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Vishesh Verma, Shivam Sharma, Kritika Gaur, and Nitin Kumar. "Role of vinca alkaloids and their derivatives in cancer therapy." World Journal of Advanced Research and Reviews 16, no. 3 (December 30, 2022): 794–800. http://dx.doi.org/10.30574/wjarr.2022.16.3.1378.
Повний текст джерелаАнотація:
Vinca alkaloids and its derivatives like Vincristine, Vinblastine etc. isolated from Catharanthus roseus plants are widely used in the treatment of various types of cancers. Mode of action of Vinca alkaloids (vinblastine, vincristine, vinorelbine) is microtubule-stabilizing agents (MTAs) i.e., arrest the cell cycle via disrupting microtubule dynamics. Vincristine major side effect is neurotoxicity. Hoverer, Vincristine induce neuropathy in mice or rat, used as animal model to study effect of drugs or plants by various authors also reported in review literature. Vinca alkaloids and its derivatives were widely used drugs in combination regimens with cyclophosphamide, doxorubicin, procarbazine, Methotrexate and dacarbazine etc. in various types of cancer. In this review, we also discussed major structure modifications position of chemically synthesized vincristine and vinblastine derivatives required for potential anticancer activities. Anticancer mechanism and some major patents on vinca alkaloids derivatives also reported in this review article. The study of Vinca alkaloids and its derivatives a class of an antimitotic compounds, found essential role in anticancer therapies.
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Montag, Gracia, Helga Stopper, Quoc Anh Ngo, and Henning Hintzsche. "The Biological Activity of the Novel Vinca Alkaloids 4-chlorochablastine and 4-chlorochacristine." Current Cancer Drug Targets 19, no. 3 (February 14, 2019): 222–30. http://dx.doi.org/10.2174/1568009618666180430142233.
Повний текст джерелаАнотація:
Background: Vinca alkaloids are important cancer drugs belonging to the class of antimitotic agents. The most commonly used substances are vinblastine and vincristine, other compounds are vinorelbine and vinflunine. All of them are very effective drugs but their use is limited by severe side-effects including neurotoxicity and bone marrow depression. Therefore, it is very important to develop novel vinca alkaloids with similar efficacy but lower toxicity. </P><P> Methods: Here, we analyzed two new compounds, 4-chlorochablastine and 4-chlorochacristine, with regard to their biological activity. These novel compounds were applied to a leukemia cell line at clinically relevant concentrations. For comparison, the established vinca alkaloids vinblastine, vincristine, vinorelbine, and vinflunine were also tested. </P><P> Results: Both novel substances decreased cellular proliferation. Apoptosis was found to be increased using two different methods reflecting early and late apoptosis. Cell cycle analysis revealed a clear decrease in G1-cells and an increase in G2/M-cells indicating an arrest in mitosis. In general, 4- chlorochablastine and 4-chlorochacristine caused these effects at concentrations higher than those needed for vinblastine, vincristine, and vinorelbine, but the potency was approximately in the range of vinflunine. </P><P> Conclusion: Taken together, the results show first indications that these novel vinca alkaloids might be effective and that they warrant further analysis.
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Huang, Yi, Yong Fang, Jinmin Wu, Jennifer M. Dziadyk, Xueming Zhu, Meihua Sui та Weimin Fan. "Regulation of Vinca alkaloid-induced apoptosis by NF-κB/IκB pathway in human tumor cells". Molecular Cancer Therapeutics 3, № 3 (1 березня 2004): 271–77. http://dx.doi.org/10.1158/1535-7163.271.3.3.
Повний текст джерелаАнотація:
Abstract Antimicrotubule Vinca alkaloids, such as vinblastine and vincristine, interfere with the dynamics of microtubules and have shown significant cell killing activity in a variety of tumor cells through induction of apoptosis. The mechanism by which Vinca alkaloids induce apoptosis is not entirely clear. In this study, we found that glucocorticoids inhibit Vinca alkaloid-induced apoptosis without affecting G2-M arrest in human breast cancer BCap37 cells and human epidermoid tumor KB cells, suggesting that Vinca alkaloid-induced apoptosis may occur via a pathway independent of cell cycle arrest. Further analyses indicated that Vinca alkaloids cause significant degradation of IκBα, which in turn results in nuclear factor-κB (NF-κB) activation. Transfection of antisense IκBα in BCap37 cells sensitizes Vinca alkaloid-induced apoptosis. Moreover, in vitro kinase assays show that the activity of IκB kinase (IKK) was activated by Vinca alkaloids and was not affected by glucocorticoids. Stable transfection of dominant-negative deletional mutant IκBα, which is insensitive to IKK-mediated phosphorylation and degradation, resulted in the inhibition of Vinca alkaloid-induced NF-κB activation and reduced sensitivity of tumor cells to Vinca alkaloid-induced apoptosis. These findings suggest that the NF-κB/IκB signaling pathway may contribute to the mediation of Vinca alkaloid-induced apoptosis in human tumor cells.
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Nithyanandham Masilamani and Dhanraj Ganapathy. "Awareness of Vinca alkaloids among dental students." International Journal of Research in Pharmaceutical Sciences 11, SPL3 (September 18, 2020): 911–14. http://dx.doi.org/10.26452/ijrps.v11ispl3.3048.
Повний текст джерелаАнотація:
Vincristine along with vinblastine are dual indole-based conjugated Vinca alkaloids formed from foliage of the herb Catharanthusroseus, traditionally known as Vincarosea vincristine , that have been effectively prescribed as single treatment and also in conjunction with other medications in hematological and stable malignancies chemotherapy for tumors. The purpose of this survey was to assess awareness of medical use of vinca alkaloids among dental undergraduate students. A cross-section study was performed with a self-directed survey questionnaire containing 10 queries distributed among 100 dental students. The questionnaire assessed the awareness about vinca alkaloids, their medicinal uses, anticancer activity, mechanism of action and side effects. The responses were recorded and analysed.94% of the respondents were not aware of medical uses of vinca alkaloids.95% were not aware of anticancer activity of vinca alkaloids.97 % were not aware of the mechanisms of action of vinca alkaloids. Again 97% were not aware of side effects of the vinca alkaloids. This study concluded the awareness about the medical use of vinca alkaloids among dental students was poor. Majority of them are not aware of the anticancer activity of vinca alkaloids.
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Mayer, Szabolcs, Péter Keglevich, András Keglevich, and László Hazai. "New Anticancer Vinca Alkaloids in the Last Decade - A Mini-Review." Current Organic Chemistry 25, no. 10 (June 1, 2021): 1224–34. http://dx.doi.org/10.2174/1385272825666210216123256.
Повний текст джерелаАнотація:
The chemistry and pharmacology of the important Vinca alkaloids such as vinblastine and vincristine used in anticancer therapy are still investigated widely. Several new derivatives, e.g., vinflunine, vinorelbine, and vindesine, have been synthesized and become successful medicines in anti-cancer therapy. In 2012, we published a paper that reviewed the Vinca derivatives. Nevertheless, the interest in the preparation of new modified structures is not decreasing either in recent years. In this review, the vinblastine-type molecules with several substituents, e.g., amide, nitrile, hydrazide, substituted side chains, etc. in different positions of catharanthine and/or vindoline cores are presented. An important part of the review is the derivatization of the monomer alkaloid vindoline, which possesses no antitumor effect. Additionally, new hybrid molecules of these alkaloids are also discussed in this mini-review.
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Sharma, Mukesh Kumar, Mohan Kumar, and Renu. "Biosynthesis and Modulation of Terpenoid Indole Alkaloids in Catharanthus roseus: A Review of Targeting Genes and Secondary Metabolites." Journal of Pure and Applied Microbiology 15, no. 4 (October 15, 2021): 1745–58. http://dx.doi.org/10.22207/jpam.15.4.05.
Повний текст джерелаАнотація:
The medicinal plant C. roseus synthesizes biologically active alkaloids via the terpenoid indole alkaloid (TIAs) biosynthetic pathway. Most of these alkaloids have high therapeutic value, such as vinblastine and vincristine. Plant signaling components, plant hormones, precursors, growth hormones, prenylated proteins, and transcriptomic factors regulate the complex networks of TIA biosynthesis. For many years, researchers have been evaluating the scientific value of the TIA biosynthetic pathway and its potential in commercial applications for market opportunities. Metabolic engineering has revealed the major blocks in metabolic pathways regulated at the molecular level, unknown structures, metabolites, genes, enzyme expression, and regulatory genes. Conceptually, this information is necessary to create transgenic plants and microorganisms for the commercial production of high-value dimer alkaloids, such as vinca alkaloids, vinblastine, and vincristine In this review, we present current knowledge of the regulatory mechanisms of these components in the C. roseus TIA pathway, from genes to metabolites.
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Noble, Robert L. "The discovery of the vinca alkaloids—chemotherapeutic agents against cancer." Biochemistry and Cell Biology 68, no. 12 (December 1, 1990): 1344–51. http://dx.doi.org/10.1139/o90-197.
Повний текст джерелаАнотація:
In folklore medicine, extracts of the leaves of the subtropical plant Catharanthus roseus (L.) G. Don (sometimes known as Madagascar periwinkle) were reputed to be useful in the treatment of diabetes. This review describes how attempts to verify the antidiabetic properties of the extracts led instead to the discovery and isolation of two complex indole alkaloids, vinblastine and vincristine, which are used in the clinical treatment of a variety of cancers. The two alkaloids, although structurally almost identical, nevertheless differ markedly in the type of tumors that they affect and in their toxic properties. These and related alkaloids have been the subject of many pharmacological and biochemical investigations both in vivo and in vitro in the search for improved cancer treatments. A model system used in these studies, a transplantable lymphoma in Noble strain rats designated Nb2 node, has serendipitously led to the development of a highly sensitive and specific bioassay for lactogenic hormones.Key words: Catharanthus roseus, vinblastine, vincristine, cancer chemotherapy, Nb rat lymphoma, lactogen bioassay.
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Agrawal, Vaibhav, Diane T. Smelser, David J. Carey, Joseph J. Vadakara, and Sharif S. Khan. "Effect of the CEP72 Genotype and CYP3A5-Mediated Metabolism in Predicting Vincristine-Associated Peripheral Neuropathy." Blood 128, no. 22 (December 2, 2016): 5963. http://dx.doi.org/10.1182/blood.v128.22.5963.5963.
