Modifications of etoposide induced toxicity by 2-deoxy-D-glucose in murine tumors

Earlier studies have shown that 2-deoxy-D-glucose (2-DG), a glucose analogue and inhibitor of glycolytic ATP production, significantly enhances the cytotoxic effects of certain anticancer agents like topoisomerase inhibitors (etoposide and camptothecin) and a radiomimetic drug (bleomycin) in established human tumor cell lines. Therefore, combinations of 2-DG and DNA damage causing cytotoxic agents could be very useful in selectively destroying tumors, while sparing the normal tissues. The purpose of the present studies was to investigate the therapeutic effects of etoposide and 2-DG in Dalton's lymphoma and Ehrlich ascites tumor cells (EAT) in vivo (grown as solid tumor as well as in the ascites form in mice). Cell growth, cell cycle perturbations (flow cytometry), cytogenetic damage (micronuclei assay) and apoptosis (DNA content, light-scatter, morphological changes) were studied as parameters of cellular response, while delay in tumor growth and cure rate (tumor free survival) were evaluated as parameters of systemic response. Intravenous administration of etoposide (30 mg/Kg b. wt.) delayed the growth of both the tumors but a cure rate of ∼11% was observed only in subcutaneous EAT bearing mice. When etoposide was combined with 2-DG (2 g/Kg b. wt.; i.v; 4 h after etoposide injection), these effects were further enhanced in subcutaneous EAT bearing mice resulting in a cure rate of ∼22% but not in lymphoma bearing mice. Analysis of cells obtained from ascitic fluid as well as solid tumors during follow up clearly showed that etoposide induced cell death was mainly due to apoptosis in EAT as well as in lymphoma, which was enhanced further by 2-DG in EAT bearing mice. These results indicate that the combined treatment of etoposide and 2-DG can improve local control of tumors, thereby enhancing the treatment efficacy. Further studies are required to understand the mechanisms of chemosensitization by 2- DG both in vitro and in vivo.