Academic literature on the topic 'Satraplatin'

14620 Background: Satraplatin is a novel oral platinum analog with potent cytotoxic and antitumor activity in preclinical models. Satraplatin showed activity in hormone refractory prostate cancer (HRPC) and other tumor types in Phase II trials. A pivotal Phase III trial evaluating satraplatin as 2nd-line therapy for HRPC completed accrual of > 900 patients in 2005. Satraplatin’s activity, safety profile and ease of administration make it attractive for combination regimens. Methods: Satraplatin and its active metabolite JM-118 were tested in vitro as single agents in the androgen-sensitive LNCaP and the androgen-insensitive PC-3 and DU-145 human prostate carcinoma (ca.) cell lines. For in vitro combination studies, PC-3 cells were treated with satraplatin or JM-118 either prior to, after, or concomitantly with paclitaxel or docetaxel. The PC-3 cell line was used for in vivo xenograft experiments in nude mice. Paclitaxel was given intravenously on Day 1, satraplatin orally on Days 2 to 6, and paclitaxel again on Day 8. Results: Satraplatin and JM-118 as single agents inhibited the growth of all three prostate ca. cell lines in vitro in a dose dependent fashion. IC50 values for JM-118 were < 1μM. Strong synergism was noted when PC-3 tumor cells were treated in vitro with paclitaxel or docetaxel followed by satraplatin or JM-118. Satraplatin administered orally inhibited the growth of PC-3 xenografts in nude mice. Treatment of advanced PC-3 tumors with paclitaxel (40 mg/kg) and satraplatin (35 mg/kg) was well tolerated and resulted in a Tumor Growth Delay equivalent to 3 Log Cell Kill, an effect superior to that of the single agents. Conclusions: In vitro, satraplatin and its metabolite JM-118 are active as single agents against human prostate ca. cells, and are synergistic with taxanes. In vivo, treatment with paclitaxel followed by satraplatin showed synergism without increased toxicity. These preclinical data support ongoing Phase I and II clinical trials that are evaluating combinations of satraplatin with paclitaxel or docetaxel. [Table: see text]

Purpose This multinational, double-blind, randomized, placebo-controlled, phase III trial assessed the efficacy and tolerability of the oral platinum analog satraplatin in patients with metastatic castrate-refractory prostate cancer (CRPC) experiencing progression after one prior chemotherapy regimen. Patients and Methods Nine hundred fifty patients were randomly assigned (2:1) to receive oral satraplatin (n = 635) 80 mg/m2 on days 1 to 5 of a 35-day cycle and prednisone 5 mg twice daily or placebo (n = 315) and prednisone 5 mg twice daily. Primary end points were progression-free survival and overall survival (OS). The secondary end point was time to pain progression (TPP). Results A 33% reduction (hazard ratio [HR] = 0.67; 95% CI, 0.57 to 0.77; P < .001) was observed in the risk of progression or death with satraplatin versus placebo. This effect was maintained irrespective of prior docetaxel treatment. No difference in OS was seen between the satraplatin and placebo arms (HR = 0.98; 95% CI, 0.84 to 1.15; P = .80). Compared with placebo, satraplatin significantly reduced TPP (HR = 0.64; 95% CI, 0.51 to 0.79; P < .001). Satraplatin was generally well tolerated, although myelosuppression and GI disorders occurred more frequently with satraplatin. Conclusion Oral satraplatin delayed progression of disease and pain in patients with metastatic CRPC experiencing progression after initial chemotherapy but did not provide a significant OS benefit. Satraplatin was generally well tolerated. These results suggest activity for satraplatin in patients with CRPC who experience progression after initial chemotherapy.

