ras mutation and platinum resistance in human ovarian carcinomas in vitro.
A panel of 16 human ovarian carcinoma cell lines comprising cisplatin naive as well as those with acquired cisplatin resistance was studied to determine if there was a relationship between ras status and cisplatin sensitivity. From the ras expression studies alongside data produced by direct DNA sequencing, there was very little to suggest that ras overexpression or mutation plays a role in the cisplatin sensitivity of the panel of human ovarian carcinoma cell lines tested. A weak correlation (r2 = 0.53) was found between total Ras protein levels and resistance to cisplatin. No relationship was found between Kirsten-Ras protein levels and cisplatin sensitivity (r2 = 0.0). Only one ras mutation (codon 13, Kirsten exon 1, glycine --> aspartate in the HX62 cell line) was observed in the cisplatin naive cell lines from the panel which comprised both cisplatin sensitive and resistant models. Of interest, however, was that the HX62 cell line was the most resistant to cisplatin. No ras mutations were found in those cell lines which had repeatedly been exposed, and acquired resistance, to cisplatin. The A2780 and CH1 human ovarian carcinoma cell lines were transfected with activated, mutant Harvey-ras and, as a result, were shown to display elevated MAP kinase phosphorylation in low serum concentration growth medium. No changes in cisplatin sensitivity were found following transfection with activated Harvey-ras in these 2 human ovarian carcinoma tumor cell models which, importantly, differed greatly in their expression of Bcl-2. Therefore, when conducted under similar conditions to previously published studies, very little evidence was found to support Harvey-ras activation as a factor which can either sensitize or confer resistance to cisplatin in human ovarian carcinoma cell lines.
Holford
J
J
CRC Centre for Cancer Therapeutics, Institute of Cancer Research, Sutton, Surrey, UK.
Rogers
P
P
Kelland
L R
LR
D002277:Carcinoma / Q000235:genetics*; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D011905:Genes, ras; D006801:Humans; D009154:Mutation; D010051:Ovarian Neoplasms / Q000235:genetics*; D010984:Platinum / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D010984:Platinum