l-744832 and Colonic-Neoplasms

Ras oncogenes are found in 25% of human tumors and they significantly affect prognosis. One of the major fields studied to improve anticancer drugs is blockade of the oncogenic ras protein function. One of the mechanisms to block the function of these proteins is to block farnesylation using a farnesyl transferase inhibitor (FTI) and thus to prevent the ras from anchoring to the cell membrane.. In this study, we investigated the effects of FTI L-744,832 either alone or in combination with 5-fluorouracil (5-FU; 1 microM/l) and radiotherapy (2, 6, and 10 Gy) on the colon cancer cell line DLD-1 with mutations in K-, N- and H-ras, c-myb, c-myc, p53, fos, sis and DNA repair genes. Drugs were added 3 h after cultivation. Radiotherapy was performed on the 3rd day of the study. On the 3rd day, medium and drugs were changed. Evaluations were performed on the 6th day.. Administration of L-744,832, neither alone nor its combination with 5-FU and radiation, affected the number of DLD-1 cells and apoptosis rates. Regarding its effects on the cell cycle, L-744,832 was shown to lead to G(0)/G(1) and G(2)/M accumulation in a dose-dependent manner when administered alone. However, in combination with 5-FU, only a G(0)/G(1) accumulation was observed.. Our study showed that FTI L-744,832 does not effect the cell number and apoptosis rate of DLD-1 cells and it cannot overcome 5-FU and radiation resistance, although it is able to modify some phases of the cell cycle.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Cell Cycle; Cell Line, Tumor; Colonic Neoplasms; Combined Modality Therapy; Farnesyltranstransferase; Fluorouracil; Humans; Methionine; Radiation Tolerance

Successful radiosensitization requires that tumor cells become more radiosensitive without causing an equivalent reduction in the survival of cells of the surrounding normal tissues. Since tumor cell radiosensitivity can be influenced by RAS oncogene activation, we have hypothesized that inhibition of oncogenic RAS activity would lead to radiosensitization of tumors with activated RAS. We previously showed in tissue culture that prenyltransferase treatment of cells with activated RAS resulted in radiosensitization, whereas treatment of cells with wild-type RAS had no effect on radiation survival. Here we ask whether the findings obtained in vitro have applicability in vivo. We found that treatment of nude mice bearing T24 tumor cell xenografts with farnesyltransferase inhibitors resulted in a significant and synergistic reduction in tumor cell survival after irradiation. The regrowth of T24 tumors expressing activated RAS was also significantly prolonged by the addition of treatment with farnesyltransferase inhibitors compared to the regrowth after irradiation alone. In contrast, there was no effect on the radiosensitivity of HT-29 tumors expressing wild-type RAS. These results demonstrate that specific radiosensitization of tumors expressing activated RAS oncogenes can be obtained in vivo.

Topics: Alkyl and Aryl Transferases; Animals; Colonic Neoplasms; Enzyme Inhibitors; Farnesyltranstransferase; Gene Expression Regulation, Neoplastic; Genes, ras; Humans; Methionine; Mice; Mice, Nude; Neoplasm Recurrence, Local; Neoplasm Transplantation; Radiation-Sensitizing Agents; Tumor Cells, Cultured; Tumor Stem Cell Assay; Urinary Bladder Neoplasms