Повний текст джерелаАнотація:
Abstract Introduction: Chemotherapy induced peripheral neuropathy (CIPN) is a recognized clinical outcome of vinca alkaloid based therapy that frequently results in dose reduction or therapy discontinuation, but the determinants of interpatient variability remain unpredictable. Previous pharmacogenetics studies have demonstrated that vincristine is metabolized through the CYP3A system with the CYP3A5*3 variant (GG allele at rs776746) having the least efficacy in metabolizing vincristine to its inactive metabolite M1 and conferring higher risk of neurotoxicity. Similarly, a single nucleotide polymorphism (SNP) in the promoter of the CEP72 gene (TT allele at rs924607) has been described as being significantly associated with increased risk and severity of vincristine-associated peripheral neuropathy in the pediatric population. Our recent studies have further studied the incidence of this risk allele and its correspondence with CIPN in the adult population treated with vincristine. This study aimed to investigate if an additive SNP analysis, both for CYP3A5*3 and CEP72, would determine increased predictability of CIPN in patients treated with vinca alkaloids. Methods: A retrospective case-control study of patients was completed in patients that were exposed to vinca alkaloids (vincristine, vinorelbine, and vinblastine) at Geisinger Medical Center from 2007-2015. Available samples of these patients were identified in the Geisinger MyCode bio banking project and the SNP of interest was genotyped using the TaqMan® SNP Genotyping Assay, with genotypic discrimination performed using SDS software (Applied Biosystems). Cases of CIPN were confirmed with retrospective chart review. Statistical analysis was conducted using SAS (SAS Institute Inc.) software, version 9.4. All genotyping and chart review was conducted by personnel blinded to sample identity. Results: A total of 121 patients had genotype mapping completed, of which 60 patients received vincristine, 33 received vinblastine, and 28 received vinorelbine. CIPN was detected in 35.5% of the study population. The CEP72 risk allele (TT) was detected in 14.9% (n=18) of the cohort and the CYP3A5*3 risk allele (GG) was detected in 89.2% (n=108) of the cohort, with similar incidence in each drug class. The median age of this population was 61 years of age with 52.9% (n=64) being males. Multivariate logistic regression analysis, controlling for age and sex, did not demonstrate a significant model for the recessive genetic model of both SNPs with all vinca alkaloids (p=0.33), vincristine alone (p=0.26), vinorelbine alone (p=0.98), or vinblastine alone (p=0.97). The incidence of the inactive G/G allele for CYP3A5*3 was seen in 87.5% (n=21) of the vincristine cohort with neuropathy, The incidence of neuropathy was higher in patients with the TT genotype (75%) in patients receiving vincristine therapy than with the CT or CC genotype (35.7%). As consistent with prior findings, a similar dominant effect was not detected in vinorelbine or vinblastine groups. In the vincristine population (n=60), diseases that were treated included diffuse large B-cell lymphoma (n=29), acute lymphoblastic leukemia (n=6), oligoastrocytoma (n=5), and Ewing's sarcoma (n=2). No disease specific variation in neuropathy incidence and association with TT genotype was detected. Patients received a median three doses of vincristine at 2 mg each (total 6 mg) before detection of CIPN. Four patients (6.67%) of the patients required dose adjustment of chemotherapy, including dose reduction (n=2) or early discontinuation (n=2). Conclusions: This study demonstrates that the CEP72 genotype confers predictive modeling for patients receiving vincristine-based therapy and that including CYP3A5*3 analysis in an additive model is not associated with an increased predictive model for CIPN in patients receiving vinca alkaloid based therapy. In our population, the high incidence of the inactive G/G allele of CYP3A5*3 made it difficult to discern a significant effect in patients that experienced neuropathy. Larger studies are needed to include a more diverse population to confirm this predictive association and to understand if this can help guide precision-based chemotherapy administration and favorably impact disease prognosis. Disclosures No relevant conflicts of interest to declare.
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Keglevich, András, Szabolcs Mayer, Réka Pápai, Áron Szigetvári, Zsuzsanna Sánta, Miklós Dékány, Csaba Szántay, Péter Keglevich, and László Hazai. "Attempted Synthesis of Vinca Alkaloids Condensed with Three-Membered Rings." Molecules 23, no. 10 (October 9, 2018): 2574. http://dx.doi.org/10.3390/molecules23102574.
Повний текст джерелаАнотація:
Our successful work for the synthesis of cyclopropanated vinblastine and its derivatives by the Simmons–Smith reaction was followed to build up further three-membered rings into the 14,15-position of the vindoline part of the dimer alkaloid. Halogenated 14,15-cyclopropanovindoline was prepared by reactions with iodoform and bromoform, respectively, in the presence of diethylzinc. Reactions of dichlorocarbene with vindoline resulted in the 10-formyl derivative. Unexpectedly, in the case of the dimer alkaloids vinblastine and vincristine, the rearranged products containing an oxirane ring in the catharanthine part were isolated from the reactions. The attempted epoxidation of vindoline and catharanthine also led to anomalous rearranged products. In the epoxidation reaction of vindoline, an o-quinonoid derivative was obtained, in the course of the epoxidation of catharanthine, a hydroxyindolenine type product and a spiro derivative formed by ring contraction reaction, were isolated. The coupling reaction of vindoline and the spiro derivative obtained in the epoxidation of catharanthine did not result in a bisindole alkaloid. Instead, two surprising vindoline trimers were discovered and characterized by NMR spectroscopy and mass spectrometry.
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Mayer, Szabolcs, András Keglevich, Csilla Sepsey Für, Hedvig Bölcskei, Viktor Ilkei, Péter Keglevich, and László Hazai. "Results in Chemistry of Natural Organic Compounds. Synthesis of New Anticancer Vinca Alkaloids and Flavone Alkaloids." Chemistry 2, no. 3 (August 10, 2020): 714–26. http://dx.doi.org/10.3390/chemistry2030046.
Повний текст джерелаАнотація:
The antitumor indole–indoline alkaloids of the evergreen Catharanthus roseus—namely vinblastine and vincristine—are widely used in chemotherapy of cancer. Many efforts were made to synthesize more efficient derivatives with less side-effect. The 14,15-cyclopropane derivative of vinblastine was synthesized successfully by a five-step procedure starting from vindoline. Vincristine, vinorelbine and several derivatives condensed with a cyclopropane ring were synthesized. Various hybrid molecules were prepared by the coupling reaction of vindoline and methyl ester of tryptophan, which were conjugated by carrier peptides of octaarginine. Studying the halogenation reactions of vindoline and catharanthine some fluorine derivatives were obtained which showed promising antitumor activity on various tumor types. The synthesis of the Aspidospermane alkaloid bannucine and 5′-epibannucine were carried out using N-acyliminium intermediates. The same intermediate was also applied in the first synthesis of sessiline. The research group have synthesized of flavonoid alkaloids: dracocephins A and B. Further three flavonoid alkaloids, namely 8-(2”-pyrrolidinon-5′′-yl)quercetin, 6-(2′′-pyrrolidinon-5′′-yl)-(−)- and 8-(2′′-pyrrolidinon-5′′-yl)-(−)-epicatechin were prepared by acid-catalyzed regioselective Mannich reaction starting from the corresponding flavonoid precursor. Vindoline was also coupled to synthetic pharmacophores, such as triphenylphosphine and various N-heterocycles. Some of these hybrid molecules showed significant antitumor activity. Furthermore, 7-OH and 7-NH modified flavonoid derivatives were synthesized by a regioselective alkylation followed by Smiles rearrangement and hydrolysis.
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Nerkar, Amit Gajanan, Rushikesh P. Nagarkar, and Shubhangi Badar. "Ethnopharmacological review of vinca plant for anticancer activity." Current Trends in Pharmacy and Pharmaceutical Chemistry 4, no. 4 (November 15, 2022): 148–51. http://dx.doi.org/10.18231/j.ctppc.2022.026.
Повний текст джерелаАнотація:
The strive of this assessment shows that Vinca rosea, many obviously grown vegetation round us which can be used for medicinal purposes. It has many known names like vinca Rosea, Madagascar periwinkle, vibrant eyes, Cape periwinkle, graveyard plant, old maid, crimson periwinkle, rose periwinkle myrtle. Ayurveda is the Indian conventional device of medication which focuses on the scientific capability of plant life. Catharanthus roseus is one plant recognized nicely in Ayurveda. It is known for its antitumour, anti-diabetic, anti-microbial, anti-oxidant and antimutagenic effects. It is an evergreen plant first originated from islands of Madagascar. The flowers can also range in color from red to pink and leaves are organized in opposite pairs. It produces nearly 130 alkaloids especially ajmalcine, vinceine, resperine, vincristine, vinblastine and raubasin. Vincristine and vinblastine are used for the treatment of various types of cancer such as Hodgkin’s disease, breast cancer, skin cancer and lymphoblastic leukemia. It has high medicinal values which need to be explored considerably. This ethnopharmacological review deals with anticancer activities and pharmacognostic study of Vinca plant.
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Linh, Tran My, Nguyen Chi Mai, Pham Thi Hoe, Ninh Thi Ngoc, Phan Thi Hong Thao, Ninh Khac Ban, and Nguyen Tuong Van. "Development of a Cell Suspension Culture System for Promoting Alkaloid and Vinca Alkaloid Biosynthesis Using Endophytic Fungi Isolated from Local Catharanthus roseus." Plants 10, no. 4 (March 31, 2021): 672. http://dx.doi.org/10.3390/plants10040672.
Повний текст джерелаАнотація:
Cell and tissue cultures of Catharanthus roseus have been studied extensively as an alternative strategy to improve the production of valuable secondary metabolites. The purpose of this study was to produce C. roseus callus and suspension cell biomass of good quality and quantity to improve the total alkaloids and bis-indole alkaloids. The young stem derived-callus of C. roseus variety Quang Ninh (QN) was grown on MS medium supplemented with 1.5 mg/L 2,4-dichlorophenoxyacetic acid (2,4-D) plus 1.5 mg/L kinetin, and the growth rate increased by 67-fold after 20 days. The optimal conditions for maintaining the cell suspension culture were 150 mg/50 mL cell inoculum, a medium pH of 5.5 and a culture temperature of 25 °C. The low alkaloid content in the culture was compensated for by using endophytic fungi isolated from local C. roseus. Cell extracts of endophytic fungi—identified as Fusarium solani RN1 and Chaetomium funicola RN3—were found to significantly promote alkaloid accumulation. This elicitation also stimulated the accumulation of a tested bis-indole alkaloid, vinblastine. The findings are important for investigating the effects of fungal elicitors on the biosynthesis of vinblastine and vincristine, as well as other terpenoid indole alkaloids (TIAs), in C. roseus QN cell suspension cultures.
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Tembhe, Harshada, and Rupali Tasgaonkar. "Vinca Alkaloids – Anti cancer drugs." International Journal for Research in Applied Science and Engineering Technology 11, no. 1 (January 31, 2023): 408–16. http://dx.doi.org/10.22214/ijraset.2023.48559.
Повний текст джерелаАнотація:
Abstract: Cancer, one of the most common disease, is responsible for nearly 10 million deaths annually. The treatment of cancer typically includes surgery, chemotherapy, radiation therapy, and drug therapy which have a significant financial impact on patients. Also, over the time, patients may develop drug resistance. By applying evidence-based preventative techniques, a significant number of cancer cases can be avoided or treated. Plant-based medications have emerged as hopeful alternatives to chemotherapy in both developed and developing countries. Alkaloids are the secondary plant metabolites that have shown to be effective and acceptable for treating cancer. The secondmost popular family of cancer medications is vinca alkaloids, and they will continue to be utilised for cancer treatment. These medications, which include vinblastine, vincristine, vindesine, and vinorelbineare frequently used either alone or in combination with other medications. These cell cycle-dependent drugs work by preventing tubulin from polymerizing into microtubules, which causes cell death. There have been several studies looking at the pharmacological behaviour of this family of antitumor drugs in both humans and animals utilising diverse in vivo and in vitro models. Despite tremendous improvements in the prevention and control of cancer progression, there are still many flaws and space for growth. Several undesirable side effects might occasionally happen when receiving chemotherapy. Natural treatments, and hence the use of cancer therapy agents produced from plants, may reduce negative side effects.
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-, Prabhavathi, and Anuradha Mal. "Nutraceutical properties of Vinca rosea." Biomedicine 42, no. 3 (July 3, 2022): 427–33. http://dx.doi.org/10.51248/.v42i3.1459.
