX+RAM and 3.9 months in nab-PTX+RAM (HR 1.04, 95% CI 0.69–1.56, P = 0.89). The ORR and DCR for PTX+RAM and nab-PTX+RAM were 20.7% vs. 20.0% (P = 0.99) and 77.4% vs. 63.5% (P = 0.15), respectively. The ascites control rate was 86.1% in PTX+RAM and 70.3% in nab-PTX+RAM (P = 0.07). The incidence of grade 3/4 neuropathy was higher in nab-PTX+RAM (7.5% vs 17.6%, P = 0.14), whereas there was no difference in neuropathy-specific quality of life between the two groups. The incidence of febrile neutropenia was higher in PTX+RAM (11.3% vs 5.9%, P = 0.49). Conclusions: The potential difference in efficacies between nab-PTX+RAM and PTX+RAM was not shown in advanced gastric cancer with peritoneal dissemination. The results of the pre-planned translational research will be available soon. Clinical trial information: jRCTs031180022.
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Zuo, Yangsong, Wenyi Shen, Lili Wang, Chengshi Wang, and Juan Pu. "Study on the Mechanism of Action of Paclitaxel-Loaded Polylactic-co-glycolic Acid Nanoparticles in Non-Small-Cell Lung Carcinoma Cells." Computational and Mathematical Methods in Medicine 2022 (April 6, 2022): 1–7. http://dx.doi.org/10.1155/2022/8524951.
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Objective. To study effective carriers that can enhance the antitumor effect of paclitaxel (PTX). Methods. PTX-loaded polylactic-co-glycolic acid (PLGA) nanoparticles (NPs) (PTX-PLGA NPs), constructed using the emulsification solvent evaporation method, were characterized by scanning electron microscopy and dynamic light scattering. Non-small-cell lung carcinoma (NSCLC) cells were divided into the dimethyl sulfoxide (DMSO) group, PLGA NPs group, PTX group, and PTX-PLGA NPs group. Cell viability was detected by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), cell apoptosis was determined by flow cytometry, and cell migration and invasion were assessed using Transwell assay. Results. PTX-PLGA NPs were smooth in the surface and spherical in shape, with a particle size of 268 ± 1.3 nm. Both PTX and PTX-PLGA NPs could effectively inhibit the activity of A549 and H1650 cells. At 12 and 24 h, PTX-PLGA NPs presented weaker inhibition on the activity of NSCLC cells than PTX, but at 48 and 72 h, PTX-PLGA NPs presented stronger inhibition. Compared with PTX, PTX-PLGA NPs were more effective in enhancing apoptosis and inhibiting migration and invasion of NSCLC cells. Conclusion. With good sustained release and the ability to promote cellular uptake, PTX-PLGA NPs can strongly inhibit the malignant activities of NSCLC cells, which can be used as a promising drug carrier.
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Kitayama, Joji, Hironori Ishigami, Hironori Yamaguchi, Jun Yamada, Daisuke Soma, Hideyo Miyato, Takao Kamei, Alan Kawarai Lefor, and Naohiro Sata. "Optimal drug delivery for intraperitoneal paclitaxel (PTX) in murine model." Pleura and Peritoneum 2, no. 2 (June 27, 2017): 95–102. http://dx.doi.org/10.1515/pp-2017-0002.
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AbstractBackgroundRepeated intraperitoneal (IP) administration of paclitaxel (PTX) with concurrent systemic chemotherapy is clinically effective for the treatment of peritoneal metastases (PM) from gastric cancer. However, it is unclear how biochemical modifications may affect the pharmacokinetics and bioavailability of IP administered PTX.MethodsIn a xenograft PM model using human gastric cancer cells, MKN45, fluorescein-conjugated PTX (OG-PTX) was given IP and the intra-tumor distribution of PTX examined with fluorescein microscopy.ResultsAfter IP injection, PTX was seen to directly infiltrate up to several hundred micrometers from the surface of the PM. Co-injection with 5 % non-animal stabilized hyaluronic acid increased PTX infiltration and suppressed the development of PM more efficiently than PTX alone. PTX solubilized with amphiphilic polymer composed of 2-methacryloyloxyethyl phosphorylcholine (MPC) and n-butyl methacrylate (BMA) efficiently formed a micellar formation 50–100 nm in diameter. IP injection of the nanomicellar PTX (PTX-30W) also showed significantly enhanced tumor infiltration and further inhibition of the growth of PM compared with PTX solubilized with Cremophor–ethanol (PTX-Cre). Finally, IP administration of NK105, another nanomicellar PTX, inhibited the growth of subcutaneous tumors as well as PM, compared with conventional PTX-Cre in the same murine model.ConclusionsPTX administered IP directly infiltrates PM and are thus a useful strategy for the treatment of PM. Drug modification with nanotechnology may further enhance penetration of PM resulting in improved clinical efficacy.
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Hussain, Talib, Sathishbabu Paranthaman, Syed Mohd Danish Rizvi, Afrasim Moin, Devegowda Vishakante Gowda, Gehad Muhammed Subaiea, Mukhtar Ansari, and Abulrahman Sattam Alanazi. "Fabrication and Characterization of Paclitaxel and Resveratrol Loaded Soluplus Polymeric Nanoparticles for Improved BBB Penetration for Glioma Management." Polymers 13, no. 19 (September 22, 2021): 3210. http://dx.doi.org/10.3390/polym13193210.
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Gliomas are one of the prominent cancers of the central nervous system with limited therapeutic modalities. The present investigation evaluated the synergistic effect of paclitaxel (PAX) and resveratrol (RESV)-loaded Soluplus polymeric nanoparticles (PNPs) against glioma cell lines along with in vivo pharmacokinetics and brain distribution study. PAX-RESV-loaded PNPs were prepared by the thin film hydration technique and optimized for different dependent and independent variables by using DoE (Design-Expert) software. The in vitro physiochemical characterization of prepared PAX-RESV-loaded PNPs exhibited appropriate particle size, PDI and % encapsulation efficiency. Cytotoxicity assay revealed that PTX-RESV loaded PNPs had a synergistic antitumor efficacy against C6 glioma cells compared with single and combined pure drugs. Finally, the pharmacokinetic and brain distribution studies in mice demonstrated that the PNPs significantly enhanced the bioavailability of PTX-RESV PNPs than pure PAX and RESV. Thus, the study concluded that PAX-RESV PNPs combination could significantly enhance anti-glioma activity, and this could be developed into a potential glioma treatment strategy.
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Chiu, Hui-Wen, Jeng-Shou Chang, Hui-Yu Lin, Hsun-Hua Lee, Chia-Hao Kuei, Che-Hsuan Lin, Huei-Mei Huang, and Yuan-Feng Lin. "FBXL7 Upregulation Predicts a Poor Prognosis and Associates with a Possible Mechanism for Paclitaxel Resistance in Ovarian Cancer." Journal of Clinical Medicine 7, no. 10 (October 6, 2018): 330. http://dx.doi.org/10.3390/jcm7100330.
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Paclitaxel (PTX) is a common regimen used to treat patients with ovarian cancer. Although approximately 60% of ovarian cancer patients exhibit a pathologic complete response (pCR), approximately 40% of patients appear to be insensitive to PTX adjuvant therapy. Thus, identifying a useful biomarker to predict pCR would be of great help to ovarian cancer patients who decide to receive PTX treatment. We found that FBXL7 was downregulated in OVSAHO (PTX-sensitive) but upregulated in KURAMOCHI (PTX-resistant) cells after PTX treatment at cytotoxic concentrations. Moreover, our data showed that the fold change of FBXL7 expression post-treatment with PTX was causally correlated with the 50% inhibitory concentrations (IC50) of PTX in a panel of ovarian cancer cell lines. In assessments of progression-free survival probability, high levels of FBXL7 transcript strongly predicted a poor prognosis and unfavorable response to PTX-based chemotherapy in patients with ovarian cancer. The knockdown of FBXL7 predominantly enhanced the cytotoxic effectiveness of PTX on the PTX-resistant KURAMOCHI cells. FBXL7 may be a useful biomarker for predicting complete pathologic response in ovarian cancer patients who decide to receive post-operative PTX therapy.
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Gomes, Fernando L. T., Raul C. Maranhão, Elaine R. Tavares, Priscila O. Carvalho, Maria L. Higuchi, Fernando R. Mattos, Fabio G. Pitta, Sergio A. Hatab, Roberto Kalil-Filho, and Carlos V. Serrano. "Regression of Atherosclerotic Plaques of Cholesterol-Fed Rabbits by Combined Chemotherapy With Paclitaxel and Methotrexate Carried in Lipid Core Nanoparticles." Journal of Cardiovascular Pharmacology and Therapeutics 23, no. 6 (May 20, 2018): 561–69. http://dx.doi.org/10.1177/1074248418778836.
