Resistance mechanisms following cisplatin and oxaliplatin treatment of the human teratocarcinoma cell line 2102EP.

BACKGROUND Oxaliplatin and cisplatin are widely used in cancer chemotherapy, however, their clinical efficiency is often limited by the development of resistance. MATERIALS AND METHODS We examined different mechanisms of resistance in the human teratocarcinoma cell line 2102EP following exposure to cisplatin or oxaliplatin. Cells were exposed ten times with IC90-doses of 30 microM cisplatin and 50 microM oxaliplatin, respectively. Different cell clones were tested for expression of resistance using the SRB-assay. Moreover, resistance mechanisms in terms of drug uptake, platinum-adduct formation, GSH metabolism, DNA mismatch repair and p53 protein function were investigated. RESULTS Three cisplatin cell clones with significant resistance factors of 2.0 to 2.6 were found. Two oxaliplatin cell clones showed only weak resistance, with resistance factors of 1.6 and 1.7, respectively. In all three cisplatin-exposed cell clones a decreased cellular uptake of cisplatin was found. Furthermore, mechanisms of DNA damage tolerance may also play a role in the development of cisplatin-resistance in these cells. However, only two cell clones showed a decreased level of platinum-DNA-adducts. An increased DNA-repair of platinum-DNA adducts was not seen. In addition, no differences in expression of mismatch-repair proteins MSH2 and MLH1, tumor suppressor protein p53, or glutathione metabolism were found. However, significant resistance mechanisms for the observed oxaliplatin resistance could not be identified, although in one oxaliplatin-exposed cell clone, there was some evidence that a decreased cellular uptake of oxaliplatin may contribute to the observed low level resistance. CONCLUSIONS The data add weight to the hypothesis that resistance mechanisms following oxaliplatin exposure may be similar to cisplatin. The precise mechanisms of resistance in the oxaliplatin-resistant cell clones are still not fully understood and current studies are underway to further eluciate this finding.