Comparative cytotoxicity of oxaliplatin and cisplatin in non-seminomatous germ cell cancer cell lines

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Abstract
Approximately 70-80% of patients with metastatic testicular cancer will become disease free with cisplatin-based chemotherapy and most of these patients will be longterm survivors. Despite these impressive results, the two limitations of cisplatin are its severe and potentially long-term side-effects, and the emergence of drug resistance which prevents a small proportion of these patients from achieving long-term remission. Oxaliplatin has an improved toxicity profile compared to cisplatin and contains the diaminocyclohexane (DACH) substituent known to be correlated with a lack of cross resistance with cisplatin. A phase II study has shown interesting activity when used in combination with cisplatin in cisplatin-refractory testicular cancer patients. Here we report the results of the first in vitro study investigating whether oxaliplatin as a single agent exhibits cross-resistance to cisplatin in a panel of non-seminomatous germ cell tumor (NSGCT) cell lines using short and long-term drug exposures in a five-day sulfhodamine B in vitro cytotoxicity assay. Oxaliplatin cytotoxicity was significantly superior to cisplatin in cell lines with both acquired (H12DDP) and intrinsic (1777NR Cl-A) intermediate level resistance to cisplatin. Following 24h or 96h drug exposure the fold resistance in H12DDP and 1777NR Cl-A was 1.7-2.2 with oxaliplatin compared to 3.9-6.1 with cisplatin. The cytotoxic activity of oxaliplatin was not significantly different from that of cisplatin in cisplatin-senstive cell lines or in cell lines with a high level (10-20 fold) of cisplatin resistance. The results of this study suggest that further pre-clinical studies in NSGCT are of interest, particularly in combination with cisplatin, ifosfamide and etoposide. Furthermore, the in vitro results support the use of an oxaliplatin administration schedules giving prolonged drug exposure, such as the flat or circadian rhythm-modulated schedule already under investigation for oxaliplatin.