Glutathione modulators reverse the pro-tumour effect of growth factors enhancing WiDr cell response to chemotherapeutic agents.

BACKGROUND Glutathione has been implicated in growth factor-mediated chemoresistance of colon cancer cells. MATERIALS AND METHODS We evaluated the influence of hepatocyte growth factor, vascular endothelial growth factor and epidermal growth factor on the effect of 5-fluorouracil, oxaliplatin and SN-38 (the active metabolite of irinotecan) on WiDr cells. We also analysed the effect of glutathione modulators (L-buthionine-SR-sulfoximine, and L-2-oxothiazolidine-4-carboxylate) on the growth-promoting effect induced by growth factors and on the antiproliferative activity of the aforementioned drugs. RESULTS Exposure to growth factors reduced drug cytotoxic activity, specially in the case of 5-fluorouracil. The addition of L-buthionine-SR-sulfoximine or L-2-oxothiazolidine-4-carboxylate to the chemotherapeutic agents abrogated pro-tumour effects of the growth factors, and produced a greater antitumour activity than the drugs alone. CONCLUSION Among the combinations analysed, the addition of L-2-oxothiazolidine-4-carboxylate to SN-38 was found to be the best chemotherapeutic combination, resulting in a near 70% increase in the cytotoxic activity of SN-38.