Platinum complexes are among the most commonly applied anticancer agents. The aim of current work is collection, analysing and comparative estimation of clinical trials and pharmacological indications of currently approved for application platinum detivatives: Cisplatin, Carboplatin, Oxaliplatin, Nedaplatin (Japan), Lobaplatin (China), Heptaplatin (North Korea), and Satraplatin. The other aim of the study includes the summarizing of the hystoric data for the stages of the developlement of these drugs, and the comparison of pharmacokimetic parameters, side effecs and the dose-liniting factors of the drugs. The observational study on pharmacokinetic parameters shows that protein binding decreases in order: 95% (Cisplatn); 90% (Oxaliplatin); 50% (Nedaplatin); low (Carboplatin). For every of Cisplatin, Carboplatin, Oxaliplatin have been reported more than 1000 clinical trials; for Lobaplatin, Nedaplatin, Satraplatin - about 10 trials. The differenses in dose-limiting effects are: neuro-, nephro-, ototoxicity (Cisplatin); neurotoxicity (Oxaliplatin); nephrotoxicity (Heptaplatin); myelosuppression: thrombocytopenia, neutropenia, leukopenia (Carboplatin, Nedaplatin, Satraplatin).

Background The role of organic anion transporting polypeptide 5A1 (OATP5A1) a member of a family of drug transporters that mediate cellular uptake of drugs has not been characterized so far. Methods Gene expression levels of OATP5A1 in small cell lung cancer (SCLC) cell lines were determined by real-time qPCR and chemosensitivity of HEK-293- SLCO5A1-transfected cells to satraplatin in MTT assays. Results Significant expression of this transporter was found at the mRNA level, primarily in drug-resistant SCLC cells, and SLCO5A1-transfected HEK-293 cells showed higher resistance to satraplatin. OATP5A1 is found preferentially in cytoplasmic membranes of tumor cells, including SCLC. Conclusions OATP5A1 seems to effect intracellular transport of drugs and may participate in chemoresistance of SCLC by sequestration, rather than mediating cellular uptake. Since satraplatin failed to improve survival in SCLC patients, the relation of OATP5A1 expression to clinical drug resistance and its use as marker of chemoresistance should be further investigated.

The problems with platinum complexes are resistance and toxicity of anticancer therapy. The aim of current study is the comparison of the influence of chemical structure and mechanism of hydrolysis on pharmacological activity and toxicological profile of approved in platinum drugs: Cisplatin, Carboplatin, Oxaliplatin, Nedaplatin, Lobaplatin, Heptaplatin, Satraplatin. Hydrolysis of Carboplatin and Nedaplatin occurs by double step hydration, to obtain the same active products as with Cisplatin: diaqudiamine-platinum. The similarity in mechanisms of hydrolysis of Oxaliplatin, Lobaplatin Heptaplatin, and Satraplatin is that the first part of the hydrolysis corresponds to the ring-opening and addition of the first water molecule, and in the second step of reaction occur the loss of the ligand and the formation of the di-aquated product by the addition of a second water molecule. Cisplatin, Carboplatin, and Oxaliplatin are nephrotoxic. Cisplatin and Heptaplatin are nephrotoxic. The similar dose-limiting effects of Carboplatin, Oxaliplatin, Nedaplatin, Lobaplatin, and Satraplatin is myelosuppression.