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In previous studies, it was demonstrated that lipid core nanoparticles (LDE) resemble the low-density lipoprotein structure and carrying the antiproliferative agent paclitaxel (PTX) strongly reduced atherosclerosis lesions induced in rabbits by cholesterol feeding. Currently, the aim was to verify whether combining LDE-PTX treatment with methotrexate (MTX) associated with LDE (LDE-MTX) could accelerate the atherosclerosis regression attained with single LDE-PTX treatment, after withdrawing the cholesterol feeding. Thirty-eight rabbits were fed 1% cholesterol chow for 8 weeks. Six of these rabbits were then euthanized for analyses of the aorta (controls). In the remaining rabbits, cholesterol feeding was withdrawn, and those 32 animals were allocated to 3 groups submitted to different 8-week intravenous treatments, all once/week: LDE-PTX (n = 10; 4 mg/kg), LDE-PTX + LDE-MTX (n = 11; 4 mg/kg), and LDE-alone (n = 11). Rabbits were then euthanized and aortas were excised for morphometric, immunohistochemical, and gene expression analyses. After cholesterol feeding withdrawal, in comparison with LDE-alone group, both LDE-PTX and LDE-PTX + LDE-MTX treatments had the ability to increase the regression of plaque areas: −49% in LDE-PTX and −59% for LDE-PTX + LDE-MTX. However, only LDE-PTX + LDE-MTX treatment elicited reduction in the intima area, estimated in −57%. Macrophage presence in aortic lesions was reduced 48% by LDE-PTX and 43% by LDE-PTX + LDE-MTX treatment. Matrix metalloproteinase 9 was reduced by either LDE-PTX (74%) or LDE-PTX + LDE-MTX (78%). Tumor necrosis factor α gene expression was reduced 65% by LDE-PTX and 79% by LDE-PTX + LDE-MTX. In conclusion, treatment with LDE-PTX indeed accelerated plaque reduction after cholesterol feeding; LDE-PTX + LDE-MTX further increased this effect, without any observed toxicity. These results pave the way for the use of combined chemotherapy to achieve stronger effects on aggravated, highly inflamed atherosclerotic lesions.
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Wilke, Hansjochen, Eric Van Cutsem, Sang Cheul Oh, Gyorgy Bodoky, Yasuhiro Shimada, Shuichi Hironaka, Naotoshi Sugimoto, et al. "RAINBOW: A global, phase III, randomized, double-blind study of ramucirumab plus paclitaxel versus placebo plus paclitaxel in the treatment of metastatic gastroesophageal junction (GEJ) and gastric adenocarcinoma following disease progression on first-line platinum- and fluoropyrimidine-containing combination therapy rainbow IMCL CP12-0922 (I4T-IE-JVBE)." Journal of Clinical Oncology 32, no. 3_suppl (January 20, 2014): LBA7. http://dx.doi.org/10.1200/jco.2014.32.3_suppl.lba7.
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LBA7 Background: RAM is a human IgG1 monoclonal antibody VEGF-receptor 2 antagonist. We conducted a global, placebo-controlled, double-blind, phase III trial to evaluate the efficacy and safety of PTX +/- RAM in patients with metastatic GEJ or gastric adenocarcinoma who had disease progression on or within 4 months after first-line platinum- and fluoropyrimidine-based combination therapy. Methods: Pts received RAM (8 mg/kg IV q2w) or placebo (PL) plus PTX (80 mg/m2 d1, 8, 15 of a 4 week cycle) until disease progression, unacceptable toxicity, or death. Eligible pts had ECOG PS ≤ 1; and adequate organ function. The primary endpoint was overall survival (OS). Secondary endpoints included progression-free survival (PFS), objective response rate (ORR), time to progression (TTP), and safety. Results: From Dec 2010 to Sep 2012, 665 pts were randomized (RAM+PTX: 330; PTX: 335). Baseline characteristics were generally balanced between arms. The OS hazard ratio (HR) was 0.807 (95% CI 0.678, 0.962; p=0.0169). Median OS was 9.63m for RAM+PTX and 7.36m for PTX. The HR for PFS was 0.635 (95% CI 0.536, 0.752; p <0.0001). Median PFS was 4.40m and 2.86m. Median TTP was 5.5m RAM+PTX; 3.0m PTX (p <0.0001). ORR was 28% RAM+PTX;16% PTX (p=0.0001). Grade ≥ 3 adverse events (AEs) occurring in >5% of patients on RAM+PTX were: neutropenia (40.7% RAM+PTX;18.8% PTX), leukopenia (17.4% vs 6.7% ), hypertension (14.1% vs 2.4%), anemia (9.2% vs 10.3%), fatigue (7.0% vs 4.0%), abdominal pain (5.5% vs 3.3%), and asthenia (5.5% vs 3.3%). Febrile neutropenia was reported in 3.1% RAM+PTX; 2.4% PTX. Conclusions: The primary endpoint of improved OS was met. A statistically significant and clinically meaningful OS benefit of > 2 months was observed for RAM+PTX vs. PTX in gastric and GEJ cancer after progression on 1st-line therapy, as were significant benefits in PFS and ORR. Neutropenia was more frequently reported in the RAM+PTX arm but incidence of febrile neutropenia was comparable between arms. Clinical trial information: NCT01170663.
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Sontag, J. M., D. Thierse, B. Rouot, D. Aunis, and M. F. Bader. "A pertussis-toxin-sensitive protein controls exocytosis in chromaffin cells at a step distal to the generation of second messengers." Biochemical Journal 274, no. 2 (March 1, 1991): 339–47. http://dx.doi.org/10.1042/bj2740339.
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The role of GTP-binding proteins (G-proteins) in the secretory process in chromaffin cells was investigated by studying the effects of pertussis toxin (PTX) on catecholamine release and generation of various second messengers. PTX was found to stimulate the catecholamine secretion induced by nicotine, 59 mM-K+ or veratridine. PTX also potentiated Ca2(+)-evoked catecholamine release from permeabilized chromaffin cells, suggesting that PTX substrate(s) regulate the exocytotic machinery at a step distal to the rise in intracellular Ca2+. We have investigated the possible intracellular pathways involved in the stimulation of secretion by PTX. PTX did not modify the translocation of protein kinase C (PKC) to membranes in intact or permeabilized cells; in addition, neither inhibitors nor activators of PKC had any effect on catecholamine release induced by PTX. Thus it seems unlikely that the effect of PTX on secretion is mediated by activation of PKC. The effect of PTX is also cyclic AMP-independent, as PTX did not change cytoplasmic cyclic AMP levels. The relationship between PTX treatment and arachidonic acid release was also examined. We found that an increase in cytoplasmic arachidonic acid concentration enhanced Ca2(+)-evoked catecholamine release in permeabilized cells, but arachidonic acid did not mimic the effect of PTX on the Ca2(+)-dose-response curve for secretion. Furthermore, PTX did not significantly modify the release of arachidonic acid measured in resting or stimulated chromaffin cells, suggesting that the stimulatory effect of PTX on secretion is not mediated by an activation of phospholipase A2. Taken together, these results suggest that PTX may modulate the intracellular machinery of secretion at a step distal to the generation of second messengers. In alpha-toxin-permeabilized cells, full retention of the PTX-induced activation of secretion was observed even 30 min after permeabilization. In contrast, when chromaffin cells were permeabilized with streptolysin-O (SLO), there was a marked progressive loss of the PTX effect. We found that SLO caused the rapid leakage of three G-protein alpha-subunits which are specifically ADP-ribosylated by PTX. We propose that a PTX-sensitive G-protein may play an inhibitory role in the final stages of the Ca2(+)-evoked secretory process in chromaffin cells.
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Li, Lingling, Saitian Zeng, Liang Guo, Ping Huang, Jie Xi, Jing Feng, Qian Li, et al. "Long Noncoding RNA RMRP Contributes to Paclitaxel Sensitivity of Ovarian Cancer by Regulating miR-580-3p/MICU1 Signaling." Journal of Oncology 2022 (January 29, 2022): 1–10. http://dx.doi.org/10.1155/2022/8301941.
