PRECLINICAL ACTIVITY OF TAXOL IN NONSEMINOMATOUS GERM-CELL TUMOR-CELLLINES AND NUDE-MOUSE XENOGRAFTS

Taxol (Paclitaxel) is a novel anti-cancer drug which has shown excelle nt clinical activity in a variety of solid tumors, particularly in met astatic breast and ovarian cancer. 70-80% of patients with metastatic non-seminomatous germ cell tumor (NSGCT) attain disease-free status wi th standard cisplatin-based combination chemotherapy but the emergence of drug resistance still prevents a small proportion of these patient s from achieving long-term remission. Here we report the results of pr e-clinical studies investigating whether taxol exhibits cross-resistan ce to cisplatin or ifosfamide in human NSGCT cell lines and in a cispl atin refractory xenograft model of human NSGCT. Following 96-h drug ex posure in a 5-day sulphohodamine B (SRB) in vitro assay, taxol demonst rated potent cytotoxicity in cell lines which were cisplatin sensitive (577 LM, H32, H12.1; mean IC5Os 1.5-3.0 nM) or those with acquired or intrinsic cisplatin resistance (H12DDP, H23.1; mean IC5Os 2.5 nM). Co mpared to the drug-sensitive cell line, H12.1, the IC50 values of taxo l were increased in cell line 1777NRp Cl-A with intermediate level res istance to cisplatin and ifosfamide (4.7 nM; p > 0.05) and significant ly elevated in cell line 1411HP, with a high level of cisplatin resist ance (6.9 nM; p < 0.01). The latter 2 cell lines may represent models corresponding to patients relapsing after high-dose platinum-based che motherapy who seem to be resistant to taxol therapy. The IC5Os of taxo l in H32 and H12DDP were approximately 100-fold lower following drug e xposure times exceeding 24 hours compared with short exposure times (1 -6 h). Dose-dependent anti-tumor activity was observed with taxol in a cisplatin-refractory xenograft model of NSGCT (H23.1), with significa nt anti-tumor activity observed at a dose of 15mg/kg/d injected intrav enously on days 1 through 5. The results of this study are in accordan ce with the most recent clinical data which showed that taxol is a use ful drug in relapsed cisplatin-refractory testicular germ cell cancer, with significant anti-tumor activity being observed in 25% of patient s, but poor activity in patients previously treated with high-dose the rapy. Further pre-clinical research, especially using models such as 1 411HP and 1777NRp Cl-A, on the combinations of taxol with other regime ns are required to enable successful treatment of the most drug-resist ant relapsed germ cell tumors.