Повний текст джерелаАнотація:
Vinca rosea (C. roseus), a member of the Apocynaceae family, is a popular medicinal plant found in many countries. It's gaining popularity because it's been discovered to have a variety of phytochemicals having a wide range of biological actions, such as free radicle scavenging, hypoglycemic, antibacterial, antifungal, and cancer-fighting properties. The most important alkaloids isolated from vinca plant is vincristine and vinblastine. These were the first anticancer medicines obtained from plants to be tested in clinical trials. New indole alkaloids have recently been identified from this plant, including human cancer cell lines which were efficiently suppressed in vitro by 14', 15'-didehydrocyclovinblastine, 17-deacetoxyvinamidine, and 17-deacetoxycyclovinblastine. This plant is high in alkaloids and other secondary metabolites. Vindoline, vindolidine, vindolicine, and vindolinine are some of the important alkaloids found in the leaf extracts of V. rosea which showed anti-diabetic activity in vitro. These findings imply that C. rosea remains a potential bioactive chemical source that warrants more investigation. This study gives a summary of the plant's botanical features, its traditional and current medical uses and phytochemical profiles. In addition, the extracts and bioactive components generated from this plant's supposed health advantages were investigated in order to establish its potential as medicinal agents.
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Pandya, Prateek, Surendra P. Gupta, Kumud Pandav, Ritu Barthwal, B. Jayaram, and Surat Kumar. "DNA Binding Studies of Vinca Alkaloids: Experimental and Computational Evidence." Natural Product Communications 7, no. 3 (March 2012): 1934578X1200700. http://dx.doi.org/10.1177/1934578x1200700308.
Повний текст джерелаАнотація:
Fluorescence studies on the indole alkaloids vinblastine sulfate, vincristine sulfate, vincamine and catharanthine have demonstrated the DNA binding ability of these molecules. The binding mode of these molecules in the minor groove of DNA is non-specific. A new parameter of the purine-pyrimidine base sequence specificty was observed in order to define the non-specific DNA binding of ligands. Catharanthine had shown ‘same’ pattern of ‘Pu-Py’ specificity while evaluating its DNA binding profile. The proton resonances of a DNA decamer duplex were assigned. The models of the drug:DNA complexes were analyzed for DNA binding features. The effect of temperature on the DNA binding was also evaluated.
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Burns, B. V., and J. C. Shotton. "Vocal fold palsy following vinca alkaloid treatment." Journal of Laryngology & Otology 112, no. 5 (May 1998): 485–87. http://dx.doi.org/10.1017/s002221510014085x.
Повний текст джерелаАнотація:
AbstractWe report two patients with Hodgkin's disease on chemotherapy, one with vincristine, the other with vinblastine, who were referred to the ENT department with a vocal fold palsy. These drugs are commonly used in the treatment of haematological malignancies, and head and neck sarcomas. Examination showed a unilateral immobile fold. No causative local pathology was identified, and they were otherwise thought to be achieving remission, but the development of a fold palsy suggested a poor response to treatment. One patient's palsy resolved following completion of chemotherapy, but the other patient's persists, despite an otherwise good response to the treatment. The vinca alkaloids are neurotoxic, usually causing a peripheralneuropathy, but cranial mononeuropathies are a rare side-effect. A total of 27 previous cases of vocal fold palsy have been reported with the use of the vinca alkaloids, and such a lesion should not be assumed to be due to advancing lymphoma.
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Lobert, Sharon, Bojana Vulevic, and John J. Correia. "Interaction of Vinca Alkaloids with Tubulin: A Comparison of Vinblastine, Vincristine, and Vinorelbine†." Biochemistry 35, no. 21 (January 1996): 6806–14. http://dx.doi.org/10.1021/bi953037i.
Повний текст джерела
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Gout, Peter W., Robert L. Noble, and Charles T. Beer. "Cultured Nb rat lymphoma cells in endocrine and cancer research." Biochemistry and Cell Biology 64, no. 7 (July 1, 1986): 659–66. http://dx.doi.org/10.1139/o86-091.
Повний текст джерелаАнотація:
This review outlines the establishment, properties, and use of two lines of cultured Nb rat lymphoma cells. The cultured cells have retained important properties of the cancers of origin, such as dependency on prolactin for growth and a high sensitivity to antineoplastic Vinca alkaloids. The cultures have been useful for defining the hormonal dependency of the lymphomas in the animal and for studying the progression of the lymphomas from hormonal dependency to autonomy. A new, specific and highly sensitive in vitro bioassay for lactogenic hormones has been developed from one of the cultures. The use of the lymphoma cell cultures has revealed unsuspected pharmacological differences between the closely related, clinically useful antineoplastic Vinca alkaloids, vinblastine and vincristine. The lymphoma cell cultures are also useful tools for studying biochemical, cell cycle related events which follow the mitogenic stimulation of cells by a polypeptide growth factor.
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Kumar, Gautam, Ravi Kumar, Girendra Kumar Gautam, and Harshit Rana. "Phytochemical and Pharmacological Properties of Catharanthus roseus (Vinca)." Science Progress and Research 1, no. 4 (October 23, 2021): 429–34. http://dx.doi.org/10.52152/spr/2021.164.
Повний текст джерелаАнотація:
Vinca alkaloids obtained from Madagascar are a subset of drugs. Generally, they are naturally extracted from the Vinca rosea plant, Catharanthus roseus G, Don and show hyperglycemia activity as well as cytotoxic effects. It is used to treat various diseases such as diabetes, hypertension, cancer, asthma, inflammation, malaria, angiogenesis, brain imbalance, dysentery, and is also used as a disinfectant that occurs due to potent microorganisms. The vinca alkaloids are played an essential role to fight cancer disease. There are some major vinca alkaloids in clinical use: Vinblastin, Vincristine, Vindesine, tabersonine, vinorelbine, and Vinpocetine, etc. The flowers juice of Vinca rosea is utilized to treat several skin problems e.g. acne, eczema, and dermatitis. According to our opinion that it may be help scientists, ayurvedic practitioners, pharmacognosists, botanists, researchers, and students who are active in the field of medicinal plants research.
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Spagnuolo, Paul A., Jiayi Hu, Rose Hurren, Xiaoming Wang, Marcela Gronda, Mahadeo A. Sukhai, Ashley Di Meo, et al. "The antihelmintic flubendazole inhibits microtubule function through a mechanism distinct from Vinca alkaloids and displays preclinical activity in leukemia and myeloma." Blood 115, no. 23 (June 10, 2010): 4824–33. http://dx.doi.org/10.1182/blood-2009-09-243055.
Повний текст джерелаАнотація:
Abstract On-patent and off-patent drugs with previously unrecognized anticancer activity could be rapidly repurposed for this new indication given their prior toxicity testing. To identify such compounds, we conducted chemical screens and identified the antihelmintic flubendazole. Flubendazole induced cell death in leukemia and myeloma cell lines and primary patient samples at nanomolar concentrations. Moreover, it delayed tumor growth in leukemia and myeloma xenografts without evidence of toxicity. Mechanistically, flubendazole inhibited tubulin polymerization by binding tubulin at a site distinct from vinblastine. In addition, cells resistant to vinblastine because of overexpression of P-glycoprotein remained fully sensitive to flubendazole, indicating that flubendazole can overcome some forms of vinblastine resistance. Given the different mechanisms of action, we evaluated the combination of flubendazole and vinblastine in vitro and in vivo. Flubendazole synergized with vinblastine to reduce the viability of OCI-AML2 cells. In addition, combinations of flubendazole with vinblastine or vincristine in a leukemia xenograft model delayed tumor growth more than either drug alone. Therefore, flubendazole is a novel microtubule inhibitor that displays preclinical activity in leukemia and myeloma.
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Kumar, Gautam, Ravi Kumar, Girendra Kumar Gautam, and Harshit Rana. "The phytochemical and pharmacological properties of Catharanthus roseus (Vinca)." Science Progress and Research 2, no. 1 (January 10, 2022): 472–77. http://dx.doi.org/10.52152/spr/2022.158.
Повний текст джерелаАнотація:
Vinca alkaloids obtained from Madagascar are a subset of drugs. Generally, they are naturally extracted from the Vinca rosea plant, Catharanthus roseus G, Don and show hyperglycemia activity as well as cytotoxic effects.In recent pharmacological studies and trad-itional utilization of Vinca rosea have proved the medicinal properties of the plant, and it is also con-tinuously used to prevent various diseases. It is used to treat various diseases such as diabetes, hypertension, cancer, asthma, inflammation, malaria, angiogenesis, brain imbalance, dysentery, and is also used as a disinfectant that occurs due to potent micro-organisms. The vinca alkaloids are played an essential role to fight cancer disease. There are some major vinca alkaloids in clinical use: Vinblastin, Vincristine, Vindesine, tabersonine, vinorelbine, and Vinpocetine, etc. The flowers juice of Vinca rosea is utilized to treat several skin problems e.g. acne, eczema, and dermatitis. Accord-ing to our opinion that it may be help scientists, ayurvedic practitioners, pharmacognosists, botanists, research-ers, and students who are active in the field of medicinal plants research.
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Bogenberger, James M., Nanna Hansen, Devora Delman, Lisa Sproat, Jeanne Palmer, Ruben Mesa, and Raoul Tibes. "Synergistic Activity of Lysine Deacetylase Inhibitors and Microtubule-Targeting Agents in AML." Blood 128, no. 22 (December 2, 2016): 3948. http://dx.doi.org/10.1182/blood.v128.22.3948.3948.
Повний текст джерелаАнотація:
Abstract Background: Treatment options for elderly acute myeloid leukemia (AML) patients, despite various novel therapies, are still limited. Relapse is common after chemotherapy, and progression on lower intensity treatment with hypomethylating agents is inevitable in all patients even after initial response. Lysine deacetylase inhibitors (KDIs or HDAC inhibitors) have shown limited single-agent clinical activity in AML. Therefore, to develop potential novel treatment options for AML, we aimed to identify synergistic KDI-based drug combinations to build upon the single-agent activity and clinical-availability of KDIs. We performed RNA-interference (RNAi) drug modifier screens of the kinome and phosphatome with the KDI vorinostat in AML cells in order to identify targets to inhibit in combination with KDIs. Based on pathway analysis of RNAi screen results that highlighted an unexpected role for p38/JNK/SAPK signaling in vorinostat activity in AML, we explored the putative p38 substrate-selective MK2 inhibitor CMPD1 combined with KDIs, and demonstrated potent synergistic activity in AML regardless of molecular, cytogenetic or lineage background. As published evidence suggests that CMPD1 can also act as a microtubule-destabilizing/targeting agent (MTA), and that MK2 can associate with microtubules and cytoskeleton-associated proteins, we examined several MTAs in combination with KDIs in AML, including vinca alkaloid microtubule-destabilizing agents vinblastine/vincristine, and taxol as a microtubule-stabilizing agent. Results: Vinblastine and vincristine dose-dependently synergized with vorinostat similarly to CMPD1 in all AML cell lines tested, with vinblastine being more potently synergistic than vincristine. Taxol only potentiated KDI activity in approximately half of AML cell lines. Importantly, preliminary data suggest preferential, dose-dependent synergy of KDIs and vinca alkaloid MTAs in the CD34+ progenitor AML cell fraction, as compared to the paired CD34-depleted fraction from the same primary AML sample in ex vivo culture. This preferential CD34+ activity was similar to that observed with CMPD1 combined with KDIs in ex vivo models. Consistent with synergistic activity of MTAs and KDIs, multiple RNAi screen hits also converged on microtubule dynamics. Subsequently, we identified the LKB1 signaling network, a critical integrator of cellular stress metabolism and hematopoietic stem cell quiescence/homeostasis, as a determinant of vorinostat activity in AML. Of 14 known kinases directly regulated by LKB1, 4 belong to microtubule-associated protein (MAP) or microtubule-affinity regulating kinases (MARK) families (e.g. screen hit MARK4). RNAi screen hits also converged on regulation of microtubule proteins, or directly on microtubule proteins themselves, (e.g. atypical MAPK4 and MAPK6 which phosphorylate microtubule-associated protein 2, or TAOK2 which has a kinase-independent role in stabilizing microtubules). Additionally, several RNAi hits such as PACSIN1 and -2, and MAST2 and -4 link the actin cytoskeleton to microtubule dynamics. Discussion: Herein we show that several types of clinically-used MTAs (i.e. vinca alkaloids or taxanes) potently synergize with KDIs in AML, and that this synergy can occur preferentially in primary CD34+ cells, as compared to the CD34-negative AML compartment. Although at high in vitro doses microtubule-destabilizing agents such as vinca alkaloids, and microtubule-stabilizing agents such as taxanes, can both induce apoptosis via mitotic perturbation, many publications show that low therapeutic MTA doses can induce apoptosis in tumor cells in vivo independent of mitosis. Therefore, we hypothesize that clinically-available KDIs (i.e. vorinostat, panobinostat) and MTAs (i.e. vinca alkaloids or taxanes) represent novel combinations with the potential to target the AML progenitor pool even in a non-proliferate state, and thus have the potential to eradicate minimal residual disease. Disclosures Mesa: Celgene: Research Funding; Incyte Corporation: Research Funding; Ariad: Consultancy; Galena: Consultancy; Novartis: Consultancy; Promedior: Research Funding; CTI: Research Funding; Gilead: Research Funding. Tibes:Italfarmaco S.p.A.: Consultancy, Honoraria.