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Ovarian cancer is a prevalent female malignancy affecting the health and life of an increasing population of women around the world. Paclitaxel (PTX) resistance is a significant clinical problem in the treatment of ovarian cancer. However, the regulation mechanism of PTX resistance remains unclear. In this investigation, we reported an innovative function of the long noncoding RNA RMRP in promoting PTX resistance and glycolysis of ovarian cancer cells. We observed that RMRP was highly expressed in the ovarian cancer samples, in which the expression of RMRP was elevated in the PTX-resistant patients compared with the PTX-sensitive patients. Meanwhile, RMRP was upregulated in PTX-resistant ovarian cancer cell lines. Functionally, we found that the silencing of RMRP by siRNA significantly enhanced the PTX sensitivity of PTX-resistant ovarian cancer cells, in which the IC50 of PTX was reduced by RMRP depletion. The RMRP knockdown reduced cell viabilities and enhanced cell apoptosis of PTX-resistant ovarian cancer cells. Moreover, we observed that glucose uptake was enhanced in PTX-resistant ovarian cancer cells. The depletion of RMRP decreased glucose uptake, lactate product, and ATP production in PTX-resistant ovarian cancer cells. About the mechanism, we identified that RMRP was able to sponge miR-580-3p to enhance mitochondrial calcium uptake 1 (MICU1) expression in PTX-resistant ovarian cancer cells. MICU1 overexpression and miR-580-3p repression could reverse the RMRP-inhibited proliferation of PTX-resistant ovarian cancer cells in vitro. Thus, we concluded that RMRP contributes to PTX resistance and glycolysis of ovarian cancer by enhancing MICU1 expression through sponging miR-580-3p. Targeting RMRP may serve as a potential therapeutic strategy for the treatment of PTX-resistant ovarian cancer patients.
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Yonemaru, M., J. R. Hatherill, H. Hoffmann, H. Zheng, K. Ishii, and T. A. Raffin. "Pentoxifylline does not attenuate acute lung injury in the absence of granulocytes." Journal of Applied Physiology 71, no. 1 (July 1, 1991): 342–51. http://dx.doi.org/10.1152/jappl.1991.71.1.342.
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Pentoxifylline (PTX), a methylxanthine, can suppress polymorphonuclear leukocyte (PMN) activation and attenuate sepsis-induced acute lung injury. We investigated whether PTX prevents non-PMN-dependent lung injury. First we studied four groups of granulocyte-depleted guinea pigs (control, PTX, Escherichia coli, and E. coli + PTX). Lung injury was assessed by wet-to-dry lung weight (W/D) ratio and lung tissue-to-plasma 125I-albumin ratio (albumin index, AI). The E. coli group showed a significant increase in the lung W/D ratio and AI compared with the control and PTX groups. However, PTX did not prevent the E. coli-induced increase in the lung W/D ratio and AI. Next we investigated the effects of PTX on endothelial cell monolayer permeability and adenosine 3′,5′-cyclic monophosphate (cAMP) levels. Whereas E. coli lipopolysaccharide (LPS) alone increased the endothelial permeability, PMNs added to the endothelial monolayers and exposed to LPS enhanced the increase. PTX attenuated the permeability increase mediated by LPS-exposed PMNs. PTX did not prevent the LPS-induced increase in permeability when PMNs were not present, although PTX increased endothelial cell cAMP levels. These data demonstrate that 1) PTX does not prevent lung injury in granulocyte-depleted guinea pigs; 2) PTX does not prevent LPS-induced increases in endothelial cell permeability, despite increased cAMP levels; and 3) PTX attenuates PMN-dependent increases in endothelial cell permeability.
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Abu Samaan, Tala M., Marek Samec, Alena Liskova, Peter Kubatka, and Dietrich Büsselberg. "Paclitaxel’s Mechanistic and Clinical Effects on Breast Cancer." Biomolecules 9, no. 12 (November 27, 2019): 789. http://dx.doi.org/10.3390/biom9120789.
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Paclitaxel (PTX), the most widely used anticancer drug, is applied for the treatment of various types of malignant diseases. Mechanisms of PTX action represent several ways in which PTX affects cellular processes resulting in programmed cell death. PTX is frequently used as the first-line treatment drug in breast cancer (BC). Unfortunately, the resistance of BC to PTX treatment is a great obstacle in clinical applications and one of the major causes of death associated with treatment failure. Factors contributing to PTX resistance, such as ABC transporters, microRNAs (miRNAs), or mutations in certain genes, along with side effects of PTX including peripheral neuropathy or hypersensitivity associated with the vehicle used to overcome its poor solubility, are responsible for intensive research concerning the use of PTX in preclinical and clinical studies. Novelties such as albumin-bound PTX (nab-PTX) demonstrate a progressive approach leading to higher efficiency and decreased risk of side effects after drug administration. Moreover, PTX nanoparticles for targeted treatment of BC promise a stable and efficient therapeutic intervention. Here, we summarize current research focused on PTX, its evaluations in preclinical research and application clinical practice as well as the perspective of the drug for future implication in BC therapy.
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Imai, Hiroo, Keigo Komine, Shin Takahashi, Ken Saijo, Yoshinari Okada, Akihiro Kobayashi, Akira Okita, et al. "Efficacy and Safety Assessment of Paclitaxel in Patients with Docetaxel-Resistant Esophageal Squamous Cell Carcinoma." Chemotherapy 61, no. 5 (2016): 262–68. http://dx.doi.org/10.1159/000444122.
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Background: Incomplete cross-resistances between paclitaxel (PTX) and docetaxel (DTX) has been demonstrated in several types of cancer. The objective of the present study was to assess the existence of cross-resistance between PTX and DTX in esophageal squamous cell carcinoma. Methods: Patients in the PTX group received PTX without DTX pretreatment, patients in the prior DTX (Pr-DTX) group received PTX after the development of resistance to DTX, and patients in the DTX group received DTX without subsequent PTX treatment. Results: A total of 73 patients were enrolled. The response rates to PTX in the PTX and Pr-DTX groups were 22.7 and 20.0%, respectively. The median progression-free survival times from the first day of PTX treatment in the PTX and Pr-DTX groups were 113 (95% CI 56-154) and 97 days (95% CI 36-189), respectively. The median overall survival times from the first day of DTX treatment in the Pr-DTX and DTX groups were 315 (95% CI 124-453) and 148 days (95% CI 139-177), respectively. Conclusions: There is no or incomplete clinical cross-resistance between PTX and DTX in esophageal squamous cell carcinoma. Replacement of DTX with PTX is a suitable treatment option for patients with DTX-resistant esophageal squamous cell carcinoma.
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Soe, Zar Chi, Wenquan Ou, Milan Gautam, Kishwor Poudel, Bo Kyun Kim, Le Minh Pham, Cao Dai Phung, et al. "Development of Folate-Functionalized PEGylated Zein Nanoparticles for Ligand-Directed Delivery of Paclitaxel." Pharmaceutics 11, no. 11 (October 30, 2019): 562. http://dx.doi.org/10.3390/pharmaceutics11110562.
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In this study, we investigated the active targeted delivery of a hydrophobic drug, paclitaxel (PTX), via receptor-mediated endocytosis by folate receptors expressed on cancer cells using a protein-based nanoparticle system. PTX was loaded on zein nanoparticles and conjugated with folate (PTX/Zein-FA) to estimate its chemotherapeutic efficacy in folate receptor-expressing KB cancer cells. PTX/Zein-FA nanoparticles were successfully developed, with a nanoparticle size of ~180 nm and narrow polydispersity index (~0.22). Accelerated release of PTX in an acidic environment was observed for PTX/Zein-FA. An in vitro cellular study of PTX/Zein-FAs in KB cells suggested that PTX/Zein-FA improved the cytotoxic activity of PTX on folate receptors overexpressed in cancer cells by inducing proapoptotic proteins and inhibiting anti-apoptotic proteins. In addition, PTX/Zein-FA exhibited anti-migratory properties and could alter the cell cycle profile of KB cells. A549 cells, which are folate receptor-negative cancer cells, showed no significant enhancement in the in vitro cellular activities of PTX/Zein-FA. We describe the antitumor efficacy of PTX/Zein-FA in KB tumor-bearing mice with minimum toxicity in healthy organs, and the results were confirmed in comparison with free drug and non-targeted nanoparticles.
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Gao, Yu, Tao Liu, Xuan Liu, and Chao Wu. "Preparation of paclitaxel-folic acid functionalized gelatin grafted mesoporous hollow carbon nanospheres for enhancing antitumor effects toward liver cancer (SMMC-7721) cell lines." Journal of Biomaterials Applications 34, no. 8 (December 26, 2019): 1071–80. http://dx.doi.org/10.1177/0885328219896457.