2554 Background: Satraplatin is an orally bioavailable platinum analog. Based on pre-clinical activity (IC500.02-8 µg/ml) including activity in cisplatin resistant cell lines, and clinical activity without neuro-, nephro-, or ototoxicity in adults with refractory tumors, we developed a phase 1 trial to determine the toxicities, maximum tolerated dose (MTD), and PKs of satraplatin in children with refractory solid tumors. Methods: Satraplatin (10 and 50 mg capsules) was administered orally once daily on days 1 - 5 of a 28 day cycle to cohorts of 3-6 patients (pts) at 60 mg/m2/dose (DL 1) and 80 mg/m2/dose (DL 2). Plasma ultrafiltrate (PUF) platinum was measured using atomic absorption spectroscopy during cycle 1 for PK analysis. Results: 9 pts [5 male, 4 female, median age 17 years (range 8-19)] with malignant glioma (n=4), ependymoma (n=2), medulloblastoma (n=1), osteosarcoma (n=1), or hepatoblastoma (n=1) received 1-10+ cycles (median 2). The MTD was exceeded at DL 2 as 2/4 pts had dose limiting toxicities (DLT) of delayed and prolonged myelosuppression (grade 3 thrombocytopenia, n=1; grade 3-4 neutropenia, n=2). 0/5 pts at DL 1 had DLTs. Grade 1 ototoxicity was seen in 1 pt at cycle 10. Non-DLTs included myelosuppression, gastrointestinal toxicities, fatigue, headache, liver enzyme elevation, and electrolyte abnormalities. No objective responses were observed, but 1 pt with gliomatosis cerebri has had radiographic stable disease through cycle 10+. Satraplatin mean exposure (AUC) and peak concentration (Cmax) were similar at both dose levels [day 1 PUF AUC0-24h 1.22 ± 0.55 µg/ml*h at DL1 (n=3), 1.02 ± 0.45 µg/ml*h at DL2 (n=3); Cmax0.17 ± 0.08 µg/ml at DL 1 (n=3), 0.16 ± 0.05 µg/ml at DL 2 (n=3)]. Terminal half-life was 14 ± 6 h and apparent clearance was 76 ± 29 L/h (n=6). Conclusions: The MTD of oral satraplatin in children with solid tumors is 60 mg/m2/dose daily x 5 q28 days. The toxicity profile was similar to adults, and delayed myelosuppression was DLT. Satraplatin exposure appears higher in pediatric pts compared to adults (PUF AUC0-24h 0.25-0.47 µg/ml*h at 60-80 mg/m2/dose). DL 1 will be expanded to gain additional experience regarding toxicities and PKs in a broader age range. Clinical trial information: NCT01259479.

170 Background: While satraplatin, a fourth generation oral platinum analogue, failed to improve overall survival (OS) in an unselected metastatic castrate-resistant prostate cancer (mCRPC) population (Sternberg, JCO 2009), anti-tumor activity was demonstrated, suggesting a “platinum-sensitive” subset of patients. Predictive biomarkers may not only select patients most likely to benefit from novel “targeted” therapies but also from standard (even discarded) cytotoxic agents. Development of predictive biomarkers in mCRPC is hampered by the fact that PC is associated with a long natural history and evolving genetic changes, highlighting the need for immediate pre-treatment metastatic tissue samples for biomarker development. In this trial, we sought to determine the feasibility of obtaining metastatic biopsies in patients with mCRPC treated with satraplatin. Methods: Docetaxel-refractory mCRPC patients underwent image-guided biopsy of metastatic lesions prior to treatment with satraplatin 80 mg/m2 PO on days 1 to 5 of a 35-day cycle and prednisone 5 mg PO twice daily. Biopsy samples are analyzed by whole exome and RNA sequencing, and peripheral blood samples are undergoing transcriptional profiling, to facilitate biomarker development. Results: Thirteen patients were enrolled with a median age of 71 (range: 55 to 80), prostate-specific antigen (PSA) of 82 ng/ml (0.04-3057), and Gleason score 8 (7 to 9). All patients received prior docetaxel, four (31%) had more than or eqaul to two prior chemotherapies, and two (15%) received abiraterone. Drug-related grade 3/4 toxicities included leukopenia (23%), neutropenia (8%), thrombocytopenia (8%), fatigue (8%), renal failure (8%), dysphagia (17%), and diarrhea (8%). A median of four cycles of satraplatin were completed, with declines of serum PSA of greater than or equal to 30% achieved in 4 of 13 patients (31%; 95% CI, 57.3 to 85.4%). Median time to PSA progression was 12.4 weeks (95% CI, 7.2 to 29.7+ weeks). Metastatic pre-treatment biopsies were collected in all study patients; genomic analysis is ongoing. Conclusions: This study confirms that satraplatin has anti-cancer activity in a subset of patients with mCRPC. Trials that require pre-treatment metastatic tumor biopsies are feasible. Analysis of the correlation between molecular signatures and treatment response will be presented at the meeting. Clinical trial information: NCT01289067.

