Oxaliplatin and cisplatin cause similar chromosomal changes in H69 SCLC cells: linking changes in genotype to the resistant phenotype

Chromosomal rearrangement has been studied in drug resistant cancer cell lines and in tumour samples from cancer patients. Many rearrangements have been observed, however what is less clear is the relationship between these rearrangements and the drug resistant phenotype. Are these changes in karyotype the cause of the drug resistance or are they a side effect of exposure to DNA targeted chemotherapeutics and not directly responsible for the resistance? We have developed a clinically relevant model of low level cisplatin and oxaliplatin resistance in human H69 small cell lung cancer cells. These cells are stably 2-fold resistant to both platinum drugs for 8 weeks in drug free culture, then they revert to a non-resistant phenotype. We have performed an Affymetrix 10K SNP Array and cytogenetic analysis to characterise the chromosomal changes in these resistant cell lines. Many chromosomal differences were found between the parental and resistant cell lines. The largest rearrangement associated with the development of platinum drug resistance was on chromosome 6, where both cisplatin and oxaliplatin have independently caused similar chromosomal breakages at 6q21 and a decrease in copy number distal to this breakpoint. This may indicate the presence of tumour suppressor genes between 6q21-qter. Other changes in common between the two drug resistant cell lines include +21 and -13pter-13q.14.11. The oxaliplatin resistant cell line had a greater number of minor changes including losses from the p arm of the X chromosome. Examining the chromosomal differences again after the loss of resistance should make clear which rearrangements are associated with the drug resistance phenotype and which are a by-product of the development of resistance. We have also compared our data from the Affymetrix array, to mRNA expression of 1000 genes associated with the stress response to chemotherapeutics and found no association for this subset of genes. This paper presents for the first time a DNA array and cytogenetic profile of the H69 small cell lung cancer cell line which harbours a large c-myc amplification. This is also the first cytogenetic analysis of an oxaliplatin resistant cell line.

Proc Amer Assoc Cancer Res, Volume 47, 2006