Summary JM216 (bis-acetato ammine dichloro cyclohexylamine Pt IV) is an oral platinum complex presently undergoing phase II clinical trials. Previous studies have identified some of its biotransformation products in clinical materials. This study evaluated the nature of JM216 biotransformation products intracellularly in two different human ovarian carcinoma cell lines, one relatively sensitive to platinum agents (CH1: JM216 4 h IC50 of 5.8 gM) and the other relatively resistant (SKOV3: JM216 4 h IC50 of 60.7 gM). Metabolic profiles were also evaluated at different growth status and in cells pretreated with buthionine sulphoximine (BSO), an agent known to decrease intracellular glutathione levels. Results showed that JM216 enters the cells and that the nature and percentage of biotransformation products was dependent upon glutathione levels. Furthermore, results support the view that the previously reported peak A biotransformation product contains a glutathione adduct. In exponentially growing SKOV3 cells which contain higher glutathione levels than CHI, (82.5 vs 37.8 nmol mg-' protein), peak A represented 89% of total platinum 4 h after JM216 exposure compared with only 24% in CHI. Moreover, 60-70% depletion of glutathione achieved by 24 h pretreatment of cells with BSO resulted in a significant decrease in peak A in both cell lines and increased the cytotoxicity of JM216 in both CHI and SKOV3 by approximately 2-fold. Following a 4 h exposure of exponentially growing SKOV3 cells to JM216, only peak A (89%) and JM216 (11%) could be detected whereas in CHI cells, peak A (24%), JM216 (73%) and JM118 [cis-ammine dichloro (cyclohexylamine) platinum II] (3%) were detected. However, in CH1 cells at confluence, where glutathione is lower (8 nmol mg-' protein) four metabolites (plus JM216 itself) were detected following exposure to 50 tM JM216; peak A, JM1 18, JM383 (bis-acetato ammine (cyclohexylamine) dihydroxy platinum IV) and an unidentified metabolite (D), also observed in patient's plasma ultrafiltrate. In confluent SKOV3 cells exposed to 50 pM JM216, peak A, JM216 and JM1 18 were detected. A further unidentified metabolite observed in patients receiving JM216 (metabolite F) was not formed inside these tumour cells. Overall, these data suggest that glutathione conjugation represents a major deactivation pathway for JM216.
JM216 [bis-acetato-ammine-dichloro-cyclohexylamine-platinum(IV)] is an oral platinum complex that is currently in phase II trials in ovarian cancer and lung cancer on a daily-times-5 schedule. This trial examined an alternative schedule of two doses given 12 h apart, which may be better tolerated by patients. A total of 19 patients were given 50 cycles of treatment at doses ranging from 150 to 350 mg/m2 b.i.d. The study was stopped before the MTD was reached due to non-linear pharmacokinetics. Toxicity was similar to that encountered in previous phase I studies, with nausea, vomiting and diarrhoea being seen at all dose levels, although this was generally mild and short-lived, and grade 3 and 4 myelosuppression being seen at dose levels ranging from 250 to 350 mg/m2. There was no nephro-, oto-, or neurotoxicity, but one patient had an allergic reaction at 300 mg/m2 on the fifth and sixth cycles. No response was seen, but two patients with mesothelioma had stable disease and received six cycles. There was considerable interpatient variability in plasma pharmacokinetics at all dose levels. There was no relationship between dose and AUC (dose 1 and dose 2) or Cmax after dose 1. In a limited number of patients the first dose was given in the morning rather than in the evening, apparently resulting in lower AUC, Cmax and Tmax values at the 250-mg/m2 dose level, but this was not seen in one patient at 300 mg/m2. This study confirms that the pharmacokinetics of JM216 is non-linear and highly variable due to saturable absorption and that the daily times 5 schedule is the optimal schedule for further phase II trials.
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