La présence de lésions sur l'ADN contribue à déstabiliser sa structure, bloquant certains processus vitaux pour la cellule. Ces altérations peuvent cependant avoir un intérêt thérapeutique, par exemple dans le cas de l'utilisation d'anticancéreux tels que les dérivés du platine. Les adduits volumineux qu'ils génèrent, s'ils ne sont pas réparés, entraînent la cellule vers l'apoptose. La compréhension de la réponse à ces anticancéreux passe par l'étude des protéines qui interagissent directement avec les dommages, et dont l'ensemble constitue l'interactome des lésions de l'ADN. Ce travail de thèse présente le développement d'outils destinés à compléter la liste des protéines associées aux adduits du platine. Dans un premier temps, nous avons utilisé un piège à protéines (ligand fishing) constitué de plasmides lésés fixés sur des billes magnétiques. Trois dérivés du platine ont été sélectionnés pour générer les lésions : le cisplatine (molécule princeps), l'oxaliplatine, et le satraplatine. Ce piège a permis d'obtenir, à partir d'extraits nucléaires issus de cellules cancéreuses HeLa et grâce à une identification par protéomique, une liste de candidats comprenant des protéines déjà connues (HMGB1, hUBF, complexe FACT), mais aussi 29 nouveaux membres de l'interactome. Parmi ceux-ci, nous avons relevé PNUTS, TOX4 et WDR82, qui constituent les sous-unités du complexe PTW/PP, très récemment découvert. La présence de ce complexe a été également validée sur un modèle d'adénocarcinome mammaire MDA MB 231, et les conséquences biologiques de son interaction avec les adduits du platine devront maintenant être précisées. Dans un second temps, nous avons mis au point une biopuce permettant d'étudier les interactions ADN lésé/protéine par SPRi. Les affinités respectives d'HMGB1 et du nouveau candidat TOX4 pour les adduits des trois dérivés du platine ont pu être ainsi confirmées. Dans un dernier temps, nous avons étudié le rôle de DDB2 (acteur de la reconnaissance des photoproduits UV) dans la prise en charge des adduits platinés. Les expérimentations menées sur les cellules MDA MB 231 exprimant DDB2 de façon différentielle nous ont permis de vérifier que cette protéine ne participe pas à la réparation des adduits du cisplatine, contribuant plutôt à potentialiser l'action cytotoxique de cet agent. Dans le futur, nos microsystèmes pourront être adaptés à l'étude de l'interactome d'autres lésions de l'ADN
DNA lesions contribute to the alteration of DNA structure, thereby inhibiting essential cellular processes. Such alterations may be beneficial for chemotherapies, for example in the case of platinum anticancer agents. They generate bulky adducts that, if not repaired, ultimately cause apoptosis. A better understanding of the biological response to such molecules can be obtained through the study of proteins that directly interact with the damages. These proteins constitute the DNA lesions interactome. This thesis presents the development of tools aiming at increasing the list of platinum adduct-associated proteins. Firstly, we designed a ligand fishing system made of damaged plasmids immobilized onto magnetic beads. Three platinum drugs were selected for our study: cisplatin, oxaliplatin and satraplatin. Following exposure of the trap to nuclear extracts from HeLa cancer cells and identification of retained proteins by proteomics, we obtained already known candidates (HMGB1, hUBF, FACT complex) but also 29 new members of the platinated-DNA interactome. Among them, we noted the presence of PNUTS, TOX4 and WDR82, which associate to form the recently-discovered PTW/PP complex. Their capture was then confirmed with a second model, namely breast cancer cell line MDA MB 231, and the biological consequences of such an interaction now need to be elucidated. Secondly, we adapted a SPRi biochip to the study of platinum-damaged DNA/proteins interactions. Affinity of HMGB1 and newly characterized TOX4 for adducts generated by our three platinum drugs could be validated thanks to the biochip. Finally, we used our tools, as well as analytical chemistry and biochemistry methods, to evaluate the role of DDB2 (a factor involved in the recognition of UV-induced lesions) in the repair of cisplatin adducts. Our experiments using MDA MB 231 cells differentially expressing DDB2 showed that this protein is not responsible for the repair of platinum damages. Instead, it appears to act as a positive mediator of their cytotoxicity. In the near future, the abovementioned microsystems will be adapted to the study of the interactome of other DNA lesions

