Cytogenetic alterations associated with the acquisition of doxorubicin resistance: possible significance of chromosome 7 alterations

Abstract

Cytogenetic abnormalities associated with the acquisition of doxorubicin (DOX) resistance (DOXR) were examined in two cell lines (HT1080 fibrosarcoma and LoVo colon adenocarcinoma) which were selected in the presence of increasing concentrations of DOX over a 2-year period. Karyotypes of both tumor lines were initially near-diploid although they differed significantly in their intrinsic sensitivities to DOX (DOX 50% inhibiting concentrations: LoVo, 0.10 micrograms/ml; HT1080, 0.006 microgram/ml). Chromosome banding analysis of DOXR sublines of the LoVo and HT1080 cell lines demonstrated a strikingly different response to DOX selection with regard to both numeric and structural chromosome alterations. DOXR LoVo cells maintained the parental modal chromosomal number of 49 despite a 285-fold increase in the level of resistance, with minimal structural chromosome changes observed. In contrast, the development of DOXR in HT1080 cells was accompanied by marked aneuploidy, including a significant increase in the complexity of the tumor karyotype with increasing levels of DOXR. Cytogenetic evidence suggestive of gene amplification (double minutes and homogeneously staining regions) was also observed in the DOXR HT1080 cell line. Examination of chromosome alterations common to both resistant lines revealed alterations of chromosomes 1, 5, 7, and 11, with chromosome 7q the most frequent site of chromosome change. Reversion of DOXR in both the HT1080 and LoVo cell lines (by continuous in vitro passage once off drug) resulted in an accompanying loss in structurally altered No. 7 chromosomes. Our data suggest that alterations of chromosome 7 are a common and perhaps significant feature of DOXR tumor cells.