Methionine dependence of tumours: a biochemical strategy for optimizing paclitaxel chemosensitivity in vitro.

Methionine dependence is a unique feature of cancer cells characterized by growth and cell cycle arrest (typically in S and G2/M) under conditions of methionine depletion. Following replenishment of media with methionine, the cell cycle blockade is reversible and during this recovery period, cells may become more susceptible to the action of cell cycle specific drugs. The response of a panel of methionine dependent (HTC, Phi-1, PC3 and 3T3) cells to vinblastine and paclitaxel was compared to methionine independent Hs-27 cells under conditions of methionine depletion (M-H+; methionine depleted media supplemented with homocysteine) and starvation (M-H-; media without methionine or homocysteine).

Cellular parameters predictive of the clinical response of colorectal cancers to irinotecan. A preliminary study.

Background: We have examined, in this study, the feasibility of determining cellular factors contributing to irinotecan activity in colorectal cancers. Irinotecan is a camptothecin derivative requiting carboxylesterase activation to SN-38, which interacts with its target enzyme, topoisomerase I.

Materials And Methods: In 9 surgical or biopsy samples of colorectal tumours and corresponding normal tissue, kept in a tumour bank, we evaluated topoisomerase I expression and activity, respectively by Western blotting and DNA relaxation assay, carboxylesterase activity using two different substrates and p53 status by immunohistochenistry.

Analysis of cell-cycle kinetics and sulfur amino acid metabolism in methionine-dependent tumor cell lines; the effect of homocysteine supplementation.

Methionine dependence is a feature unique to cancer cells, exhibited as inability to grow in a methionine-depleted environment supplemented with homocysteine, the immediate metabolic precursor of methionine. This study explores the effect of methionine depletion and homocysteine supplementation on the viability, sulfur amino acid metabolism and cell-cycle kinetics of normal and cancer cells, as well as their ability to recover from the treatments. An array of cells including hepatomas (HTC, Phi-1), prostate adenocarcinomas (PC-3) and transformed (3T3) and normal (HS-27) fibroblasts, has been used aiming to evaluate the importance of tissue specificity.

Determinants of the cytotoxicity of irinotecan in two human colorectal tumor cell lines.

Purpose: Irinotecan is a drug of the camptothecin family that has proven activity in advanced colon cancer, with about 20% responses in untreated as well as in 5-fluorouracil-resistant tumors. Irinotecan is considered as a prodrug which needs to be activated to SN-38 by carboxylesterases to become able to interact with its target, topoisomerase I. The work reported here intended to identify the determinants of the cytotoxicity of irinotecan in two human colorectal tumor cell lines, LoVo and HT-29, at the level of the target of the drug and at the level of the availability of the active metabolite to the target.