epidermal-growth-factor and 2-oxothiazolidine-4-carboxylic-acid

Glutathione has been implicated in growth factor-mediated chemoresistance of colon cancer cells.. 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.. 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.. 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.

Topics: Antineoplastic Combined Chemotherapy Protocols; Buthionine Sulfoximine; Camptothecin; Cell Growth Processes; Cell Line, Tumor; Colonic Neoplasms; Drug Synergism; Epidermal Growth Factor; Fluorouracil; Glutathione; Hepatocyte Growth Factor; Humans; Intercellular Signaling Peptides and Proteins; Irinotecan; Organoplatinum Compounds; Oxaliplatin; Pyrrolidonecarboxylic Acid; Thiazolidines; Vascular Endothelial Growth Factor A

A common cause of treatment failure in colorectal cancer is chemoresistance, which may be related to the redox state of cancer cells and the tumour microenvironment, where growth factors (GFs) play an important role. Glutathione (GSH), a key regulator of the redox balance, is involved in GF signalling systems and may also protect against drug-induced cellular injury.. The effect of GSH modulation on 5-fluorouracil (5-FU) activity on the WiDr colon cancer cell line was studied. Cell proliferation and GSH content were assessed. Cells were exposed to the GSH modulators, L-buthionine-SR-sulfoximine (BSO) or L 2 oxothiazolidine-4-carboxylate (OTZ), before treatment with 5-FU in the presence of hepatocyte growth factor (HGF), vascular endothelial growth factor (VEGF) or epidermal growth factor (EGF).. Exposure to GFs significantly increased GSH levels and induced a pro-tumour effect. During the first 48 h of incubation, VEGF and EGF induced a near 30% reduction in 5-FU antitumour activity, while exposure to HGF abrogated the drug-induced growth inhibition. Treatment with OTZ and BSO abrogated the growth-promoting effects of GFs. Moreover, the addition of either of the GSH modulators to 5-FU produced an increase of nearly 40% in the 5-FU activity in the case of HGF or VEGF, and a 25% increase in the case of EGF.. GSH manipulation could yield a therapeutic gain for chemotherapy with 5-FU in the presence of GFs.

Topics: Buthionine Sulfoximine; Cell Growth Processes; Cell Line, Tumor; Colonic Neoplasms; Epidermal Growth Factor; Fluorouracil; Glutathione; Hepatocyte Growth Factor; Humans; Intercellular Signaling Peptides and Proteins; Pyrrolidonecarboxylic Acid; Thiazolidines; Vascular Endothelial Growth Factor A