[Pharmacological approach to the platinum compounds].
Cis-Diamminedichloroplatinum (II) (cisplatin) is one of the key drugs in the treatment of solid tumors. Cis-Diammine-1, 1-cyclobutanedicarboxylateplatinum (II) (carboplatin) and cis-diammine (glycolato)-platinum (254-S) are second-generation platinum-coordination complexes developed in recent years not only to reduce nephrotoxicity but also to have antitumor activity equivalent or superior to cisplatin. Comparative pharmacological study among these three compounds was performed. Six different small cell lung cancer (SCLC) and six non-small cell lung cancer (NSCLC) lines were exposed to different concentration of the three platinum compounds, cisplatin, carboplatin and 254-S in colony assay. The IC50 values for cisplatin, carboplatin and 254-wS in SCLC cell lines were significantly lower than those in NSCLC cell lines. In addition, the IC50s for carboplatin were significantly higher than those for cisplatin and 254-S in both SCLC and NSCLC lines. A total of 15 patients entered the pharmacological study. In all, 80 mg/sqm cisplatin, 450 mg/sqm carboplatin, and 100 mg/sqm 254-S were each given to five patients by intravenous drip infusion over 30 min. Ultrafilterable platinum declined biexponentially for carboplatin and 254-S, whereas the free platinum of cisplatin fitted to a monoexponential equation. We reported the equation between nadir platelet count (NPC) and Ccr, by retrospective analysis in 38 "Training Set" patients; [NPC] = 2,783.4 x [Ccr.]- [NPC] = 2,783.4 x [Ccr.]- 64,264.7. To evaluate prospectively the equation in the "Test Set" patient and to refine it. Thirty four patients who entered phase II study of 254-S for NSCLC were prospectively analysed. Significant correlation was observed between observed NPC and predicted NPC which was calculated by the equation (R = 0.51). To refine the equation, all patients in both "Training Set" and "Test Set" were reanalyzed. Simple linear least model is shown as the best fit and refined equation is as follows: [NPC] = 2,201.7 x [Ccr.]-17,695.0. Bioassay was achieved by clonogenic techniques using NCI-H-69 (SCLC cell line) and PC-9 (NSCLC cell line) as target. Biological comparison was performed on the basis of the antitumor activity of patient's plasma using the antitumor index (ATI). The ATIs obtained by bioassay showed better correlation than the AUCs obtained by chemical assay with the clinical response for the three agents against SCLC and NSCLC according to the following equation: [Reported Response(%)] = 11.5668 + 0.0014 x [ATI] (r = 0.97).
Sasaki
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Dept. of Medical Oncology, National Cancer Center.
D016190:Carboplatin / Q000493:pharmacokinetics / Q000494:pharmacology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism / Q000473:pathology; D002945:Cisplatin / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology; D009944:Organoplatinum Compounds / Q000493:pharmacokinetics / Q000494:pharmacology*; D014407:Tumor Cells, Cultured / Q000187:drug effects
D009944:Organoplatinum Compounds; C053989:nedaplatin; D016190:Carboplatin; D002945:Cisplatin