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Spagnuolo, Paul A., Jiayi Hu, Rose Hurren, Ashley Di Meo, Jonathan Boss, Iman Ashali, Marcela Gronda, et al. "The Antihelmintic Flubendazole Inhibits Microtubules through a Mechanism Distinct From Vinca Alkaloids and Displays Preclinical Activity in Leukemia and Myeloma." Blood 114, no. 22 (November 20, 2009): 1017. http://dx.doi.org/10.1182/blood.v114.22.1017.1017.
Повний текст джерелаАнотація:
Abstract Abstract 1017 Poster Board I-39 On patent and off-patent drugs with previously unrecognized anti-cancer activity, could be rapidly repurposed for this new indication given their prior toxicity testing. To identify such compounds, we compiled and screened a chemical library for potential anti-leukemia agents. From these screens, we identified the antihelmintic flubendazole that is currently used for the treatment of gastrointestinal and systemic parasites, but has not been evaluated for the treatment of malignancy. To explore its efficacy as an anti-cancer agent, leukemia and myeloma cell lines were treated with increasing concentrations of flubendazole. Seventy-two hours after incubation, cell viability was measured by the MTS assay. Flubendazole reduced cell viability with an LD50 ≤ 1 μM in 8/8 myeloma and 4/6 leukemia cell lines, a concentration that is pharmacologically achievable. Likewise, flubendazole reduced the clonogenic growth of primary AML samples at nanomolar concentrations. Cell death was confirmed by Trypan blue staining. Given the effects in leukemia and myeloma cells lines, we evaluated the effects of flubendazole in mouse models of leukemia and myeloma. Sublethally irradiated SCID mice were injected subcutaneously with OCI-AML2 leukemia or OPM2 myeloma cells. Mice were then treated intraperitoneally with flubendazole (20-50 mg/kg/day – doses more than 10-fold lower than the LD50) or buffer alone. Flubendazole decreased tumor weight and volume in both mouse models up to 5-fold compared to control without evidence of weight loss or gross organ toxicity. Mechanistically, flubendazole inhibited bovine-tubulin polymerization in cell-free assays and disrupted microtubule architecture in intact cells as visualized by confocal microscopy. We demonstrated that flubendazole bound tubulin at the colchicine binding site, a region distinct from where vinca-alkaloids bind. Flubendazole arrested cells in the G2 phase of the cell cycle and increased the number of multi-nucleated cells. We also demonstrated that cell death after flubendazole treatment was related to its ability to inhibit microtubule polymerization by using cell lines with tubulin mutations (gifts from Dr F. Loganzo, Wyeth, Pearl River, NY and Drs. S. Band Horwitz and C. Yang, Albert Einstein College of Medicine, Bronx, NY). Vinca-alkaloids are p-glycoprotein (Pgp) substrates and Pgp over-expression can limit the efficacy of these agents. Therefore, we tested the effects of Pgp over-expression on flubendazole's cytotoxicty. CEM-VBL cells over-expressing Pgp remained fully sensitive to flubendazole, but were over 1000-fold more resistant to vinblastine than wild type CEM cells. Therefore, flubendazole can overcome some forms of vinca-alkaloid resistance. Given that flubendazole binds tubulin at a site distinct from vinca-alkaloids, we evaluated the combination of flubendazole and vinblastine in vitro and in vivo. OCI-AML2 leukemia cells were treated with increasing concentrations of flubendazole and vinblastine. Flubendazole and vinblastine synergistically induced cell death with combination index (CI) values of 0.09, 0.017, 0.003 and 0.001 at the EC 50, 25, 10 and 5, respectively, where CI values <1 are considered synergistic. In contrast, cell death produced by the combination of flubendazole and colchicine was closer to additive with CI values of 0.54, 0.70, 0.897 and 1.07 at EC 50, 25, 10 and 5, respectively. As the combination of flubendazole and vinblastine were synergistic in cell culture, we evaluated the combination in vivo. Mice injected subcutaneously with OCI-AML2 cells were treated with flubendazole (15 mg/kg), vinblastine (0.3 mg/kg) or the combination of the two agents. The combination decreased tumor weight and volume greater than either agent alone without behavioural changes, weight loss, or gross organ toxicity. Similar effects were observed with the in vivo combination of flubendazole and vincristine. Since neurotoxicity is a dose limiting toxicity of vinca-alkaloids such as vincristine, we evaluated the neurotoxicity of flubendazole in mice using the Tail Flick assay. At doses up to 200mg/kg daily of flubendazole, no neurotoxicity was observed. Thus, flubendazole is a novel microtubule inhibitor that displays preclinical activity in leukemia and myeloma. Given its prior safety record when evaluated for the treatment of parasitic disease, flubendazole could be rapidly repurposed for the treatment of hematologic malignancies. Disclosures: Off Label Use: Flubendazole is used to treat gastrointestinal and systemic parasite infections.
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Ahn, Eugene R., John J. Byrnes, Vincenzo Fontana, Pamela Dudkiewicz, Carlos J. Bidot, and Yeon S. Ahn. "Recurrence of Severe ITP Following Administration of G-CSF: Remission Following Platelet and Vinca-Alkaloid Infusion." Blood 110, no. 11 (November 16, 2007): 3222. http://dx.doi.org/10.1182/blood.v110.11.3222.3222.
Повний текст джерелаАнотація:
Abstract Introduction: In ITP, platelets opsonized with antibodies are phagocytosed by macrophages. Activation of macrophages often triggers aggravation or relapses of ITP as demonstrated following vaccination, infections. G-CSF stimulates granulocyte colonies but can stimulate macrophages at higher concentrations in vitro. We report recurrence of severe life threatening ITP following G-CSF therapy, successfully managed by selective injury of macrophages with sequential infusions of platelets and vinca-alkaloids. Case Study: A 30 year old healthy Caucasian man developed severe ITP in 9/03 with wet purpura, epistaxis, multiple hematomas in the mouth, tongue and lips and a platelet count <2 K. He suffered severe headaches, refractory gastrointestinal (GI) and genitourinary (GU) bleeding requiring numerous platelet and pRBC transfusions. Increased megakaryocytes were seen in a bone marrow biopsy. CT scans of the head and body were normal, including normal spleen size. ITP was refractory to several measures including high dose glucocorticoids, IV immunoglobulins (IVIG), danazol, rituximab, and vinca-alkaloids. Splenectomy in 5/04 induced a complete remission, lasting for over 3 years. On 2/12/07 he presented with agranulocytosis and neutropenic fever. His Hgb and platelet counts were normal but leukocyte count was 0.9 with absent granulocytes. IVIG infusions began for immune neutropenia with partial improvement of granulocytopenia. Beginning 5/31/07, he was treated with a biweekly regimen of IVIG and Neulasta with normalization of WBC. However, a month following this normalization, patient presented with a platelet count of 9K, wet purpura, epistaxis, multiple hematomas in the tongue and oral mucosa, GI and GU bleeding, headaches and dizzy spells. In spite of high dose IV steroids, daily platelet and pRBC transfusions were required, with little change in platelet counts. He also suffered hypotensive episodes from GI bleeding and pseudomonas bacteremia. Using a rationale described in our previous work (NEJM298:1101, 1978), vincristine 1mg injection was given immediately following platelet transfusion and one week later, 4mg vinblastine immediately following another platelet transfusion. Vinca rapidly binds to transfused platelets and serve as targeted therapy against the activated macrophages that phagocytose platelets. The therapy was effective. Platelet count rose to 72K 1 week after vinblastine, and then normalized. Additional vincristine 1mg was given at discharge. ITP underwent remission. Summary/Discussion: A patient with refractory ITP who underwent CR for over three years after splenectomy suffered severe life threatening thrombocytopenia following injections of G-CSF. This case report is highlighted by the following features. While ITP was in CR, severe granulocytopenia developed which responded to IVIG, indicating an autoimmune cause of leukopenia. Treatment with G-CSF for leukopenia triggered recurrence of severe ITP. Platelet transfusion immediately followed by injection of vinca-alkaloids was successful in inducing remission of life threatening ITP. G-CSF should be used with caution in patients with history of ITP, since it may activate macrophages and trigger relapse of ITP. The immediate sequence of platelet transfusion followed by vinca injection might be particularly useful in this scenario, and is less cumbersome compared to the previously described procedure of incubating platelets ex-vivo with vinca prior to infusion (NEJM298:1101, 1978; AmJHem81:423, 2006).
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Harvey, Michael J., Martin G. Banwell, and David W. Lupton. "The synthesis of compounds related to the indole–indoline core of the vinca alkaloids (+)-vinblastine and (+)-vincristine." Tetrahedron Letters 49, no. 32 (August 2008): 4780–83. http://dx.doi.org/10.1016/j.tetlet.2008.05.082.
Повний текст джерела
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Dragoi, Alexandra, and Oana Alexandru. "PLANT-DERIVED CHEMOTHERAPEUTICS DRUGS FOR CANCER CHEMOTHERAPY." Medico Oncology 1, no. 1 (May 18, 2021): 28–37. http://dx.doi.org/10.52701/monc.2020.v1i1.8.
Повний текст джерелаАнотація:
Cancer chemotherapeutic drugs acts in different manner to kill malignant cells. Most of the anticancer drugs available in clinical practice to treat cancer patients, are natural products including whole plant extract, crude plant extracts, isolated constituents, plant –based drug formulations etc. These natural compounds have been a basis for the development of several drugs against cancer. Agents such as topotecan, taxol, vinca alkaloids (vincristine, vinblastine, vinorelbine and vindesine), are important anticancer agents in widespread clinical use. Other agents, such as combretastatin, flavopiridol, betulinic acid were shown to have anti-tumor effects in both in vitro and in vivo experiments.
In this review, we aim to make a brief description of classical plant-derived chemotherapeutics drugs and also to highlight the importance of these natural compounds in the development of new potential drugs in cancer treatment.
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Willingham, M. C. "Apoptosis And Resistance To Anti-Microtubule Agents." Microscopy and Microanalysis 4, S2 (July 1998): 1036–37. http://dx.doi.org/10.1017/s1431927600025307.
Повний текст джерелаАнотація:
Several clinically important anti-cancer agents exert their effects on tumor cells through interference with the function of microtubules. In addition to the Vinca alkaloids, such as vinblastine and vincristine, the taxanes, such as paclitaxel (Trade Name: Taxol), kill tumor cells through a microtubular target. Treatment with taxol leads to the inability of microtubules to depolymerize, leading to the formation of large intracellular microtubular bundles. In tumor cells that progress through the cell cycle, this leads to the inability of these cells to disassembly interphase microtubule networks and a failure to form functional mitotic spindles. These cells arrest in M phase, from which they eventually progress, either by the induction of apoptotic cell death, or by micronucleation and the formation of tetraploid cells. There is also the possibility that taxol has other effects on the regulation of genes or other systems to enhance cell killing, perhaps through lowering the threshold of cells to the induction of apoptotic cell death.
