Pre-clinical activity of taxol in non-seminomatous germ cell tumor cell lines and nude mouse xenografts.
Taxol (Paclitaxel) is a novel anti-cancer drug which has shown excellent clinical activity in a variety of solid tumors, particularly in metastatic breast and ovarian cancer. 70-80% of patients with metastatic non-seminomatous germ cell tumor (NSGCT) attain disease-free status with standard cisplatin-based combination chemotherapy but the emergence of drug resistance still prevents a small proportion of these patients from achieving long-term remission. Here we report the results of pre-clinical studies investigating whether taxol exhibits cross-resistance to cisplatin or ifosfamide in human NSGCT cell lines and in a cisplatin refractory xenograft model of human NSGCT. Following 96-h drug exposure in a 5-day sulphohodamine B (SRB) in vitro assay, taxol demonstrated potent cytotoxicity in cell lines which were cisplatin sensitive (577 LM, H32, H12.1; mean IC50s 1.5-3.0 nM) or those with acquired or intrinsic cisplatin resistance (H12DDP, H23.1; mean IC50s 2.5 nM). Compared to the drug-sensitive cell line, H12.1, the IC50 values of taxol were increased in cell line 1777NRp Cl-A with intermediate level resistance to cisplatin and ifosfamide (4.7 nM; p > 0.05) and significantly elevated in cell line 1411HP, with a high level of cisplatin resistance (6.9 nM; p < 0.01). The latter 2 cell lines may represent models corresponding to patients relapsing after high-dose platinum-based chemotherapy who seem to be resistant to taxol therapy. The IC50s of taxol in H32 and H12DDP were approximately 100-fold lower following drug exposure 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 significant anti-tumor activity observed at a dose of 15 mg/kg/d injected intravenously on days 1 through 5. The results of this study are in accordance with the most recent clinical data which showed that taxol is a useful drug in relapsed or cisplatin-refractory testicular germ cell cancer, with significant anti-tumor activity being observed in 25% of patients, but poor activity in patients previously treated with high-dose therapy. Further pre-clinical research, especially using models such as 1411HP and 1777NRp Cl-A, on the combinations of taxol with other regimens are required to enable successful treatment of the most drug-resistant relapsed germ cell tumors.
Dunn
T A
TA
Hannover Medical University, Department of Hematology and Oncology, Germany.
Grünwald
V
V
Bokemeyer
C
C
Casper
J
J
D000818:Animals; D002945:Cisplatin / Q000627:therapeutic use; D054278:Embryonal Carcinoma Stem Cells; D018237:Germinoma / Q000188:drug therapy*; D006801:Humans; D007069:Ifosfamide / Q000627:therapeutic use; D066298:In Vitro Techniques; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D014411:Neoplastic Stem Cells; D017239:Paclitaxel / Q000627:therapeutic use*; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
D017239:Paclitaxel; D002945:Cisplatin; D007069:Ifosfamide