l-744832 and Neoplasms

Farnesyltransferase inhibitors, butyrate and butyric acid derivatives have previously been reported to exert anti-tumor activity in experimental models in vitro and in vivo and have recently gained acceptance as potential anticancer agents. In our study, we examined antitumor effects of a combination of a farnesyltransferase inhibitor L-744,832 and butyrate in vitro against MDA-MB-231 and MIA PaCa-2 human cancer cells. This combination therapy showed synergistic antitumor activity against MDA-MB-231 cells, which was at least in part due to induction of p27KIP1 expression. Both drugs increased intracellular levels of p53 as well but there was no significant difference between the groups treated with single drugs and the group treated with their combination. In MIA PaCa-2 cells, the combination therapy exerted additive antitumor activity. Our results illustrate possible application of the farnesyltransferase inhibitor L-744,832 and butyrate as a combination therapy of cancer.

Topics: Alkyl and Aryl Transferases; Antineoplastic Agents; Butyrates; Cell Cycle Proteins; Cell Line, Tumor; Cell Proliferation; Cyclin-Dependent Kinase Inhibitor p27; Drug Therapy, Combination; Farnesyltranstransferase; Humans; Methionine; Neoplasms; Tumor Suppressor Protein p53; Tumor Suppressor Proteins

Many tumors contain extensive regions of hypoxia. Because hypoxic cells are markedly more resistant to killing by radiation, repeated attempts have been made to improve the oxygenation of tumors to enhance radiotherapy. We have studied the oxygenation of tumor xenografts in nude mice after treatment with the farnesyltransferase inhibitor L744,832. Hypoxia was assessed by measuring the binding of the hypoxic cell marker pentafluorinated 2-nitroimidazole. We show that xenografts from two tumor cell lines with mutations in H-ras had markedly improved oxygenation after farnesyltransferase treatment. In contrast, xenografts from two tumors without ras mutations had equivalent hypoxia regardless of treatment. The effect on tumor oxygenation could be detected at 3 days and remained after 7 days of treatment. These results indicate that treatment with farnesyltransferase inhibitors can alter the oxygenation of certain tumors and suggest that such treatment might be useful in the radiosensitization of these tumors.

Topics: Alkyl and Aryl Transferases; Animals; Antineoplastic Agents; Cell Hypoxia; Enzyme Inhibitors; Farnesyltranstransferase; Gene Expression; Genes, ras; HT29 Cells; Humans; Methionine; Mice; Mice, Nude; Mutation; Neoplasms; Oxygen; ras Proteins; Xenograft Model Antitumor Assays