Induction of micronuclei by a new non-peptidic mimetic farnesyltransferaseinhibitor RPR-115135: role of gene mutations

To investigate the relationship between oncogene activation and induction o f micronuclei by a new non-peptidic mimetic farnesyltransferase inhibitor, RPR-115135, two isogenic cell lines, human colon cancer line HCT-116, which harbors a K-ras mutation, and spontaneously immortalized human breast epit helial cell line MCF-10A, were utilized. HCT-116 cells were transfected wit h an empty control pCMV vector (clone CMV-2) or with a dominant negative mu tated p53 transgene (clone Mu-p53-2) to disrupt p53 function. In both clone s RPR-115135 induced a significant increase in the frequency of micronuclea tion at concentrations that did not affect cell membrane integrity. RPR-115 135 produced a significant increase in the ratio of CREST + to CREST- micro nuclei. MCF-10A cells were stably transfected with either c-Ha-ras or c-erb B-2 or both H-ras + c-erbB-2. No induction of micronuclei was observed. No induction of micronuclei was reported in human lymphocytes and in primary s pinal cells obtained from 7-day chick embryos. In conclusion, RPR-115135 ac ts as an aneugenic agent in a complex manner, dependent upon the complement of mutations in cell regulatory genes in tumour cells and this activity ma y be independent of ras genotype.