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Mhaidat, NM, KH Alzoubi, OF Khabour, KZ Alawneh, LA Raffee, ES Alsatari, EI Hussein, and KE Bani-Hani. "Assessment of genotoxicity of vincristine, vinblastine and vinorelbine in human cultured lymphocytes: a comparative study." Balkan Journal of Medical Genetics 19, no. 1 (June 1, 2016): 13–20. http://dx.doi.org/10.1515/bjmg-2016-0002.
Повний текст джерелаАнотація:
AbstractVincristine (VCR), vinblastine (VBL) and vinorelbine (VRL) are anticancer agents from the Vinca alkaloid family that have the potential to induce genotoxic effect. The aim of the present study was to compare the genotoxic effect of VCR, VBL and VRL. Levels of 8-hydroxy-2-deoxy guanosine (8-OHdG) and sister chromatid exchanges (SCEs) were measured in cultured human blood lymphocytes treated with VCR, VBL and VRL at concentrations of 0.01 and 0.1 μg/mL. Results showed that VCR, VBL and VRL significantly increased the 8-OHdG levels (p <0.05), whereas it did not cause a significant increase in the frequencies of SCEs in human blood lymphocytes as compared to controls. On the other hand, all three agents significantly increased cells mitotic index (p <0.05). At both tested concentrations, the magnitude of the increase in 8-OHdG was VBL>VCR>VRL. In conclusion, VCR, VBL and VRL induce DNA damage as indicated by the increase in the 8-OHdG biomarker but with different magnitude.
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Mistry, Neelam, Diana Abbott, Japera Walker Wilkison, Ajay Major, Brad M. Haverkos, and Manali Kamdar. "Dose Reduction or Omission of Vinca Alkaloids during Initial Chemotherapy Treatment Does Not Impact Outcomes in Patients with Lymphoma." Blood 134, Supplement_1 (November 13, 2019): 4126. http://dx.doi.org/10.1182/blood-2019-129208.
Повний текст джерелаАнотація:
Background: Vincristine- or vinblastine-induced peripheral neuropathy (VIPN) is a common adverse event during lymphoma treatment that can profoundly impact quality of life and survivorship. VIPN often leads to dose-reduction or discontinuation of these agents. However, there is limited data (Annals of Hematology, Utsu 2016; Annals of Hematology, Morth 2018) evaluating the impact of dose reduction or omission of vinca alkaloids on progression-free survival (PFS) or overall survival (OS). We report on a series of lymphoma patients (pts) who had vincristine (Vn) or vinblastine (Vb) dose-reduced or omitted from their initial chemotherapy. Methods: We performed a retrospective chart review of lymphoma pts who were seen in consultation at the University of Colorado from 2015 to 2018. Data included demographics, lymphoma subtypes, Vn- or Vb-containing treatment regimens, PFS, and OS. PFS and OS were examined using Kaplan-Meier method, and stratification techniques were used to compare survival based on full dose versus dose-reduced/omitted treatments. Cox regression methods were used to assess the impact of refractory or progressive disease, disease stage, and prognostic score on PFS. Results: 373 pts who received Vn- or Vb-containing chemotherapy were identified. Of those, 228 pts had complete records available for review for treatment, response and survival data. 133 pts (58.3%) were male. Median age was 56 years (range 19 to 85 years). The most common diagnoses were diffuse large B-cell (59.2%), Hodgkin (26.3%), follicular (8.3%), PTLD (3.1%), Burkitt, (2.6%), and gray zone (0.4%) lymphomas. Chemotherapy regimens administered were REPOCH (35.1%), RCHOP (32.9%), and ABVD/AVD (21.9%). Incidence of neuropathy during treatment was 36.4%. The median follow up is 23.7 months (range 2.5 to 150.7 months). We categorized patients into 2 groups based on chemotherapy dosing: full dose (Group 1: n=155/228; 68%) and dose-reduced or omitted (Group 2: n= 73/228; 32%). There was not a significant difference in stage or prognostic score between Group 1 and Group 2. Group 2 was further sub-categorized into Subgroup 2A (patients with Vn/Vb omitted at any point: n= 46/228; 20.2%) and Subgroup 2B (patients with Vn/Vb dose-reduced: n=27/228; 11.8% ). Of the 73 patients in Group 2, 67 patients had Vn/Vb omitted or reduced due to neuropathy; 6 patients had the drugs omitted (5/73) or reduced (1/73) due to GI side effects. Complete response (CR) rates between Group 1 and Group 2 were similar (81.3% vs 87.7%, respectively). Patients in Group 1 had a higher number of patients with relapsed/refractory disease compared to Group 2 (p<0.01). PFS was better in Group 2 compared to Group 1 (p=0.027). There was no significant difference in OS between the two groups (p=0.83) (Figure 1). There was no significant difference in response rates, PFS, or OS when comparing Subgroup 2A to Group 1 and Subgroup 2B to Group 1 (Figures 2 and 3). There was also no statistically significant difference in response rate, PFS, or OS if Vn/Vb was dose reduced early (first half of total cycles) versus late, when comparing Group 1 versus Group 2, Subgroup 2A, or Subgroup 2B. Conclusions: Our single-center retrospective analysis of patients suggests that reduction or omission of vinca alkaloids from initial chemotherapy does not deleteriously affect outcomes in lymphoma pts. Prospective clinical trials are underway investigating the substitution of vinca alkaloids with novel targeted agents. Our findings further validate the rationale and design of these contemporary trials. Disclosures Kamdar: University of Colorado: Employment; Celgene: Consultancy; Pharmacyclics: Consultancy; AstraZeneca: Consultancy; Seattle Genetics: Speakers Bureau.
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Nagaraja, Padmarajaiah, Ramanathapura A. Vasantha, and Hemmige S. Yathirajan. "Sensitive and Rapid Spectrophotometric Methods for Determination of Anticancer Drugs." Journal of AOAC INTERNATIONAL 85, no. 5 (September 1, 2002): 1021–24. http://dx.doi.org/10.1093/jaoac/85.5.1021.
Повний текст джерелаАнотація:
Abstract Sensitive, rapid, and simple spectrophotometric methods were developed for determination of the anticancer drugs vinblastine sulfate (VBS) and vincristine sulfate (VCS), which belong to the class of vinca alkaloids. The first method is based on the reaction of VBS and VCS with diazotized dapsone, forming yellow azo products with absorption maxima at 430 nm. The colored species obey Beer's law in the concentration range of 0.5–24 μg/mL for VBS and 0.5–12 μg/mL for VCS. The second method describes the reaction of VBS and VCS with iron(III) and subsequent reaction with ferricyanide in hydrochloric acid medium to yield blue products with absorption maxima at 750 nm. The Beer's law range for this method is 0.1–4 μg/mL for VBS and 0.5–10 μg/mL for VCS. With both methods, colored species were stable for 1 h. The methods are simple and reproducible and are applied for determination of VBS and VCS in pharmaceutical formulations. Commonly encountered pharmaceuticals added as excipients do not interfere in the analysis and the results obtained in the analysis of dosage forms agree well with the labeled contents.
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Prakash, Om, Shazia Usmani, Ruchi Singh, Debarshi K. Mahapatra, and Amresh Gupta. "Cancer Chemotherapy by Novel Bio-active Natural Products: Looking Towards the Future." Current Cancer Therapy Reviews 15, no. 1 (February 22, 2019): 37–49. http://dx.doi.org/10.2174/1573394714666180321151315.
Повний текст джерелаАнотація:
Background: Cancer is the second leading cause of death globally and accounted for 8.8 million deaths annually in humans. Lung, prostate, colorectal, stomach and liver cancer are the most common types of cancer in men, while breast, colorectal, lung, cervix and stomach cancer are the most common among women. Numerous drugs that the US Food and Drug Administration (FDA) have approved for use in cancer therapy are derived from plants, including taxanes such as paclitaxel and vinca alkaloids such as vincristine and vinblastine. Still, there is an intense need for a search for numerous bioactive sources to develop a novel anti-cancer drug to overcome this chronic disorder. About more than thirty plants derived natural products have been isolated till date and are currently under clinical trials. As per literature survey from various journals and texts has been found to be novel medicinal agents from bioactive sources are clinically active against various types of cancer cells. Conclusion: Current review has been highlighted on the novel medicinal agents from plant sources have potential effects against many types of cancer, which have been supported by clinical trials. The main findings of these active novel medicinal agents were also summarized and discussed here.
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Ardeshna, Kirit M., Peter Hoskin, Paul Smith, Nicholas Chadwick, Nivette Braganca, Wai-Lup Wong, Irfan Kayani, et al. "Young Adults Aged 18 to 30 Years with Hodgkin Lymphoma Can Tolerate a Modified Version of the Combined Modality German Paediatric HD95 Protocol with Minimal Neurotoxicity and Excellent Outcome. Results of the UK NCRN 18–30 Study (CRUK/08/012)." Blood 120, no. 21 (November 16, 2012): 1621. http://dx.doi.org/10.1182/blood.v120.21.1621.1621.
Повний текст джерелаАнотація:
Abstract Abstract 1621 The outcome for children with Hodgkin's Lymphoma treated using the German-Austrian paediatric risk-adapted combined modality regimen appears superior to that of adults treated with ABVD +/− radiotherapy. Whether this is related to the superiority of the therapy or a biological difference in the disease in the different age groups is unclear. As a preliminary step to try and compare these regimens directly we enrolled 47 patients between 18 and 30 years of age (median 23y range 18–30) recruited from 8 centres across the UK onto the 18–30 study which used a modified version of the HD95 protocol. Patients were allocated to one of three treatment groups according to stage TG1=1A, 1B, 2A (n=16), TG2=2AE, 2B, 3A (n=11) TG3=2BE, 3AE, 3BE, 3B, 4A, 4B (n=20). Patients in TG1 received 2 cycles of OEPA (vincristine 1.5mg/m2 iv d1,d8,d15 (capped at 2mg/dose), etoposide 125mg/m2 iv d1–5, adriamycin 40mg/m2 iv d1 & 15, prednisolone 60mg/m2 po d1–15). Patients in TG2 received 2xOEPA and 2 xCOPP (cyclophosphamide 500mg/m2 iv d1 and 8 vincristine 1.5mg/m2 iv d1,8 (capped 2mg/dose) procarbazine 100mg/m2 po d1–15, prednisolone 40mg/m2 po d1–15). Patients in TG3 received OEPAx2 and COPPx4. All patients (except those in TG1 who were in CR by CT and PET criteria) went on to receive involved site radiotherapy to all sites of previous disease. The dose of radiotherapy was 20Gy for patients in CR and VGPR (>75% reduction) by CT criteria with areas of residual abnormality on scan >50ml receiving a 30Gy boost. Patients with a PR (50–75% reduction) received the same doses if they were PET negative however those who were PET positive received 30Gy to all sites of previous disease. The schedule of vinca alkaloids in HD95 is compressed with those in TG3 receiving 16 doses of vincristine 1.5mg/m2 (max 2mg) given over 6 months compared with 16 doses of vinblastine 6mg/m2 given over 8 months in ABVD. In view of this and the increase in vinca alkaloid related neurotoxicity with age the primary endpoint of this study was to establish the level of neurotoxicity using this paediatric regimen in young adults. 45 patients (23 male) completed therapy. 1 patient was withdrawn after a hypersensitivity reaction to etoposide on d1 OEPA1 and 1 patient withdrew consent prior to starting therapy. Worst neurotoxicity grade was recorded as: 0 (n=8), 1 (n=17), 2 (n=16) 3 (n=4 [with 2 motor in TG1 &TG2, 1 sensory inTG2, 1 ileus inTG3). In 3 of the 4 patients with severe neurotoxicity vincristine was converted to vinblastine 6mg/m2 according to protocol. No progression of the neuropathy was seen and patients were able to complete their scheduled therapy. In one case (TG2) vincristine was omitted in the final cycle. Neurotoxicity grade at last FU was 0 (n=34) 1 (n=8) 2 (n=3). All 4 cases of grade 3 neurotoxicity reverted to grade 0. Seven patients with grade 2 neuropathy had adjustments made to the dose or type of vinca alkaloid at the request of the physician. Current grade of neuropathy at last FU in these 7 patients:0 (n=4) 1 (n=2) 2 (n=1). There were 8 episodes of febrile neutropenia. Other grade 3 toxicities included diarrhoea (n=2), vomiting (n=3), mucositis (n=3), abdominal pain (n=3) and thrombosis (n=2). Bone/joint pain was seen in 4 patients. Two patients (both TG3) have developed proven osteonecrosis. All 45 patients who completed the chemotherapy achieved a CR or PR. Four did not require radiotherapy, 36 required 20Gy and 5 required 30Gy as a baseline dose to previously involved sites. The median follow up to date is 18 months. Four patients have progressed (1=TG2, 3=TG3) giving a 2yr PFS of 89%. All patients are currently alive. Quality of life data has been collected and assessments of late effects are ongoing. In conclusion, young adults aged 18–30 can tolerate a modified HD95 protocol with a minority of patients experiencing grade 3 neurotoxicity which is reversible when adjustments are made. Outcome with this regimen (which contains only 160mg/m2of adriamycin and no bleomycin) seems encouraging and this (or a more up to date German Austrian Paediatric protocol e.g.with dacarbazine replacing procarbazine in an attempt to spare fertility and omission of radiotherapy based on PET scan after OEPA) warrants testing against ABVD in this age group. Disclosures: No relevant conflicts of interest to declare.
