Ras inhibitors and radiation therapy.
Jones HA., Hahn SM., Bernhard E., McKenna WG.
Local recurrence after a definitive course of radiation therapy remains a significant clinical problem and represents a common pattern of failure for many solid tumors. The sensitivity of tumor cells to the cytotoxicity of ionizing radiation is thought to be one of the major determinants of local control for tumors in patients treated with radiation therapy. There is substantial experimental evidence to demonstrate that increased radiation resistance is associated with the expression of activated oncogenes, including Ras. Mutated forms of Ras are found in 30% of human cancers including a substantial proportion of pancreatic and colon adenocarcinomas. Mutated Ras produces proteins that remain locked in a constitutively active state, thereby relaying uncontrolled signals. Ras proteins are guanosine triphosphate-binding proteins that play a pivotal role in the control of many cellular processes, including growth and differentiation. Preclinical studies have shown that expression of mutant Ras increases cellular radioresistance. Ras function is dependent on its localization to the plasma membrane. This is achieved by posttranslational modifications, including the addition of a farnesyl isoprenoid moiety in a reaction catalyzed by the enzyme protein farnesyltransferase (FTase). This enzyme has become an important target for the design of new agents that target Ras. FTase inhibitors (FTIs) block the farnesylation of Ras and reverse Ras-mediated radioresistance in human cell lines. FTIs have been well tolerated in animal studies and appear not to cause generalized cytotoxicity. There are ongoing clinical trials to determine the optimal therapeutic schedules and dose for FTIs. A phase 1 trial of the FTI L778-123 and radiotherapy has recently been completed.