Disease relevance of Poplat

• Satraplatin (JM-216), an oral platinum derivative, shows activity in lung cancer with a favourable adverse effect profile, with no neurotoxicity or nephrotoxicity [1].
• The combination of oral JM-216 and paclitaxel is well-tolerated with minimal non-hematologic and reversible hematologic toxicity [2].
• The objective of this study was to determine the safety profile and anti-tumor activity of JM-216 in patients with hormone refractory prostate cancer (HRPC) when given orally daily x 5 days [3].
• Higher doses of JM-216 are associated with more severe thrombocytopenia and delayed hematologic recovery resulting in subsequent dosing delays [2].
• CONCLUSION: For JM-216 and UFT administered at 20 mg/day and 300 mg/day over 14 days, nausea and emesis were observed as the principal dose-limiting toxicities [4].

High impact information on Poplat

• Although JM-216 had moderate activity in HRPC when given on daily basis for 5 days, it is associated with significant treatment related toxicities in this patient population [3].
• Phase II study of oral bis (aceto) ammine dichloro (cyclohexamine) platinum (IV) (JM-216, BMS-182751) given daily x 5 in hormone refractory prostate cancer (HRPC) [3].
• Dose-limiting toxicity, consisting of febrile neutropenia and grade 3 thrombocytopenia, was encountered in 2 patients at the seventh dose level (JM-216 80 mg/m2/day + paclitaxel 175 mg/m2) [2].
• There are now increasing options also for second-line therapies in the palliative treatment of HRPC, and ongoing studies on new drugs such as satraplatin and ixabepilone will define the role of these agents in this setting [5].
• Novel mechanisms of platinum drug resistance identified in cells selected for resistance to JM118 the active metabolite of satraplatin [6].

Chemical compound and disease context of Poplat

• Phase III trial of satraplatin, an oral platinum plus prednisone vs. prednisone alone in patients with hormone-refractory prostate cancer [7].
• PURPOSE: The goal of this study was to identify molecular determinants of sensitivity and resistance to JM118, the active metabolite of satraplatin, an orally bioavailable cisplatin analog that has activity in prostate cancer [6].

Biological context of Poplat

• This phase I study was conducted to determine the dose limiting toxicity, maximum tolerated doses, and recommended phase II doses of the combination of JM-216 and paclitaxel [2].
• The presence of several different platinum-containing species and very little intact parent drug in the systemic circulation indicates extensive biotransformation of satraplatin in vivo [8].
• Pharmacokinetics of satraplatin (JM216), an oral platinum (IV) complex under daily oral administration for 5 or 14 days [9].

Anatomical context of Poplat

• After the addition of drug to red blood cells that had been prepared from whole blood and suspended in 0.9% NaCl, satraplatin also disappeared very rapidly [8].
• METHODS: Satraplatin was incubated in solution with heme proteins and liver microsomes [10].
• The enthusiasm for oral anticancer agents and the therapeutic importance of platinum compounds has led to the development of JM216 (satraplatin), a novel platinum IV coordination complex with oral activity in cisplatin-resistant cell lines, which is now in phase III trials in prostate cancer [11].

Associations of Poplat with other chemical compounds

• JM118 is the most abundant species found in the plasma following the oral ingestion of satraplatin and has anti-tumor activity in vitro against cell lines that are resistant to cisplatin (DDP) [12].
• PURPOSE: To determine the feasibility, maximal tolerated doses, and response rates for a combined regimen of the platinum and 5-fluorouracil oral analogues bis-acetato-ammine-dichloro-cyclohexyl-amine platinum(IV) (JM-216) and uracil/ftorafur (UFT) coadministered as a 14 consecutive-day every 28-day schedule [4].
• Cytochrome c and liver microsomes also reduced satraplatin to JM118 in a manner that depended upon the presence of NADH and was inhibited by carbon monoxide [10].
• Satraplatin plus prednisone is being investigated in a large Phase III trial as second-line chemotherapy for HRPC [13].
• However, for doublets with docetaxel or second-line chemotherapy, multiple studies have shown interesting and promising results with calcitriol, thalidomide, bevacizumab, satraplatin, vaccines, ixabepilone, and atrasentan [14].

Gene context of Poplat

• Satraplatin activation by haemoglobin, cytochrome C and liver microsomes in vitro [10].
• RESULTS: In fresh human whole blood in vitro, satraplatin concentrations fell very rapidly, resulting in a half-life for the disappearance of the drug of only 6.3 min (95% CI, 5.9 to 6.7 min) [8].

Analytical, diagnostic and therapeutic context of Poplat

• Combination chemotherapy involving orally administered etoposide and JM-216 in murine tumor models [15].
• Satraplatin was much more stable in fresh human plasma (t(1/2) 5.3 h) and fully supplemented cell culture medium (t(1/2) 22 h) [8].
• The activities of LA-12 in all doses and all used tumor xenografts were higher than equimolar doses of satraplatin [16].
• In addition, a randomized trial suggested that satraplatin plus prednisone improved progression-free survival compared with prednisone alone [13].
• Satraplatin entered clinical trials in 1992 and is now undergoing Phase III evaluation [17].

References