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Cullen, M. H., N. S. Stuart, C. Woodroffe, A. Murphy, J. Fletcher, G. R. Blackledge, J. A. Child, R. J. Grieve, and E. L. Jones. "ChlVPP/PABlOE and radiotherapy in advanced Hodgkin's disease. The Central Lymphoma Group." Journal of Clinical Oncology 12, no. 4 (April 1994): 779–87. http://dx.doi.org/10.1200/jco.1994.12.4.779.
Повний текст джерелаАнотація:
PURPOSE The United Kingdom Central Lymphoma Group (CLG) has modified mechlorethamine, vincristine, procarbazine, and prednisone/doxorubicin, bleomycin, vinblastine, and dacarbazine (MOPP/ABVD) by substituting mechlorethamine with chlorambucil and dacarbazine with etoposide in the treatment of patients with advanced Hodgkin's disease (HD). Prednisolone is included in the bleomycin-containing combination, and the vinca alkaloids have been switched to balance the myelotoxicity of the two component regimens. PATIENTS AND METHODS The resulting ChlVPP/PABlOE regimen is as follows: on days 1 to 14, chlorambucil 6 mg/m2 orally, procarbazine 100 mg/m2 orally, and prednisolone 30 mg/m2 orally; on days 1 and 8, vinblastine 6 mg/m2 intravenously (i.v.); on day 29, doxorubicin 40 mg/m2 i.v.; on days 29 and 36, vincristine 1.4 mg/m2 (maximum, 2 mg) i.v., and bleomycin 10 mg/m2 i.v.; on days 30, 31, and 32, etoposide 200 mg/m2/d orally; on days 29 to 43, inclusive, prednisolone, 30 mg/m2 orally. The second full cycle restarts on day 50. Treatment continues to maximum response plus two full cycles, but with a minimum of three full cycles. Radiotherapy is administered, after chemotherapy, to sites of previously bulky disease. Since 1983, 216 patients with previously untreated, advanced Hodgkin's disease (HD) have entered this study. RESULTS The complete remission (CR) rate after chemotherapy was 73% (95% confidence interval [CI], 67% to 79%), and after additional radiotherapy was 85% (95% CI, 80% to 90%). The failure-free survival (FFS) rate at 5 years was 68% (95% CI, 61% to 74%), and the overall actuarial survival at 5 years was 78% (95% CI, 72% to 84%). The CR rate in patients in the poorer prognostic categories was high: 81% in patients with albumin levels less than 37 g/L, 79% in patients older than 40 years of age, 84% in stages IIIB plus i.v. disease, and 79% in patients presenting with B symptoms. As expected, nausea and vomiting were not major problems, although infection, often in the context of myelosuppression, complicated almost half the cases, and 29% of patients required admission at some stage for treatment of infection. CONCLUSION In this multicenter study, ChlVPP/PABlOE produced results comparable to those reported for MOPP/ABVD, but with less nausea and vomiting. Treatment duration was shorter than in the original MOPP/ABVD regimen, and than that used in the Cancer and Leukemia Group B (CALGB) trial. It will now be compared with PABlOE alone.
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Gouazé, Valerie, Jing Y. Yu, Richard J. Bleicher, Tie-Yan Han, Yong-Yu Liu, Hongtao Wang, Michael M. Gottesman, Arie Bitterman, Armando E. Giuliano, and Myles C. Cabot. "Overexpression of glucosylceramide synthase and P-glycoprotein in cancer cells selected for resistance to natural product chemotherapy." Molecular Cancer Therapeutics 3, no. 5 (May 1, 2004): 633–40. http://dx.doi.org/10.1158/1535-7163.633.3.5.
Повний текст джерелаАнотація:
Abstract Resistance to natural product chemotherapy drugs is a major obstacle to successful cancer treatment. This type of resistance is often acquired in response to drug exposure; however, the mechanisms of this adverse reaction are complex and elusive. Here, we have studied acquired resistance to Adriamycin, Vinca alkaloids, and etoposide in MCF-7 breast cancer cells, KB-3-1 epidermoid carcinoma cells, and other cancer cell lines to determine if there is an association between expression of glucosylceramide synthase, the enzyme catalyzing ceramide glycosylation to glucosylceramide, and the multidrug-resistant (MDR) phenotype. This work shows that glucosylceramide levels increase concomitantly with increased drug resistance in the KB-3-1 vinblastine-resistant sublines KB-V.01, KB-V.1, and KB-V1 (listed in order of increasing MDR). The levels of glucosylceramide synthase mRNA, glucosylceramide synthase protein, and P-glycoprotein (P-gp) also increased in parallel. Increased glucosylceramide levels were also present in Adriamycin-resistant KB-3-1 sublines KB-A.05 and KB-A1. In breast cancer, detailed analysis of MCF-7 wild-type and MCF-7-AdrR cells (Adriamycin-resistant) demonstrated enhanced glucosylceramide synthase message and protein, P-gp message and protein, and high levels of glucosylceramide in resistant cells. Similar results were seen in vincristine-resistant leukemia, etoposide-resistant melanoma, and Adriamycin-resistant colon cancer cell lines. Cell-free glucosylceramide synthase activity was higher in lysates obtained from drug-resistant cells. Lastly, glucosylceramide synthase promoter activity was 15-fold higher in MCF-7-AdrR compared with MCF-7 cells. We conclude that selection pressure for resistance to natural product chemotherapy drugs selects for enhanced ceramide metabolism through glucosylceramide synthase in addition to enhanced P-gp expression. A possible connection between glucosylceramide synthase and P-gp in drug resistance biology is suggested.
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Mitsiades, Constantine S., Cecile Rouleau, Krishna Menon, Beverly Teicher, Massimo Iacobelli, Kenneth C. Anderson, and Paul G. Richardson. "Defibrotide (DF) Targets Tumor-Microenvironmental Interactions and Sensitizes Multiple Myeloma and Solid Tumor Cells to Cytotoxic Chemotherapeutics." Blood 104, no. 11 (November 16, 2004): 286. http://dx.doi.org/10.1182/blood.v104.11.286.286.
Повний текст джерелаАнотація:
Abstract Introduction: Defibrotide (DF) is a polydisperse oligonucleotide with anti-thrombotic, thrombolytic, anti-ischemic, and anti-adhesive properties, which selectively targets the microvasculature and has minimal hemorrhagic risk. DF is an effective treatment for veno-occlusive disease (VOD), an important regimen-related toxicity in stem cell transplantation characterized by endothelial cell injury. DF also augments stem cell mobilization by modulating adhesion in vivo. Because of its cytoprotective effect on the endothelium, we specifically investigated whether DF protects tumor cells from cytotoxic anti-tumor agents. Further, because of its broad anti-adhesive properties, we evaluated whether DF modulates the interaction of MM cells with bone marrow stromal cells (BMSCs), which confers growth, survival and drug resistance in the BM milieu. Methods: In vitro studies in isogenic dexamethasone (Dex)-sensitive and resistant MM cell lines (MM-1S and MM1R, respectively) showed that DF does not attenuate the sensitivity of MM cells to Dex, the proteasome inhibitor bortezomib (PS-341), melphalan (MEL), vinca alkaloids (vincristine, vinblastine), taxanes (paclitaxel) or platinum (cisplatin), but does decrease their sensitivity to doxorubicin. These selective effects in vitro of DF in protecting tumor cells against doxorubicin and modestly sensitizing MM cells to platinum was also confirmed in solid tumor breast (MCF-7) and colon (HT-29) carcinoma cell lines. Although DF had minimal in vitro inhibitory effect on MM or solid tumor cell growth in vitro, it showed in vivo activity as a single agent and enhanced the responsiveness of MM tumors to cytotoxic chemotherapeutics, such as MEL or cyclophosphamide, in human MM xenografts in SCID/NOD mice. The in vivo single-agent activity and chemosensitizing properties of DF, coupled with its lack of major in vitro activity, suggested that DF may not directly target tumor cells, but rather modulate tumor cell interaction with BMSCs. In an ex vivo model of co-culture of primary MM tumor cells with BMSCs (which protects MM cells against conventional chemotherapy), DF alone had a only modest effect on tumor cell viability, but it significantly enhanced MM cell sensitivity to cytotoxic chemotherapy (e.g. MEL), suggesting that a major component of the biological effects of DF may be attributable not to direct targeting of tumor cells, but to modulation of the interactions that tumor cells develop with the local stromal milieu. Conclusion: Our studies show that DF mediates in vivo anti-MM activity by abrogating interactions of MM cells with their BM milieu, thereby enhancing sensitivity and overcoming resistance to conventional chemotherapy. These data support future clinical trials of DF, in combination with both conventional and novel therapies, to improve patient outcome in MM.
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Bokemeyer, C., C. C. Berger, M. A. Kuczyk, and H. J. Schmoll. "Evaluation of long-term toxicity after chemotherapy for testicular cancer." Journal of Clinical Oncology 14, no. 11 (November 1996): 2923–32. http://dx.doi.org/10.1200/jco.1996.14.11.2923.
