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

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.

• Authors: C Ottoboni, A Crippa, C Falugi, P Russo
• Journal: Mutagenesis (Mutagenesis) Vol. 16 Issue 5 Pg. 423-30 (Sep 2001) ISSN: 0267-8357 [Print] England
• PMID: 11507242 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Enzyme Inhibitors
• Indoles
• RPR115135
• Alkyl and Aryl Transferases
• Farnesyltranstransferase

Topics

• Alkyl and Aryl Transferases (antagonists & inhibitors)
• Animals
• Chick Embryo
• Drug Resistance, Neoplasm (genetics)
• Enzyme Inhibitors (toxicity)
• Farnesyltranstransferase
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Indoles (toxicity)
• Micronuclei, Chromosome-Defective (drug effects, enzymology, metabolism)
• Molecular Mimicry
• Mutagenesis (genetics, physiology)
• Time Factors
• Tumor Cells, Cultured