METHIONINE DEPLETION MODULATES THE ANTITUMOR AND ANTIMETASTATIC EFFICACY OF ETHIONINE

The elevated methionine requirement for the growth of tumors, termed m ethionine dependence, is a potentially highly effective therapeutic ta rget. To attack this target we are developing anti-methionine chemothe rapy. In this study of anti-methionine chemotherapy we have observed t hat the methionine analog ethionine is synergistic with methionine dep letion in arresting the growth of the Yoshida sarcoma both in vitro an d when transplanted to nude mice. In contrast, ethionine in vitro in a methionine-containing medium is not effective against Yoshida sarcoma cells. Similarly, ethionine administered along with a methionine-cont aining diet is ineffective against the Yoshida sarcoma growing in nude mice. A methionine-depleted diet alone is only partially effective ag ainst tumor growth. The Yoshida sarcoma gave rise to metastases in 75 % of the- organs observed in the mice on the methionine-containing die t, and 43 % of the organs in the mice on the methionine-free diet. In striking contrast no metastases were observed in the ethionine-treated animals on the methionine-free diet. Anti-methionine chemotherapy con sisting of dietary methionine depletion and ethionine administration c aused an initial weight loss but the animals weight stabilized resulti ng in no animal deaths. The synergism of ethionine and methionine depl etion is markedly similar in vitro and in vivo suggesting the observed efficacy is due to the specific anti-methionine targeting. Thus methi onine depletion highly potentiates the anti-tumor and anti-metastatic effectiveness of ethionine suggesting that anti-methionine chemotherap y consisting of methionine depletion as a modulator of methionine anal ogs holds great promise as a new, tumor-selective therapeutic approach .