Повний текст джерелаАнотація:
PURPOSE The current study evaluates the extent and reversibility of late sequelae after chemotherapy in longterm survivors of testicular cancer. The influence of therapy and patient characteristics and the relationship between different toxicities are assessed. PATIENTS AND METHODS Ninety patients with a median age of 28 years (range, 19 to 53) and a median followup time of 58 months (range, 15 to 159) participated in the clinical examinations, a personal interview, and technical investigations. Overall health and the impact of late toxicity were assessed by the patients. All patients were in complete remission (CR) for at least 1 year. Chemotherapy had consisted of cisplatin (P), bleomycin (B), and vinblastine (V) in 30 patients (33%); P, B, and etoposide (E) in 26 patients (29%); P, B, E, and a vinca alkaloid in 22 patients (24%); and other P-based combination regimens in 12 patients (13%). RESULTS Alterations of gonadotropin levels (follicle-stimulating hormone [FSH] luteinizing hormone [LH]) in up to 68% of patients and Leydig cell insufficiency in one third of patients were the most frequently detected abnormalities. Approximately 20% of patients had low serum magnesium [Mg] or phosphate levels, or elevated creatinine levels. Cardiovascular risk factors were identified in one third of patients with elevated serum cholesterol levels with or without obesity; 15% had developed arterial hypertension after chemotherapy. The most frequent symptomatic toxicities were Raynaud's phenomenon (RP) in 30% of patients, ototoxicity in 21%, and peripheral neuropathy in 17%. Major risk factors for the development of toxicity were cumulative dose of P (P < .0001 for ototoxicity and neurotoxicity; P < .01 for overall toxicity, gonadal toxicity, and dehydroepiandrosteron elevation; P < .05 for hypertension and Mg depletion) and type of chemotherapy (57% of PVB-treated patients v25% of PEB +/- vincristine-treated patients with RP; P < .01). CONCLUSION The cumulative dose of P was a major predictor for toxicity. Patients and treatment characteristics such as noise exposure, age, history of smoking, and mode of B application were less important. Further clinical trials should evaluate the sequelae of chemotherapy treatment for testicular cancer prospectively.
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Ehrhardt, Harald, David Schrembs, Christian Moritz, Franziska Wachter, Subrata Haldar, Ulrike Graubner, Michaela Nathrath, and Irmela Jeremias. "Optimized anti–tumor effects of anthracyclines plus Vinca alkaloids using a novel, mechanism-based application schedule." Blood 118, no. 23 (December 1, 2011): 6123–31. http://dx.doi.org/10.1182/blood-2010-02-269811.
Повний текст джерелаАнотація:
Abstract Application of anthracyclines and Vinca alkaloids on the same day represents a hallmark of polychemotherapy protocols for hematopoietic malignancies. Here we show, for the first time, that both drugs might act most efficiently if they are applied on different days. Proof-of-concept studies in 18 cell lines revealed that anthracyclines inhibited cell death by Vinca alkaloids in 83% of cell lines. Importantly, in a preclinical mouse model, doxorubicin reduced the anti–tumor effect of vincristine. Both drugs acted in a sequence-dependent manner and the strongest anti–tumor effect was obtained if both drugs were applied on different days. Most notably for clinical relevance, in 34% of 35 fresh primary childhood leukemia cells tested in vitro, doxorubicin reduced the anti–tumor effect of vincristine. As underlying mechanism, doxorubicin activated p53, p53 induced cell-cycle arrest, and cell-cycle arrest disabled inactivation of antiapoptotic Bcl-2 family members by vincristine; therefore, vincristine was unable to activate downstream apoptosis signaling. As molecular proof, antagonism was rescued by knockdown of p53, whereas knockdown of cyclin A inhibited vincristine-induced apoptosis. Our data suggest evaluating anthracyclines and Vinca alkaloids on different days in future trials. Selecting drug combinations based on mechanistic understanding represents a novel conceptional strategy for potent polychemotherapy protocols.
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Humbert, Martine, Armelle Goubard, Colin Mansfield, Olivier Hermine, Patrice Dubreuil, and The AB8939 Study Group. "Anticancer Activity of a Highly Potent Small Molecule Tubulin Polymerization Inhibitor, AB8939." Blood 134, Supplement_1 (November 13, 2019): 2075. http://dx.doi.org/10.1182/blood-2019-122540.
Повний текст джерелаАнотація:
We have identified the small chemical molecule AB8939 as being a structurally novel, synthesized tubulin inhibitor that can circumvent resistance mechanisms known to limit the effectiveness of existing tubulin inhibitors; e.g., P-glycoprotein (Pgp) and myeloperoxidase (MPO) mediated resistance. A series of in vitro preclinical studies provide proof-of-concept that AB8939 has broad applicability as a potent anticancer drug, particularly in tumors of hematopoietic and lymphoid tissues, including acute myeloid leukemia (AML). Regarding mechanism of action, x-ray crystallography demonstrated that AB8939 binds to the colchicine-binding site on the beta-subunit of tubulin. Cell cycle arrest in the G2/M phase was evaluated using HCT116 cells (a human colorectal tumor), treated at various concentrations of AB8939 for 24 hours. It was seen that AB8939 produced a strong mitotic arrest at the sub-micromolar concentration range (90% of cells in G2/M phase at 10 nM), which was of comparable strength to that of established microtubule targeting agents, each at a concentration of 100 nM. Additional assays using cytarabine (Ara-C) resistant MOLM14 AML cells confirmed this activity, also demonstrating dose dependent (2 to 20 nM) G2/M phase cell cycle arrest in patient-derived AML blasts and that G2/M cell cycle arrest lead to cellular death by apoptosis at nanomolar concentrations. The effect of AB8939 (100 nM) on the integrity of the microtubule and actin networks was tested in 3T3NIH cells (murine embryonic fibroblast cell line). AB8939 induced a rapid (within 1 hour) and radical destabilization of the microtubule network but did not affect the actin network. Similarly, destabilization of the microtubule network was observed in human primary cardiomyocytes and primary human lung fibroblast cells treated for 24 hours at 10 to 1000 nM AB8939. Further in vitro analysis showed that AB8939 produces a direct and potent, dose-dependent depolymerization effect (50% inhibition of in vitro microtubule polymerization at around 1 µM, with 100% inhibition at >5 µM). The potential of AB8939 to overcome resistance to chemotherapeutic agents in Pgp-dependent multidrug-resistant cell lines was assessed using the drug-sensitive human sarcoma cell line MES-SA (parental) and its multidrug-resistant counterparts MES-SA/MX2 and MES-SA/Dx5 in a 6-day proliferation/survival assay. AB8939 efficiently inhibited each of these cells with an IC50 ≤10 nM. By comparison, the MES-SA/MX2 and MES-SA/Dx5 cell lines were highly resistant to the chemotherapeutic agents of doxorubicin and vincristine, as compared with the effect on parental cells (IC50 <1.5 - 2.0 µM versus 20 nM, respectively). Additional tests showed that AB8939 is a very poor substrate of Pgp efflux pump, comparable with combretastatin-4, and therefore has the potential to overcome multidrug resistance in cancer patients. The anti-proliferative activity of AB8939 in various hematopoietic tumors and solid tumors was evaluated using a colorimetric cell proliferation and viability assay. AB8939 produced good anti-tumor activity after 72 hours (IC50 of ≤50 nM) in 19 hematopoietic tumor cell lines tested, including AML (3 cell lines), B cell lymphoma (8 cell lines), T cell lymphoma (6 cell lines), and multiple myeloma (2 cell lines). AB8939 also showed good anti-tumor activity after 6 days (IC50 of ≤10 nM) in several solid tumor cell lines, including breast, colon, glioblastoma, head and neck, lung, kidney, melanoma neuroblastoma, ovary, pancreas and prostate cell lines. The therapeutic potential of AB8939 in refractory/resistant AML was investigated further on doxorubicin-resistant AML cell lines (HL60 and U937), doxorubicin being a commonly used AML induction drug and Pgp substrate. AB8939 produced a strong anti-proliferative effect in both cell lines whereas both were resistant to doxorubicin, thus demonstrating AB8939's potential to overcome refractory/resistant AML. Notably, HL60 and U937 are respectively MPO-positive and MPO-negative, indicating that unlike vinca alkaloids (e.g. vincristine or vinblastine) AB8939 it is not deactivated by this myeloid enzyme. These data show that AB8939 is a prolific and highly potent (nanomolar concentrations) Pgp-independent, next-generation microtubule-destabilizer drug for cancer therapy; in particular, difficult to treat hematopoietic tumors such as relapsed/refractory AML. Disclosures Humbert: AB Science: Employment. Goubard:AB Science: Employment. Mansfield:AB Science: Employment, Patents & Royalties. Hermine:AB Science: Membership on an entity's Board of Directors or advisory committees. Dubreuil:AB Science: Employment, Membership on an entity's Board of Directors or advisory committees, Research Funding. AB8939 Study Group:AB Science: Consultancy, Employment.
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Vu, Phuong Thi Bach, Dai Minh Cao, Anh Lan Bui, Nhut Nhu Nguyen, Le Van Bui, and Phuong Ngo Diem Quach. "In vitro growth and content of vincristine and vinblastine of Catharanthus roseus L. hairy roots in response to precursors and elicitors." Plant Science Today 9, no. 1 (January 1, 2022): 21–28. http://dx.doi.org/10.14719/pst.1337.
Повний текст джерелаАнотація:
Catharanthus roseus L. is a medicinal plant that produces numerous indole terpenoid alkaloids, including vincristine and vinblastine, which are used for cancer treatment. The effect of specified precursors (L-phenylalanine, L-tyrosine) and elicitors (chitosan, methyl jasmonate) on C. roseus hairy roots (CHR) growth has been examined in order to increase the content of vincristine and vinblastine. Our results showed that CHR generated by an Agrobacterium rhizogenes strain isolated in Vietnam was capable of producing both vincristine and vinblastine when subjected to precursors, but only vinblastine when exposed to elicitors. However, both precursors and elicitors were evaluated to have an effect on increasing the accumulation of TIAs in CHR. In particular, the use of elicitors required more time to find the appropriate induction conditions, while the use of precursors gave outstanding efficiency in the treatment with 1 µM phenylalanine. The greatest yields of vincristine (51.99 µg g-1 DW) and vinblastine (699.92 µg g-1 DW) were obtained in the 7th week (with 0.306 g DW biomass). This result is the first time we might boost the levels of vincristine and vinblastine in our CHR clone generated by the Vietnam strain of A. rhizogenes.
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Pliankong, Pawnpirun, Padungsak Suksa-Ard, and Surawit Wannakrairoj. "Chitosan Elicitation for Enhancing of Vincristine and Vinblastine Accumulation in Cell Culture of Catharanthus roseus (L.) G. Don." Journal of Agricultural Science 10, no. 12 (November 15, 2018): 287. http://dx.doi.org/10.5539/jas.v10n12p287.
Повний текст джерелаАнотація:
Catharanthus roseus (L.) G. Don is an important herbal plant. There are two important alkaloids, vinblastine and vincristine, use in anti-cancer drugs. In this study production of the two alkaloids was enhanced in C. roseus cell cultures, in a Murashige and Skoog (MS) liquid medium supplemented with 1.5 mg/L 2,4-D, 0.5 mg/L kinetin and 30 g/L sucrose, by adding 0, 50, 100, 250 or 500 mg/L medium molecular weight chitosan or chitosan derived from shrimp shell. After 14 days of culture, the cell suspension at stationary phase in the 100 mg/L medium molecular weight chitosan could produce the highest amounts of vinblastine and vincristine at 4.15 and 5.48 µg/mg cell dry weight, respectively. At the same time, the controls (0 mg/L chitosan) produced the two alkaloids at only 2.43 and 2.49 µg/mg cell dry weight, respectively. For chitosan from shrimp shell, it was found that 100 mg/L chitosan could lead to the highest quantity of 4.09 µg vinblastine/mg cell dry weight. The highest amount of 5.47 µg vincristine/mg cell dry weight was obtained when 250 mg/L chitosan was added.
