MODULATION OF CYTOSTATIC DRUGS BY NIFEDIPINE IN 2 HETEROTRANSPLANTED HUMAN TESTICULAR-CANCER CELL-LINES DIFFERING IN THEIR SENSITIVITY TO STANDARD AGENTS

Drug resistance is an important clinical problem in testicular cancer patients with relapsed or refractory disease after first-line chemothe rapy. Here we report that the relative reduction in tumour volume in n ude mice heterotransplanted with either H 12.1 or H 23.1 human testicu lar cancer cell lines was significantly increased by addition of the c alcium antagonist nifedipine to the maximum tolerated dose (MTD) of ci splatin (DDP). The mean reduction in relative tumour volume at day 30 (rVR) reached statistical significance for both cell lines following c ombination therapy of DDP with nifedipine compared to DDP alone (55 +/ - 7% verses 12 +/- 4% for H 23.1 and 60 +/- 9% vs. 24 +/- 4% for H 12. 1). The synergistic anti-tumour activity of DDP with nifedipine has al so been confirmed in H 12.1 cells in vitro. However, in vivo, this com bination was associated with a concordant increase in therapeutic toxi city. In contrast, no improvement in in vivo anti-tumour activity was obtained by combining similar dose-schedules of nifedipine with the MT D of epirubicin, or with MTDs of vinblastine or etoposide. These resul ts are in agreement with our immunohistochemical finding that H 12.1 a nd H 23.1 do not over-express the Pgp 170 glycoprotein which mediates the multiple drug resistance (MDR) phenotype and involves both anthrac yclines and vinblastine, but not DDP. We conclude that another Pgp-MDR modulator, nifedipine, is able to increase the anti-tumour activity o f DDP in vivo and in vitro via a specific but as yet unknown mechanism , which is most likely not MDR-related. However, the increased anti-tu mour activity is, in vivo, associated with a considerable increase in overall toxicity. Further studies are necessary to decrease therapeuti c toxicity, before clinically relevant models for modifiers of DDP-res istance could possibly be applied to patients. (C) 1994 Wiley-Liss, In c.