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Folic acid functionalized gelatin-coated mesoporous hollow carbon nanospheres (FGMCN) were synthesized and applied to enhance the antitumor curative effect of paclitaxel (PTX) for human liver cancer cell lines (SMMC-7721). PTX was loaded in FGMCN by the adsorption method and the PTX-loaded samples (PTX-FGMCN) had a drug content of 29.8 ± 1.06%. The PTX-FGMCN with a sustained release effect was characterized by X-ray diffraction and differential scanning calorimeter in order to analyze the PTX state in FGMCN. In vitro cell experiments showed that FMHSN improves the uptake of PTX and promotes apoptosis due to the nano-targeting effect of FMHSN. An in vivo tumor bearing experiment in mice indicated that the PTX-FGMCN significantly inhibited the growth of tumors. All of these results suggested that the PTX-FGMCN may be an effective anti-hepatoma drug in the future.
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Kuznetsov, Konstantin, Alena Stepanova, Ren Kvon, Timothy Douglas, Nikita Kuznetsov, Vera Chernonosova, Ivan Zaporozhchenko, et al. "Electrospun Produced 3D Matrices for Covering of Vascular Stents: Paclitaxel Release Depending on Fiber Structure and Composition of the External Environment." Materials 11, no. 11 (November 2, 2018): 2176. http://dx.doi.org/10.3390/ma11112176.
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Paclitaxel is a natural, highly lipophilic anti proliferative drug widely used in medicine. We have studied the release of tritium-labeled paclitaxel (3H-PTX) from matrices destined for the coating of vascular stents and produced by the electrospinning method from the solutions of polycaprolactone (PCL) with paclitaxel (PTX) in hexafluoisopropanol (HFIP) and/or solutions of PCL with PTX and human serum albumin (HSA) in HFIP or HIFP-dimethyl sulphoxide (DMSO) blend. The release of PTX has been shown to depend on the composition of electrospinning solution, as well as the surrounding medium, particularly the concentration of free PTX and PTX-binding biomolecules present in human serum. It was shown that 3D matrices can completely release PTX without weight loss. Two-phase PTX release from optimized 3D matrices was obtained: ~27% of PTX was released in the first day, another 8% were released over the next 26 days. Wherein ~2.8%, ~2.3%, and ~0.25% of PTX was released on day 3, 9, and 27, respectively. Considering PTX toxicity, the rate of its diffusion through the arterial wall, and the data obtained the minimum cytostatic dose of the drug in the arterial wall will be maintained for at least three months.
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Zhong, Aimin, Viswanath Billa, Lorne E. Rotstein, Pui Y. Wong, Joanne M. Bargman, Stephen I. Vas, and Dimitrios G. Oreopoulos. "Recurrence of Hyperparathyroidism after Total Parathyroidectomy and Autotransplantation in Peritoneal Dialysis Patients." Peritoneal Dialysis International: Journal of the International Society for Peritoneal Dialysis 20, no. 2 (March 2000): 200–208. http://dx.doi.org/10.1177/089686080002000207.
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Objective To evaluate the effectiveness of total parathyroidectomy (PTX) with autotransplantation in the treatment of secondary hyperparathyroidism (HPT), and to assess recurrence rate of HPT in this peritoneal dialysis (PD) population. Design A retrospective study in a single home PD unit. Patients Between 1994 and 1998, 19 of 574 patients on PD underwent PTX for treatment of secondary HPT. Main Outcome Measures Clinical and biochemical improvement, recurrence of HPT, improvement in anemia post-PTX. Results Nineteen (3.3%) patients required PTX between 1994 and 1998. These 5 men and 14 women ranged in age from 22 to 66 years; they had been on maintenance PD pre-PTX for 47.5 ± 38.1 months, and were followed for 26.1 ± 15.5 months post-PTX. Sixteen patients had temporary hypocalcemia that was managed by oral (n = 10) or intravenous (n = 6) calcium supplements and calcitriol, while 3 patients had severe “hungry bone” syndrome postoperatively. One patient had recurrent laryngeal nerve palsy post-PTX. Bone pain disappeared in all 12 patients. Pruritus improved in 12/13 patients; fatigue improved in 15/16 patients. Comparison showed significant differences between hemoglobin and hematocrit values 1 month pre-PTX and 12 months post-PTX ( p < 0.05). Parathyroid hormone (PTH) level in 15 (79%) patients returned to normal (≤€7.6 pmol/L) during the first month post-PTX. In 5/12 (42%) patients, PTH level was ≤ 7.6 pmol/L 2 years post-PTX, while in 2/12 (17%), PTH was > 22.8 pmol/L (three times normal) 2 years post-PTX, and 3/5 (60%) patients had a PTH > 22.8 pmol/L 3 years post-PTX. Conclusions Total PTX with autotransplantation is associated with a tendency for recurrence of HPT. Our findings suggest that total PTX with autotransplantation may be an ineffective procedure in controlling HPT over the long term.
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Kimura, Yasue, Tetsuya Kusumoto, Eiji Kusumoto, Masahiko Sugiyama, Mitsuhiko Ohta, Norifumi Tsutsumi, Yoshihisa Sakaguchi, and Koji Ikejiri. "The comparison of the usefulness of nab-paclitaxel and paclitaxel for advanced or recurrent gastric cancer." Journal of Clinical Oncology 33, no. 3_suppl (January 20, 2015): 217. http://dx.doi.org/10.1200/jco.2015.33.3_suppl.217.
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217 Background: For patients who do not respond to S-1-based treatment in Japan, weekly paclitaxel (PTX) therapy is more frequently used as second-line chemotherapy. On the other hand, the agent could not be used for alcohol hypersensitivity in some cases. Nab-Paclitaxel (N-PTX), which is the protein-bound paclitaxel, has recently been introduced in Japan. The purpose of this study was to retrospectively determine the more preferable agent, N-PTX or PTX, following the S-1-containing chemotherapy in patients with advanced or recurrent gastric cancer (ARGC). Methods: We conducted a retrospective review of the data for 40 patients with ARGC, who received either N-PTX monotherapy for 5 patients or PTX monotherapy for 35 patients. N-PTX was used as the second-line for all patients in this group. On the other hand, in the PTX group, 4, 28 and 3 patients received PTX monotherapy as the 1st-, 2nd- and 3rd-line, respectively. N-PTX was administered intravenously at a dose of 260 mg/m2 repeated triweekly. PTX was administered intravenously at a dose of 80 mg/m2repeated weekly (on days 1, 8 and 15) every four weeks. The objective response rate (ORR), adverse events, progression-free survival (PFS) were compared between the two groups. Results: For tumor response, in the N-PTX group, CR/PR/SD/PD were 0/3/1/1, respectively for an ORR of 60% and a DCR of 80%; in the PTX group, CR/PR/SD/PD were 0/3/15/13, respectively for an ORR of 10% and a DCR of 58%. The ORR of the N-PTX group was higher, which might result from the higher dose intensity in the group, compared with the PTX group. For the adverse toxicity, in the both group, events of grade ≥ 3 were not observed. Serious neurotoxicity (≥grade 3), as commonly described for treatment with paclitaxel, was not observed in this study. The survival data showed that the PFS was 253 days in the N-PTX group, compared with 176 days in the PTX group, which were not significantly different. Conclusions: We suggest the application of N-PTX in place of PTX after S-1 containing chemotherapy for ARGC, only from the perspective of the tumor response. Further data accumulation is required for overall survival.
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Zajdel, Alicja, Adam Wilczok, Katarzyna Jelonek, Monika Musiał-Kulik, Aleksander Foryś, Suming Li, and Janusz Kasperczyk. "Cytotoxic Effect of Paclitaxel and Lapatinib Co-Delivered in Polylactide-co-Poly(ethylene glycol) Micelles on HER-2-Negative Breast Cancer Cells." Pharmaceutics 11, no. 4 (April 6, 2019): 169. http://dx.doi.org/10.3390/pharmaceutics11040169.
