Reversal of acquired cisplatin resistance by modulation of metallothionein in transplanted murine tumors

BACKGROUND: The platinum-based chemotherapeutic agent cisplatin is involved in a broad spectrum of activities against human systemic malignancies. However, acquired resistance to cisplatin reduces its clinical efficacy. Elucidation of the molecular basis of cisplatin resistance is required to improve the effectiveness of cisplatin. In the present study, the mechanism of acquired resistance to cisplatin was studied in C3H mice inoculated with MBT-2 murine bladder tumor cells. METHODS: C3H mice were subcutaneously inoculated with 1.0 x 10(6) MBT-2 cells/mouse on day 0. The mice were given intraperitoneal injections of 10 micro mol/kg cisplatin and subcutaneous injections of 1000 micro mol/kg propargylglycine, an inhibitor of gamma-cystathionase, once a day for 10 consecutive days from day 11 to day 20. RESULTS: The metallothionein content of the tumors was increased to twice the control level by repeated administration of cisplatin. Co-administration of propargylglycine reduced metallothionein induction in the tumors and markedly enhanced the antitumor activity of cisplatin. In contrast, the glutathione content in the tumors did not change from the control level after cisplatin administration. The platinum accumulation in tumors treated with cisplatin alone was 1.7-fold greater than when propargylglycine was administered concomitantly. The platinum concentrations changed in accordance with the metallothionein contents. CONCLUSIONS: These observations suggest that metallothionein, but not glutathione or reduced platinum accumulation, might play a role in the acquired resistance to cisplatin of C3H mice inoculated with MBT-2. Moreover, reversal of this resistance might be possible by biochemical modulation of metallothionein.