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 develop a selective and effective therapy against metastatic breast and other cancers. Methionine starvation leads to depleted methionine levels in cells, modifies methylation reactions, lowers glutathione levels and alters folate distribution and leads to a tumor-selective cell cycle arrest in late-S/G2. 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 methionine depletion can strongly modulate the efficacy of cisplatin against the MX-t human breast carcinoma cell line when grown in nude mice. The tumor-bearing nude mice were subjected to a methionine-free diet and were additionally treated with cisplatin i.p. at one mg/kg once a week for 3 weeks. The MX-t tumor was relatively resistant to both methionine starvation and cisplatin alone but was very sensitive to the combination of methionine starvation and cisplatin with a 32.1% T/C ratio. The intratumoral platinum concentration was higher in combination with methionine starvation than cisplatin alone, possibly accounting for at least part of the modulating effect of methionine depletion. Future studies will focus on methionine depletion via the enzyme methioninase to modulate cisplatin as well as other classes of chemotherapeutic agents in order to develop a new approach to the treatment of cancer.