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To find better strategies to enhance the cytotoxic effect of paclitaxel (PTX) and lapatinib (LAP) against breast cancer cells, we analyzed the efficacy of a novel delivery system containing polylactide-co-poly(ethylene glycol) (PLA-PEG) filomicelles of over 100 nm in length and spherical micelles of approximately 20 nm in diameter. The 1H NMR measurements confirmed the incorporation of PTX and LAP into micelles. Analysis of the drug release mechanism revealed the diffusion-controlled release of LAP and anomalous transport of PTX. Drug content analysis in lyophilized micelles and micellar solution showed their good storage stability for at least 6 weeks. Blank micelles, LAP-loaded micelles and free LAP did not affect MCF-7 breast cancer cell proliferation, suggesting that the cytotoxicity of PTX-, PTX/LAP-loaded micelles, and the binary mixture of free PTX and LAP was solely caused by PTX. PTX/LAP-loaded micelles showed greater toxicity compared to the binary mixture of PTX and LAP after 48 h and 72 h. Only free PTX alone induced P-gp activity. This study showed the feasibility of using a LAP and PTX combination to overcome MDR in MCF-7 cells, particularly when co-loaded into micelles. We suggest that PTX/LAP micelles can be applicable not only for the therapy of HER-2-positive, but also HER-2-negative breast cancers.
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Yang, Qilei, Chang Zu, Wengang Li, Weiwei Wu, Yunlong Ge, Lingling Wang, Li Wang, Yong Li, and Xiuhua Zhao. "Enhanced Water Solubility and Oral Bioavailability of Paclitaxel Crystal Powders through an Innovative Antisolvent Precipitation Process: Antisolvent Crystallization Using Ionic Liquids as Solvent." Pharmaceutics 12, no. 11 (October 22, 2020): 1008. http://dx.doi.org/10.3390/pharmaceutics12111008.
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Paclitaxel (PTX) is a poor water-soluble antineoplastic drug with significant antitumor activity. However, its low bioavailability is a major obstacle for its biomedical applications. Thus, this experiment is designed to prepare PTX crystal powders through an antisolvent precipitation process using 1-hexyl-3-methylimidazolium bromide (HMImBr) as solvent and water as an antisolvent. The factors influencing saturation solubility of PTX crystal powders in water in water were optimized using a single-factor design. The optimum conditions for the antisolvent precipitation process were as follows: 50 mg/mL concentration of the PTX solution, 25 °C temperature, and 1:7 solvent-to-antisolvent ratio. The PTX crystal powders were characterized via scanning electron microscopy, Fourier transform infrared spectroscopy, high-performance liquid chromatography–mass spectrometry, X-ray diffraction, differential scanning calorimetry, thermogravimetric analysis, Raman spectroscopy, solid-state nuclear magnetic resonance, and dissolution and oral bioavailability studies. Results showed that the chemical structure of PTX crystal powders were unchanged; however, precipitation of the crystalline structure changed. The dissolution test showed that the dissolution rate and solubility of PTX crystal powders were nearly 3.21-folds higher compared to raw PTX in water, and 1.27 times higher in artificial gastric juice. Meanwhile, the bioavailability of PTX crystal increased 10.88 times than raw PTX. These results suggested that PTX crystal powders might have potential value to become a new oral PTX formulation with high bioavailability.
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Wei, Yuping, Liang Zhang, Yankai Fu, and Xia Xu. "Rapid delivery of paclitaxel with an organic solvent-free system based on a novel cell penetrating peptide for suppression of tumor growth." Journal of Materials Chemistry B 5, no. 37 (2017): 7768–74. http://dx.doi.org/10.1039/c7tb01259d.
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PTX is rapidly translocated into HeLa cells with the help of R7. The intracellular PTX concentration of R7/PTX complex group is 3 fold that of the free PTX group. This delivery system does not contain any organic solvent. The tumor growth is significantly suppressed by a tail vein injection of the R7/PTX complex.
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Pan, Wang, Qian Wang, Yi Zhang, Naishu Zhang, Jiamin Qin, Wei Li, Jing Wang, Fangfang Wu, Lingsen Cao, and Guanglin Xu. "Verteporfin can Reverse the Paclitaxel Resistance Induced by YAP Over-Expression in HCT-8/T Cells without Photoactivation through Inhibiting YAP Expression." Cellular Physiology and Biochemistry 39, no. 2 (2016): 481–90. http://dx.doi.org/10.1159/000445640.
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Background/Aims: Paclitaxel (PTX) is one of the most effective anti-cancer drugs. However, multiple drug resistance is still the main factor that hinders the effective treatment of cancer with PTX. Several factors including YAP over-expression can cause PTX resistance. In this study, we aimed to verify the role YAP plays in PTX resistance, explore the reversal of PTX resistance by verteporfin (VP) and investigate the effect of combination therapy of PTX and VP on the PTX resistant colon cancer cells (HCT-8/T). Methods: To study the relationship between YAP and PTX resistance, a stable YAP-over-expression or YAP silencing cell line was generated by transfected with YAP-plasmids or siYAP-RNA. WST-1 assay was performed to detect the cytotoxicity of PTX on HCT-8 and HCT-8/T cells. Clone formation assay and Transwell assay was preformed to determine the cell proliferation and invasion ability respectively. Immunofluorescence and Western blot analysis was performed for protein detection. Results: YAP was stronger expressed in HCT-8/T than in HCT-8, and PTX resistance was positively correlated with the level of YAP expression. VP, a strongly YAP inhibitor, could reduce the PTX resistance on HCT-8/T cells without light activation by inhibiting YAP. Beside, VP and PTX combination therapy showed synergism on inhibition of YAP and cytotoxicity to HCT-8/T. Moreover, verteporfin and PTX combination therapy affect the invasion and colony formation ability and induce apoptosis of HCT-8/T cells. Conclusions: VP can reverse the PTX resistance induced by YAP over-expression in HCT-8/T cells without photoactivation through inhibiting YAP expression.
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Prinetti, Alessandro, Danilo Millimaggi, Sandra D'Ascenzo, Matilda Clarkson, Arianna Bettiga, Vanna Chigorno, Sandro Sonnino, Antonio Pavan, and Vincenza Dolo. "Lack of ceramide generation and altered sphingolipid composition are associated with drug resistance in human ovarian carcinoma cells." Biochemical Journal 395, no. 2 (March 28, 2006): 311–18. http://dx.doi.org/10.1042/bj20051184.
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PTX (Paclitaxel®) is an antimitotic agent used in the treatment of a number of major solid tumours, particularly in breast and ovarian cancer. This study was undertaken to gain insight into the molecular alterations producing PTX resistance in ovarian cancer. PTX treatment is able to induce apoptosis in the human ovarian carcinoma cell line, CABA I. PTX-induced apoptosis in CABA I cells was accompanied by an increase in the cellular Cer (ceramide) levels and a decrease in the sphingomyelin levels, due to the activation of sphingomyelinases. The inhibition of acid sphingomyelinase decreased PTX-induced apoptosis. Under the same experimental conditions, PTX had no effect on Cer and sphingomyelin levels in the stable PTX-resistant ovarian carcinoma cell line, CABA-PTX. The acquisition of the PTX-resistant phenotype is accompanied by unique alterations in the complex sphingolipid pattern found on lipid extraction. In the drug-resistant cell line, the levels of sphingomyelin and neutral glycosphingolipids were unchanged compared with the drug-sensitive cell line. The ganglioside pattern in CABA I cells is more complex compared with that of CABA-PTX cells. Specifically, we found that the total ganglioside content in CABA-PTX cells was approximately half of that in CABA I cells, and GM3 ganglioside content was remarkably higher in the drug-resistant cell line. Taken together our findings indicate that: i) Cer generated by acid sphingomyelinase is involved in PTX-induced apoptosis in ovarian carcinoma cells, and PTX-resistant cells are characterized by their lack of increased Cer upon drug treatment, ii) PTX resistance might be correlated with an alteration in metabolic Cer patterns specifically affecting cellular ganglioside composition.
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Nakatani, Yuki, Aya Nakaya, Takayasu Kurata, Takashi Yokoi, Yuki Takeyasu, Maiko Niki, Kayoko Kibata, et al. "Interstitial Lung Disease Following Single-Agent Nanoparticle Albumin-Bound Paclitaxel Treatment in Patients with Advanced Non-Small Cell Lung Cancer." Case Reports in Oncology 10, no. 2 (August 4, 2017): 683–88. http://dx.doi.org/10.1159/000479148.
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Interstitial lung disease (ILD) is a serious and potentially fatal adverse event in lung cancer therapy. Nanoparticle albumin-bound paclitaxel (nab-PTX) is a novel, solvent-free formulation of paclitaxel (PTX). Although the incidence of nab-PTX-induced ILD is not clear, it is generally considered that this formulation presents a similar risk of developing ILD as PTX. Here, we report 3 patients who developed severe ILD following treatment with nab-PTX. We draw attention to the risk of developing drug-induced ILD following nab-PTX treatment, and highlight that this novel formulation might therefore not be as safe as PTX with respect to the development of ILD.