Trabalho Final de Mestrado Integrado, Ciências Farmacêuticas, Universidade de Lisboa, Faculdade de Farmácia, 2015
Os compostos de platina são, fundamentalmente, agentes quimioterápicos utilizados em monoterapia ou em terapia combinada com outros agentes sistémicos e/ou radioterapia em situações oncológicas. Os três compostos de platina aprovados pela FDA - Cisplatina, Carboplatina e Oxaliplatina são administrados por via endovenosa. A Satraplatina é o primeiro fármaco deste grupo que se administra oralmente e que se encontra sob intensa investigação clínica. A Satraplatina e o seu principal metabolito (JM-118) evidenciaram actividade anti-neoplásica in vitro, in vivo e em ensaios clínicos. A utilização da Satraplatina como alternativa enquanto agente citotóxico de platina é particularmente atrativa devido à comodidade da administração, ao perfil de toxicidade mais moderado, à ausência de resistências cruzadas com a Cisplatina, à vantagem teórica como radio-sensibilizante e à atividade em tipos de cancro que, usualmente, não respondem a fármacos de platina. Os dados clínicos mais robustos relativamente à Satraplatina provêm de um ensaio clínico de Fase III, em que foi investigada a eficácia da Satraplatina e da Prednisona em pacientes com HRPC e para os quais tenha falhado o recurso a outros agentes quimioterápicos. Esta combinação foi estatisticamente superior ao Placebo e à Prednisona em monoterapia em muitos endpoints. No entanto, as diferenças entre os grupos no parâmetro de sobrevida global não foram significativas. Nesta monografia, o objectivo principal centra-se na caracterização da Satraplatina como alternativa terapêutica no grupo dos compostos de platina, evidenciando o seu modo de ação e aplicações clínicas.

La présence de lésions sur l'ADN contribue à déstabiliser sa structure, bloquant certains processus vitaux pour la cellule. Ces altérations peuvent cependant avoir un intérêt thérapeutique, par exemple dans le cas de l'utilisation d'anticancéreux tels que les dérivés du platine. Les adduits volumineux qu'ils génèrent, s'ils ne sont pas réparés, entraînent la cellule vers l'apoptose. La compréhension de la réponse à ces anticancéreux passe par l'étude des protéines qui interagissent directement avec les dommages, et dont l'ensemble constitue l'interactome des lésions de l'ADN. Ce travail de thèse présente le développement d'outils destinés à compléter la liste des protéines associées aux adduits du platine. Dans un premier temps, nous avons utilisé un piège à protéines (ligand fishing) constitué de plasmides lésés fixés sur des billes magnétiques. Trois dérivés du platine ont été sélectionnés pour générer les lésions : le cisplatine (molécule princeps), l'oxaliplatine, et le satraplatine. Ce piège a permis d'obtenir, à partir d'extraits nucléaires issus de cellules cancéreuses HeLa et grâce à une identification par protéomique, une liste de candidats comprenant des protéines déjà connues (HMGB1, hUBF, complexe FACT), mais aussi 29 nouveaux membres de l'interactome. Parmi ceux-ci, nous avons relevé PNUTS, TOX4 et WDR82, qui constituent les sous-unités du complexe PTW/PP, très récemment découvert. La présence de ce complexe a été également validée sur un modèle d'adénocarcinome mammaire MDA MB 231, et les conséquences biologiques de son interaction avec les adduits du platine devront maintenant être précisées. Dans un second temps, nous avons mis au point une biopuce permettant d'étudier les interactions ADN lésé/protéine par SPRi. Les affinités respectives d'HMGB1 et du nouveau candidat TOX4 pour les adduits des trois dérivés du platine ont pu être ainsi confirmées. Dans un dernier temps, nous avons étudié le rôle de DDB2 (acteur de la reconnaissance des photoproduits UV) dans la prise en charge des adduits platinés. Les expérimentations menées sur les cellules MDA MB 231 exprimant DDB2 de façon différentielle nous ont permis de vérifier que cette protéine ne participe pas à la réparation des adduits du cisplatine, contribuant plutôt à potentialiser l'action cytotoxique de cet agent. Dans le futur, nos microsystèmes pourront être adaptés à l'étude de l'interactome d'autres lésions de l'ADN.