Methionine depletion enhances the antitumoral efficacy of cytotoxic agentsin drug-resistant human tumor xenografts

Efficacy of chemotherapy is limited in numerous tumors by specific cellular mechanisms that inactivate cytotoxic antitumoral drugs, such as ATP-depend ent drug efflux and/or drug detoxification by glutathione. In reducing ATP pools and/or glutathione synthesis, it might be possible to enhance the eff icacy of drugs affected by such resistance mechanisms. Reduction of the ATP pool and glutathione content is achievable in cancer cells by depleting th e exogenous methionine (Met) supply and ethionine, Thus, the rationale for the present study was to use Met depletion to decrease the ATP and glutathi one pools so as to sensitize tumors refractory to cytotoxic anticancer drug s. Met depletion was achieved by feeding mice a methionine-free diet supple mented with homocysteine. The effects of Met depletion combined with ethion ine and/or chemotherapeutic agents were studied using human solid cancers x enografted into nude mice, TC71-MA (a colon cancer) SCLC6 (a small cell lun g cancer), and SNB19 (a glioma) were found to be refractory to cisplatin, d oxorubicin, and carmustine, respectively, These three drugs are used to tre at such tumors and are dependent for their activity on the lack of cellular ATP- or glutathione-dependent mechanisms of resistance. TC71-MA, SCLC6 and SNB19 were Met dependent because their proliferation in vitro and growth i n vivo were reduced by Met depletion, Cisplatin was inactive in the treatme nt of TC71-MA colon cancer, whereas a methionine-free diet, alone or in com bination with ethionine, prolonged the survival of mice by 2-fold and 2.8-f old, respectively, When all three approaches were combined, survival was pr olonged by 3.3-fold. Doxorubicin did not affect the growth of SCLC6, a MDR1 -MRP-expressing tumor. A Met-deprived diet and ethionine slightly decreased SCLC6 growth and, in combination,vith doxorubicin, an inhibition of 51%,Fa s obtained, with survival prolonged by 1.7-fold. Combined treatment produce d greater tumor growth inhibition (74%) in SCLC6-Dox, a SCLC6 tumor pretrea ted with doxorubicin. Growth of SNB19 glioma was not inhibited by carmustin e, but when it was combined with Met depletion, survival duration was prolo nged by 2-fold, with a growth inhibition of 80%. These results indicate the potential of Met depletion to enhance the antitumoral effects of chemother apeutic agents on drug-refractory tumors.