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Cui, Hongmei, Kinsie Arnst, Duane D. Miller, and Wei Li. "Recent Advances in Elucidating Paclitaxel Resistance Mechanisms in Non-small Cell Lung Cancer and Strategies to Overcome Drug Resistance." Current Medicinal Chemistry 27, no. 39 (November 24, 2020): 6573–95. http://dx.doi.org/10.2174/0929867326666191016113631.
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Paclitaxel (PTX) is a first-line drug for late-stage non-small cell lung cancer (NSCLC) patients who do not benefit from targeted therapy or immunotherapy. However, patients invariably develop resistance to PTX upon prolonged treatments. Although diverse mechanisms leading to PTX resistance have been well-documented in the literature, strategies to overcome PTX resistance in NSCLC based on these mechanisms are still challenging. In this article, we reviewed recent advancements elucidating major mechanisms of PTX resistance in NSCLC, including the overexpression of ABC transporters, alternations to tubulin structures, and the involvement of cytokines, miRNAs, kinase signaling pathways, and epithelial-mesenchymal transition. Potential markers of PTX resistance or PTX response that could help to direct treatment decisions and restore cellular sensitivity to PTX were also discussed. Finally, we summarized the corresponding strategies to overcome PTX resistance in NSCLC cells, which might provide new insights into clinical trials and benefit lung cancer patients in the future.
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Nguyen, Thi Lan, Thi Hiep Nguyen, and Dai Hai Nguyen. "Development and In Vitro Evaluation of Liposomes Using Soy Lecithin to Encapsulate Paclitaxel." International Journal of Biomaterials 2017 (2017): 1–7. http://dx.doi.org/10.1155/2017/8234712.
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The formulation of a potential delivery system based on liposomes (Lips) formulated from soy lecithin (SL) for paclitaxel (PTX) was achieved (PTX-Lips). At first, PTX-Lips were prepared by thin film method using SL and cholesterol and then were characterized for their physiochemical properties (particle size, polydispersity index, zeta potential, and morphology). The results indicated that PTX-Lips were spherical in shape with a dynamic light scattering (DLS) particle size of 131±30.5 nm. Besides, PTX was efficiently encapsulated in Lips, 94.5±3.2% for drug loading efficiency, and slowly released up to 96 h, compared with free PTX. More importantly, cell proliferation kit I (MTT) assay data showed that Lips were biocompatible nanocarriers, and in addition the incorporation of PTX into Lips has been proven successful in reducing the toxicity of PTX. As a result, development of Lips using SL may offer a stable delivery system and promising properties for loading and sustained release of PTX in cancer therapy.
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Ribeiro, Edson A., Luiz F. Poli-de-Figueiredo, Rodrigo Vincenzi, Flavio H. F. Galvao, Nelson Margarido, Mauricio Rocha-e-Silva, and Ruy J. Cruz. "Intraportal versus Systemic Pentoxifylline Infusion after Normothermic Liver Ischemia: Effects on Regional Blood Flow Redistribution and Hepatic Ischemia-Reperfusion Injury." HPB Surgery 2013 (August 29, 2013): 1–6. http://dx.doi.org/10.1155/2013/689835.
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Pentoxifylline (PTX) has been shown to have beneficial effects on microcirculatory blood flow. In this study we evaluate the potential hemodynamic and metabolic benefits of PTX during hepatic ischemia. We also test the hypothesis that portal PTX infusion can minimize the I/R injury when compared to systemic infusion. Methods. Twenty-four dogs ( kg) were subjected to portal triad occlusion (PTO) for 45 min. The animals were assigned to 3 groups: CT (control, PTO, ), PTX-syst (PTO + 25 mg/Kg of PTX IV, ), and PTX-pv (PTO + 25 mg/Kg of PTX in the portal vein, ). Animals were followed for 120 min. Systemic hemodynamics, gastrointestinal tract perfusion, oxygen-derived variables, and liver enzymes were evaluated throughout the experiment. Results. Animals treated with PTX presented significantly higher CO in the first hour after reperfusion, when compared to the CT (~3.7 vs. 2.1 L/min, ). Alanine aminotransferase (ALT) was similar in the PTX groups two hours after reperfusion but significantly higher in the CT (227 vs. ~64 U/L, ). Conclusion. PTX infusion was associated with hemodynamic benefits and was able to minimize liver injury during normothermic hepatic I/R. However, local PTX infusion was not associated with any significant advantage over systemic route.
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Kigawa, J., W. Kawaguchi, H. Itamochi, Y. Kanamori, T. Oishi, M. Shimada, S. Sato, S. Sato, and N. Terakawa. "Effect of simultaneous inhibition of MEK and PI3K/Akt pathways on paclitaxel sensitivity in ovarian cancer." Journal of Clinical Oncology 25, no. 18_suppl (June 20, 2007): 16046. http://dx.doi.org/10.1200/jco.2007.25.18_suppl.16046.
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16046 Background: Paclitaxel (PTX) is one of the key drugs for ovarian cancer treatment. PTX activates the Raf-mitogen-activated protein kinase kinase (MEK) and phosphatidylinositol 3’-kinase (PI3K) pathways that lead to cell survival pathways. The purpose of this study was to clarify whether and how the inhibitors of MEK and/or PI3K affect the sensitivity to PTX in ovarian cancer cells. Methods: We treated five ovarian cancer cell lines in combination with PTX and MEK- [PD98059 (PD)] and/or PI3K-inhibitor [LY294002 (LY)] and assessed cell viability, apoptosis, and the expression of phosphorylated (p) MEK and pAkt. The sensitivity of the cell lines to PTX was determined by 3-(4,5- dimethylthiazol-2-yl) -2,5-dyphenyltetrazolium bromide (MTT) assay. The level of protein expression was analyzed by western blot analysis. The drug-induced apoptosis was assessed by Annexin V-FITC staining. Additionally, KOC-2S was injected to intraperitoneal cavity of nude mouse. The effect of combined treatment on the survival in xenograft model was investigated. Results: The levels of pMEK and pAkt protein expression were higher in PTX resistant cell lines (KOC-2S and KFTx) than that in sensitive cell lines (KF, SHIN-3, SK-OV-3). Treatment of PTX induced MEK activation in all five ovarian cancer cell lines. The combination of PTX with either PD or LY led to additive effect on cell growth inhibition. In contrast, synergistic effect was observed in the combination of PTX with PD and LY. Furthermore, apoptotic cells were significantly increased after exposure to PTX and both inhibitors in comparison with other treatment conditions, such as PTX alone, PTX with either PD or LY. The level of pMEK induced by PTX was down-regulated by PD. Interestingly, the level of pAkt was up-regulated by the combination of PTX with PD, which was reduced by LY. Treatment with PTX, PD, and LY prolonged survival in an ovarian cancer xenograft model (p < 0.01). Conclusions: The present study suggests that simultaneous inhibition of MEK and PI3K/Akt pathways enhances the sensitivity to PTX in ovarian cancer. The combination of PTX with MEK- and PI3K-inhibitor may be a new treatment strategy for ovarian cancer. No significant financial relationships to disclose.
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Cheng, Xingzhen, Fang Yang, Yang Wang, Wei Nie, Adarsha Mahendra Upadhyay, Maolin Zhang, Qian Wang, and Zhiqiang Yan. "Albumin Paclitaxel Compared with 5-Penfluorouracil, Lobaplatin, and Albumin Paclitaxel Combined with 5-Penfluorouracil in the Treatment of Human Gastric Cancer Cell AGS Line Autophagy and Apoptosis." Canadian Journal of Gastroenterology and Hepatology 2022 (June 10, 2022): 1–14. http://dx.doi.org/10.1155/2022/6015877.
