METHIONINE STARVATION MODULATES THE EFFICACY OF CISPLATIN ON HUMAN BREAST-CANCER IN NUDE-MICE

There are few agents with activity against metastatic breast cancer We therefore exploited the elevated methionine dependence of tumors to d evelop a selective and effective therapy against metastatic breast and other cancers. Methionine starvation leads to depleted methionine lev els in cells, modifies methylation reactions, lowers glutathione level s and alters folate distribution and leads to a tumor-selective cell c ycle arrest in late-S/G(2). These effects present the opportunity for methionine depletion to modulate the efficacy of a number of different classes of chemotherapeutic drugs. This report demonstrates that meth ionine depletion can strongly modulate the efficacy of cisplatin again st the MX-1 human breast carcinoma cell line when grown in nude mice. The tumor-bearing nude mice were subjected to a methionine-free diet a nd were additionally treated with cisplatin i.p. at one mg/kg once a w eek for 3 weeks. The MX-1 tumor was relatively resistant to both methi onine starvation and cisplatin alone brit was very sensitive to the co mbination of methionine starvation and cisplatin with a 32. 1% T/C rat io. The intratumoral platinum concentration was higher in combination with methionine starvation than cisplatin alone, possibly accounting f or at least part of the modulating effect of methionine depletion. Fut ure studies will focus on methionine depletion via the enzyme methioni nase to modulate cisplatin as well as other classes of chemotherapeuti c agents in order to develop a new approach to the treatment of cancer .