Induction of micronuclei by a new non-peptidic mimetic farnesyltransferase inhibitor RPR-115135: Role of gene mutations

Cristina Ottoboni, Alessandra Crippa, Carla Falugi, Patrizia Russo

Research output: Contribution to journalArticlepeer-review

Abstract

To investigate the relationship between oncogene activation and induction of 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 epithelial cell line MCF-10A, were utilized. HCT-116 cells were transfected with an empty control pCMV vector (clone CMV-2) or with a dominant negative mutated p53 transgene (clone Mu-p53-2) to disrupt p53 function. In both clones RPR-115135 induced a significant increase in the frequency of micronucleation at concentrations that did not affect cell membrane integrity. RPR-115135 produced a significant increase in the ratio of CREST + to CREST- micronuclei. MCF-10A cells were stably transfected with either c-Ha-ras or c-erbB-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 spinal cells obtained from 7-day chick embryos. In conclusion, RPR-115135 acts as an aneugenic agent in a complex manner, dependent upon the complement of mutations in cell regulatory genes in tumour cells and this activity may be independent of ras genotype.

Original languageEnglish
Pages (from-to)423-430
Number of pages8
JournalMutagenesis
Volume16
Issue number5
Publication statusPublished - 2001

ASJC Scopus subject areas

  • Genetics
  • Health, Toxicology and Mutagenesis
  • Genetics(clinical)
  • Toxicology

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