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Background. Gastric cancer is one of the most common malignant tumors in the world. Albumin paclitaxel (Nab-PTX) is a novel microtubule inhibitor with albumin as the carrier. Several clinical trials are underway in gastric cancer, but the autophagy mechanism of Nab-PTX on gastric cancer is still unclear. The autophagy and apoptosis effects of Nab-PTX compared with 5-pentafluorouracil (5-Fu) and lobaplatin (LBP) in gastric cancer are also unclear. Objective. This article will compare the effects of Nab-PTX, 5-Fu, LBP, and albumin paclitaxel + 5-pentafluorouracil (Nab-PTX + 5-Fu) on AGS cells from the perspective of autophagy and apoptosis, which is to provide new ideas and experimental evidence for gastric cancer. Method. (1) Experimental groups were control (Ctrl), Nab-PTX, 5-Fu, LBP, and Nab-PTX + 5-Fu. (2) CCK-8 assay was used to reflect cell viability and proliferation. (3) The flow cytometry was used to perform the 24-hour apoptosis and cell cycle of each group. (4) Western blot assay was used to investigate autophagy signal proteins LC3I/LC3II, LC3II/LC3I, SQSTM1/p62, Beclin-1, Atg12, Atg5, p-mULK1, p-AMPK, p-mTOR, and apoptosis signal proteins Bax and Bcl-2. Results. Nab-PTX, 5-Fu, LBP, and Nab-PTX + 5-Fu inhibited AGS cells' proliferation and arrested the cell cycle. At the same time, each group increased the apoptosis of AGS cells to various degrees (Nab-PTX + 5-Fu > Nab-PTX > 5-Fu > LBP, respectively). The experimental results showed that Nab-PTX and Nab-PTX + 5-Fu promoted autophagy and apoptosis of AGS cells. The comparison of Nab-PTX, 5-Fu, and LBP between groups revealed that 5-Fu inhibited autophagy and the expression of apoptosis protein Bax. In LBP, abnormal activation of autophagy downstream, blocking of autophagy flow, abnormal increase of ATG12, and increased expression of apoptosis protein Bax occurred. Further study found that the autophagy upstream mechanism is different. Conclusion. Nab-PTX, 5-Fu, LBP, and Nab-PTX + 5-Fu can inhibit cell proliferation, promote cell apoptosis, and induce the difference in autophagy expression. The autophagy difference of this antitumor drug may be related to its inducing apoptosis. Meanwhile, Nab-PTX has a better antitumor effect than 5-Fu and LBP in gastric cancer, and the combination of Nab-PTX + 5-Fu has more antitumor advantages.
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Zharikov, Sergey I., Karina Y. Krotova, Leonid Belayev, and Edward R. Block. "Pertussis toxin activates l-arginine uptake in pulmonary endothelial cells through downregulation of PKC-α activity." American Journal of Physiology-Lung Cellular and Molecular Physiology 286, no. 5 (May 2004): L974—L983. http://dx.doi.org/10.1152/ajplung.00236.2003.
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Pertussis toxin (PTX) induces activation of l-arginine transport in pulmonary artery endothelial cells (PAEC). The effects of PTX on l-arginine transport appeared after 6 h of treatment and reached maximal values after treatment for 12 h. PTX-induced changes in l-arginine transport were not accompanied by changes in expression of cationic amino acid transporter (CAT)-1 protein, the main l-arginine transporter in PAEC. Unlike holotoxin, the β-oligomer-binding subunit of PTX did not affect l-arginine transport in PAEC, suggesting that Gαi ribosylation is an important step in the activation of l-arginine transport by PTX. An activator of adenylate cyclase, forskolin, and an activator of protein kinase A (PKA), Sp-cAMPS, did not affect l-arginine transport in PAEC. In addition, inhibitors of PKA or adenylate cyclase did not change the activating effect of PTX on l-arginine uptake. Long-term treatment with PTX (18 h) induced a 40% decrease in protein kinase C (PKC)-α but did not affect the activities of PKC-ϵ and PKC-ζ in PAEC. An activator of PKC-α, phorbol 12-myristate 13-acetate, abrogated the activation of l-arginine transport in PAEC treated with PTX. Incubation of PTX-treated PAEC with phorbol 12-myristate 13-acetate in combination with an inhibitor of PKC-α (Go 6976) restored the activating effects of PTX on l-arginine uptake, suggesting PTX-induced activation of l-arginine transport is mediated through downregulation of PKC-α. Measurements of nitric oxide (NO) production by PAEC revealed that long-term treatment with PTX induced twofold increases in the amount of NO in PAEC. PTX also increased l-[3H]citrulline production from extracellular l-[3H]arginine without affecting endothelial NO synthase activity. These results demonstrate that PTX increased NO production through activation of l-arginine transport in PAEC.
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Monroe, J. J., and A. H. Tashjian. "Palytoxin modulates cytosolic pH in human osteoblast-like Saos-2 cells via an interaction with Na(+)-K(+)-ATPase." American Journal of Physiology-Cell Physiology 270, no. 5 (May 1, 1996): C1277—C1283. http://dx.doi.org/10.1152/ajpcell.1996.270.5.c1277.
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Palytoxin (PTx) at nanomolar concentrations enhances the permeability of mammalian cell membranes to both Na+ and Ca2+. In basal human osteoblast-like Saos-2 cells, PTx (8 nM) caused a persistent decrease in cytosolic pH (pHi) of about 0.2 units, which required the presence of extracellular Ca2+ (Cae2+) and Na+ (Nae+). We acidified Saos-2 cells by incubation with nigericin to examine the action of PTx in cells with an activated Na+/H+ antiporter. Under these conditions, PTx increased the pHi without requiring Cae2+ or Nae+, and the alkalinization was unaffected by hexamethylene amiloride. We conclude that the PTx-induced rise in pHi did not involve the Na+/H+ antiporter. PTx increased the rate of 86Rb+ efflux. We propose that PTx induced alkalinization in nigericin-acidified cells by collapsing the K+ gradient. Exposure to ouabain had no effect on pHi, but it prevented the actions of PTx on PHi in both basal and nigericin-acidified cells. Ouabain-resistant mutant cells were less sensitive to PTx in extruding 86Rb+ than their ouabain-sensitive parents. We conclude that PTx interacts with the Na(+)-K(+)-adenosinetriphosphatase to regulate pHi in both basal and nigericin-acidified Saos-2 cells.
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Markeb, Ahmed A., Nagwa A. El-Maali, Douaa M. Sayed, Amany Osama, Mohamed A. Y. Abdel-Malek, Amen H. Zaki, Mostafa E. A. Elwanis, and James J. Driscoll. "Synthesis, Structural Characterization, and Preclinical Efficacy of a Novel Paclitaxel-Loaded Alginate Nanoparticle for Breast Cancer Treatment." International Journal of Breast Cancer 2016 (2016): 1–8. http://dx.doi.org/10.1155/2016/7549372.
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Purpose. The antitumor activity of a novel alginate (ALG) polymer-based particle that contained paclitaxel (PTX) was evaluated using human primary breast cancer cells.Materials and Methods. PTX was combined with ALG in a nanoparticle as a drug delivery system designed to improve breast cancer tumor cell killing. PTX-ALG nanoparticles were first synthesized by nanoemulsification polymer cross-linking methods that improved the aqueous solubility. Structural and biophysical properties of the PTX-ALG nanoparticles were then determined by transmission electron microscopy (TEM) and high performance liquid chromatography (HPLC) fluorescence. The effect on cell cycle progression and apoptosis was determined using flow cytometry.Results. PTX-ALG nanoparticles were prepared and characterized by ultraviolet (UV)/visible (VIS), HPLC fluorescence, and TEM. PTX-ALG nanoparticles demonstrated increased hydrophobicity and solubility over PTX alone. Synthetically engineered PTX-ALG nanoparticles promoted cell-cycle arrest, reduced viability, and induced apoptosis in human primary patient breast cancer cells superior to those of PTX alone.Conclusion. Taken together, our results demonstrate that PTX-ALG nanoparticles represent an innovative, nanoscale delivery system for the administration of anticancer agents that may avoid the adverse toxicities with enhanced antitumor effects to improve the treatment of breast cancer patients.
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Xu, Xiaoyan, Chao Wu, Andi Bai, Xuan Liu, Huiling Lv, and Ying Liu. "Folate-Functionalized Mesoporous Silica Nanoparticles as a Liver Tumor-Targeted Drug Delivery System to Improve the Antitumor Effect of Paclitaxel." Journal of Nanomaterials 2017 (2017): 1–13. http://dx.doi.org/10.1155/2017/2069685.
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The aim of this study was to prepare and characterize an innovative hepatocellular carcinoma-targeted therapeutic drug delivery system based on folate-PEG-mesoporous silica nanoparticles (FA-PEG-MSNs) loaded with paclitaxel (PTX). In vitro cell experiments and an in vivo antitumor efficacy study demonstrated that FA-PEG-MSNs-PTX produced significantly higher tumor inhibition compared with pure PTX and mesoporous silica nanoparticles loaded with paclitaxel (MSNs-PTX). The biodistribution investigation of PTX in nude mice revealed that the FA-PEG-MSNs-PTX could accumulate in tumors. Folic acid functionalized MSNs resulted in a good targeting effect, confirming that FA-PEG-MSNs-PTX is a promising tumor-targeted drug delivery system for liver cancer chemotherapy.