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Rahmani-Jourdheuil, Dominique, Fabrice Coloma, Michel Placidi, and Roger Rahmani. "Human Hepatic Uptake of Two Vinca Alkaloids: Navelbine and Vincristine." Journal of Pharmaceutical Sciences 83, no. 4 (April 1994): 468–71. http://dx.doi.org/10.1002/jps.2600830404.
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Rai, Vartika, Pramod Kumar Tandon, and Sayyada Khatoon. "Effect of Chromium on Antioxidant Potential ofCatharanthus roseusVarieties and Production of Their Anticancer Alkaloids: Vincristine and Vinblastine." BioMed Research International 2014 (2014): 1–10. http://dx.doi.org/10.1155/2014/934182.
Повний текст джерелаАнотація:
Catharanthus roseus(L.) G. Don, a medicinal plant, has a very important place in the traditional as well as modern pharmaceutical industry. Two common varieties of this plantroseaandalbaare named so because of pink and white coloured flowers, respectively. This plant comprises of about 130 terpenoid indole alkaloids and two of them, vincristine and vinblastine, are common anticancer drugs. The effect of chromium (Cr) on enzymatic and non-enzymatic antioxidant components and on secondary metabolites vincristine and vinblastine was studied under pot culture conditions of both varieties ofC. roseus. Antioxidant responses of these varieties were analyzed under 0, 10, 50, and 100 μM chromium (Cr) level in order to investigate the plant’s protective mechanisms against Cr induced oxidative stress. The results indicated that Cr affects all the studied parameters and decreases growth performance. However, vincristine and vinblastine contents were increased under Cr stress. Results are quite encouraging, as this plant shows good antioxidant potential and increased the level of active constituents under Cr stress.
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Naeem, M., Mohd Idrees, Tariq Aftab, M. Masidur Alam, M. Masroor A. Khan, Moin Uddin, and Lalit Varshney. "Radiation Processed Carrageenan Improves Plant Growth, Physiological Activities, and Alkaloids Production in Catharanthus roseus L." Advances in Botany 2015 (January 22, 2015): 1–11. http://dx.doi.org/10.1155/2015/150474.
Повний текст джерелаАнотація:
Catharanthus roseus (L.) G. Don (Apocynaceae) is a medicinal plant that produces indole alkaloids used in cancer chemotherapy. Commercially important antineoplastic alkaloids, namely, vinblastine and vincristine, are mainly present in the leaves of C. roseus. Gamma-rays irradiated carrageenan (ICR) has been proven as plant growth promoting substance for a number of medicinal and agricultural plants. Considering the importance of ICR as a promoter of plant growth and alkaloids production in C. roseus, a pot experiment was carried out to explore the effect of ICR on the plant growth, physiological activities, and production of anticancer alkaloids in C. roseus at 120 and 150 days after planting (DAP). Foliar application of ICR (at 0, 20, 40, 60, 80, and 100 mg L−1) significantly improved the performance of C. roseus. 80 mg L−1 of ICR enhanced the leaf yield by 29.2 and 35.4% and the herbage yield by 32.5 and 37.4% at 120 and 150 DAP, respectively, over the control. The spray of ICR at 80 mg L−1 increased the yield of vinblastine by 64.3 and 65.0% and of vincristine by 75.5 and 77.0% at 120 and 150 DAP, respectively, as compared to the control.
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Napolitano, Andrea, Salvatore Provenzano, Chiara Colombo, Marco Vitellaro, Antonella Brunello, Giuseppe Badalamenti, Margherita Nannini, et al. "Familial adenomatosis polyposis–related desmoid tumours treated with low-dose chemotherapy: results from an international, multi-institutional, retrospective analysis." ESMO Open 5, no. 1 (January 2020): e000604. http://dx.doi.org/10.1136/esmoopen-2019-000604.
Повний текст джерелаАнотація:
IntroductionDesmoid tumour (DT) is a locally aggressive fibroblastic proliferative disease representing the most common extraintestinal manifestation of familial adenomatosis polyposis (FAP). As data on the activity of chemotherapy in these patients are limited, we examined the outcomes of patients treated with low-dose methotrexate (MTX)+vinca alkaloids (vinorelbine or vinblastine).Patients and methodsWe retrospectively reviewed clinical and outcome data from all patients with confirmed FAP-associated DTs treated with weekly MTX+vinca alkaloids in seven European sarcoma reference centres between January 2000 and December 2018. Radiological responses were assessed using RECIST V.1.0 and V.1.1. The Kaplan-Meier method associated to the log-rank test was used to estimate and compare survival curves.ResultsWe identified 37 patients (median age 29 years, range 7–44). According to RECIST, 20/37 (54.1%) patients achieved partial response (PR), 15/37 (40.5%) patients had stable disease and 2/37 (5.4%) had progressive disease as best response. Overall, the median progression-free survival (PFS) was 6.5 years (range, 0.3–12.1 years). In the subset of patients achieving PR as best response, the median PFS was not reached. In a subset of 11 patients with progressive disease offered MTX+vinca alkaloids rechallenge (after chemotherapy withdrawal following prolonged disease control), the disease control rate was 100%, resulting in a median PFS after rechallenge of 5.8 years.ConclusionsThis is the largest series on the activity of low-dose chemotherapy in patients with FAP-related DT. In this population, MTX+vinca alkaloids is an active combination, as already reported in patients with sporadic DT.
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Don, Sima, Nicole M. Verrills, Tracy Y. E. Liaw, Marjorie L. M. Liu, Murray D. Norris, Michelle Haber та Maria Kavallaris. "Neuronal-associated microtubule proteins class III β-tubulin and MAP2c in neuroblastoma: Role in resistance to microtubule-targeted drugs". Molecular Cancer Therapeutics 3, № 9 (1 вересня 2004): 1137–46. http://dx.doi.org/10.1158/1535-7163.1137.3.9.
Повний текст джерелаАнотація:
Abstract Advanced stage neuroblastoma has a poor clinical outcome and microtubule-destabilizing agents, such as the Vinca alkaloids, are an important component in the treatment of this childhood cancer. Vinca alkaloids bind to β-tubulin on the α/β-tubulin heterodimer and disrupt microtubule dynamics, leading to cell death. To date, studies examining the contribution of microtubules and associated proteins to the efficacy of microtubule-destabilizing agents in neuroblastoma have been limited. In this study, BE(2)-C neuroblastoma cells previously selected for resistance to either vincristine (BE/VCR10) or colchicine (BE/CHCb0.2) were found to display significant decreases in neuronal-specific class III β-tubulin. Interestingly, vincristine-selected cells exhibited increased levels of polymerized tubulin that were not due to α-tubulin and class I, II, or III β-tubulin mutations. Expression levels of the microtubule-depolymerizing protein stathmin were significantly increased in BE/VCR10 cells. In contrast, levels of MAP2a and MAP2b were relatively unaltered. A marked decrease in the neuronal protein, MAP2c, was identified in the vincristine-selected cells and, to a lesser extent, in the colchicine-selected cells. This is the first report describing specific microtubule alterations in neuroblastoma cells resistant to tubulin-targeted agents. The results indicate a need to identify the factors responsible for resistance to tubulin-targeted agents in neuroblastoma so that improved and novel treatment strategies can be developed for this drug refractory disease.
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NOORMOHAMMADI, ZAHRA, MARYAM TABAN, and FARAH FARAHANI. "Short Communication: The impact of Gamma radiation on Tdc and Str gene expressions in Catharanthus roseus regenerated plantlets." Biodiversitas Journal of Biological Diversity 19, no. 5 (September 21, 2018): 1805–10. http://dx.doi.org/10.13057/biodiv/d190531.
Повний текст джерелаАнотація:
Noormohammadi Z, Taban M, Farahani F. 2018. Short Communication: The impact of Gamma radiation on Tdc and Str gene expressions in Catharanthus roseus regenerated plantlets. Biodiversitas 19: 1805-1810. Catharanthus roseus L.G. Don, is the essential medicinal plant with considerable attention. This plant is a rich source of terpenoid indole alkaloids (TIAs). The main alkaloids in C. roseus are vinblastine, vincristine, and ajmalicine. The tryptophan decarboxylase (Tdc) and Strictosidine synthase (Str) are key enzymes in TIA biosynthesis. In the present study, Tdc and Str gene expressions, as well as vinblastine production were evaluated in tissue culture regenerated plantlets in 4 groups; control, 60 Gy irradiation, 50 mg/L putrescine and 60 Gy irradiation + 50mg/L putrescine treatments. The results revealed significant increase in Tdc and Str gene expressions in 60 Gy irradiation + 50mg/L putrescine treated plantlets in comparison with control samples by using qPCR methods. HPLC analysis showed a higher amount of vinblastine in 60 Gy + 59 mg/L putrescine treated plantlets. Gamma radiation and putrescine as elicitor and polyamine, respectively, are able to improve vinblastine production in C. roseus.
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Szabó, Lajos, Hedvig Bölcskei, Baitz-Gács Eszter, Marianna Mák, and Csaba Szántay. "Synthesis of vinca alkaloids and related compounds, Part XCVI[1] Nitration study of vinblastine-type bisindole alkaloids." Archiv der Pharmazie 334, no. 12 (December 2001): 399–405. http://dx.doi.org/10.1002/1521-4184(200112)334:12<399::aid-ardp399>3.0.co;2-1.
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Hendriks, Hans R., Simon Langdon, Dietmar P. Berger, Knut Breistøl, Heinz H. Fiebig, Øystein Fodstad, and Gilberto Schwartsmann. "Comparative antitumour activity of vinblastine-isoleucinate and related vinca alkaloids in human tumour xenografts." European Journal of Cancer 28, no. 4-5 (April 1992): 767–73. http://dx.doi.org/10.1016/0959-8049(92)90112-f.
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Szabo, Lajos, Hedvig Boelcskei, Baitz-Gacs Eszter, Marianna Mak, and Csaba Szantay. "ChemInform Abstract: Synthesis of Vinca Alkaloids and Related Compounds. Part 96. Nitration Study of Vinblastine-Type Bisindole Alkaloids." ChemInform 33, no. 18 (May 21, 2010): no. http://dx.doi.org/10.1002/chin.200218202.
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Birat, Kanchan, Reem Binsuwaidan, Tariq Omar Siddiqi, Showkat Rasool Mir, Nawaf Alshammari, Mohd Adnan, Rahila Nazir, et al. "Report on Vincristine-Producing Endophytic Fungus Nigrospora zimmermanii from Leaves of Catharanthus roseus." Metabolites 12, no. 11 (November 15, 2022): 1119. http://dx.doi.org/10.3390/metabo12111119.
Повний текст джерелаАнотація:
Vincristine is an anti-cancer compound and one of the most crucial vinca alkaloids produced by the medicinal plant Catharanthus roseus (L.) G. Don. (Apocynaceae). This plant is home to hundreds of endophytic microbes, which produce a variety of bioactive secondary metabolites that are known for their medicinal properties. In this study, we focused on isolating an endophytic fungus that could increase the yield of vincristine under laboratory conditions as an alternative to plant-mediated extraction of vincristine. The endophytic fungus Nigrospora zimmermanii (Apiosporaceae) was isolated from Catharanthus roseus and it was found to be producing the anticancer compound vincristine. It was identified using high-performance thin-layer chromatography by matching the Rf value and spectral data with the vincristine standard and mass spectrometry data and the reference molecule from the PubChem database. The generation study of this microbe showed that the production of vincristine in the parent fungus was at its maximum, i.e., 5.344 µg/mL, while it was slightly reduced in subsequent generations. A colonization study was also performed and it showed that the fungus N. zimmermanii was able to re-infect the plant Catharanthus roseus after 20 days of inoculation. The colonization study showed that N. zimmernanii could infect the plant after isolation. This method is an efficient and easy way to obtain a high yield of vincristine, as compared to plant-mediated production.