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Yang, Haotian, Jun Zhang, Ying Huan, Yawei Xu, and Rong Guo. "Pentraxin-3 Levels Relate to the Wells Score and Prognosis in Patients with Acute Pulmonary Embolism." Disease Markers 2019 (March 12, 2019): 1–6. http://dx.doi.org/10.1155/2019/2324515.
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Objective. To investigate the value of the PTX-3 test in evaluating the prognosis of acute pulmonary embolism (APE). Method. 117 APE patients were selected and divided into two groups according to plasma PTX-3 levels, including the group in which PTX−3≥3.0 ng/mL (n=42) and the group in which PTX−3<3.0 ng/mL (n=75). Patients were stratified into high-risk, medium-risk, and low-risk groups according to the Wells scores, and the PTX-3 levels were compared among the groups. Patients had been followed-up as well. Results. According to the Wells scores, 11 patients were classified as high-risk (9.4%) and 68 were medium-risk (58.1%), while 38 were low-risk (32.5%). The PTX-3 levels in different risk groups were statistically different (all P<0.05). During the follow-up period, 6 deaths occurred in the group with elevated PTX-3 (≥3.0 ng/mL), while 2 deaths occurred in the group with nonelevated PTX-3 (<3.0 ng/mL). The difference between the two groups was statistically significant (P<0.01). 13 patients were hospitalized due to recurrent pulmonary embolism, of which 12 were in the group with elevated PTX-3 (≥3.0 ng/mL), while 1 patient was in the group with nonelevated PTX-3 (<3.0 ng/mL). The difference was statistically significant (P<0.01). Conclusion. The plasma PTX-3 level in APE patients is correlated with PE risk stratification. There is a significant correlation between PTX-3 levels and PE-related cardiac deaths, as well as the prognosis of recurrent PE. PTX-3 can be used as a clinical indicator of PE prognosis.
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Sun, Hongwen, Xiaoting Zhou, Yanan Bao, Guosheng Xiong, Yue Cui, and Hua Zhou. "Involvement of miR-4262 in paclitaxel resistance through the regulation of PTEN in non-small cell lung cancer." Open Biology 9, no. 7 (July 2019): 180227. http://dx.doi.org/10.1098/rsob.180227.
Full textAbstract:
Non-small cell lung cancer (NSCLC) is considered to be the primary cause of cancer-related mortalities worldwide. Paclitaxel (PTX), either as a monotherapy or in combination with other drugs, is an alternative therapy for advanced NSCLC. However, cancer cell resistance against PTX represents a major clinical problem. This study aimed to investigate the role and underlying mechanism of miR-4262 in PTX-resistant NSCLC. The levels of miR-4262 were analysed by quantitative reverse transcription polymerase chain reaction. A luciferase reporter assay and bioinformatics were used to explore the potential target gene of miR-4262. Regulation of miR-4262 and PTEN expressions in NSCLC was conducted by transfection. PTX-resistant A549 and H1299 cells were established by stepwise screening through increasing the PTX concentration in the cultures. In vivo , tumorigenesis experiments were used to explore the effects of miR-4262 and PTX. Cell proliferation, apoptosis and cell migration were detected using a CCK-8 assay, flow cytometry and Transwell migration assay, respectively. PI3 K/Akt pathway-related proteins were detected by western blot. miR-4262 expression was significantly upregulated in NSCLC tissues and cell lines, and miR-4262 targeted PTEN. In addition, miR-4262 induced PTX chemoresistance by promoting survival and migration in A549/PTX and H1299/PTX cells. Moreover, miR-4262 expression and PI3 K/Akt signalling pathway-related proteins were upregulated and PTEN was downregulated in A549/PTX and H1299/PTX. Our results indicate that miR-4262 enhances PTX resistance in NSCLC cells through targeting PTEN and activating the PI3 K/Akt signalling pathway. The inhibition of miR-4262 expression might be an improved treatment to overcome PTX resistance in NSCLC.
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Liao, Shang-Chih, Sin-Hua Moi, Fong-Fu Chou, Cheng-Hong Yang, and Jin-Bor Chen. "Changes in Serum Concentrations of Fibroblast Growth Factor 23 and Soluble Klotho in Hemodialysis Patients after Total Parathyroidectomy." BioMed Research International 2016 (2016): 1–6. http://dx.doi.org/10.1155/2016/6453803.
Full textAbstract:
Background. We examined the changes in circulating fibroblast growth factor 23 (FGF23) and Klotho concentrations in hemodialysis patients after parathyroidectomy (PTX). Methods. We enrolled a cohort of hemodialysis patients who received PTX. Postoperatively, patients received calcium supplements and/or vitamin D analogue (calcitriol) to maintain serum calcium within 7.0–8.0 mg/dL. Information on clinical parameters including bone-mineral metabolic variables was collected pre-PTX and on days 5 and 90 after PTX. Concomitantly, serum full-length FGF23 and α-Klotho levels were measured. The relationship between FGF23 and clinical parameters was analyzed by single linear regression. Results. Forty-six participants (33 women; 13 men) were enrolled in the study. Their mean age was 56.49 years. Serum FGF23 and α-Klotho concentrations were elevated on days 5 and 90 after PTX compared to baseline (p>0.05). Serum FGF23 concentrations negatively correlated with serum calcium concentrations pre-PTX (Beta -0.31; R2 0.0949; p=0.040), day 5 post-PTX (Beta -0.31; R2 0.0982; p=0.036), and day 90 post-PTX (Beta -0.39; R2 0.1528; p=0.008). Conclusions. There was no change in circulating FGF23 and Klotho concentrations after PTX in hemodialysis patients given postoperative calcium supplements and/or vitamin D analogue. Serum FGF23 concentrations pre-PTX and at days 5 and 90 after PTX were inversely related to serum calcium concentrations.
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Airoldi, M., L. Cattel, R. Passera, P. Milla, L. Delprino, C. Boselli, C. Buffa, and F. Pedani. "Paclitaxel and pegylated liposomal doxorubicin in recurrent head/neck cancer: An unexpected administration interval-dependent pharmacokinetic interaction." Journal of Clinical Oncology 24, no. 18_suppl (June 20, 2006): 2042. http://dx.doi.org/10.1200/jco.2006.24.18_suppl.2042.
Full textAbstract:
2042 Background: Combination of paclitaxel (PTX) with pegylated liposomal doxorubicin (PLD) is an interesting opportunity for recurrent head/neck cancer treatment. Their pharmacokinetic (PK) behavior could be dependent not only on PTX excipient (polyethoxylated castor oil) interference, but also on different iv administration interval between the two drugs. The study endpoint was to evaluate any possible administration interval-dependent PK interaction, when PLD infusion start is delayed from 0 to 24 h after PTX infusion end. Methods: 24 patients affected by recurrent cisplatin pre-treated squamous cellhead/neck cancer were enrolled, receiving PTX 80 mg/m2 q 1w and PLD 12.5 mg/m2 q 2w for 6w/2w rest. Administration interval was 0 h at d1 (PTX-PLD 0) and 24 h at d15 (PTX-PLD 24). Blood sampling was performed at d1–15, PTX and PLD blood levels were analyzed by high performance liquid chromatography techniques, while PK parameters by non-compartmental analysis. Results: PTX PK parameters had large statistically significant differences (median/IQR, PTX-PLD 0 vs. PTX-PLD 24, Mann-Whitney test): Cmax 261/219–531 vs. 407/250–1473 ng/ml p=0.142, AUC 869/688–1331 vs. 3361/969–7853 ng*h/ml p=0.013, Kel 0.39/0.26–0.57 vs. 0.11/0.02–0.26 h⁁−1 p=0.001, Cl 153/89–198 vs. 41/17–138 l/h p=0.013. Similarly, PLD Cmax and AUC were higher in PTX-PLD 24 (Cmax 5.1/3.3–8.1 vs. 6.8/5.3–7.8 mg/l p=0.043, AUC 341/104–1472 vs. 603/106–1006 mg*h/l p=1.000). The overall response rate was 37.5%, including 1 CR (4%); median response duration was 5.5 months (range, 2–16), median overall survival 10 months (range, 2–25+). Conclusions: This exploratory study, having a favourable palliative role in heavily pre-treated patients, showed that PTX PK profile is unexpectedly affected by a different administration interval. In PTX-PLD 0, PTX AUC is fourfold reduced, with a similar increase in Cl, totally due to Kel alteration: therefore, patients could be underexposed to PTX. PLD PK behavior confirmed previous studies results, in which PTX modified PLD disposition, prolonging the duration of its elimination phase and increasing total body exposure to PLD. No significant financial relationships to disclose.