Clinical relevance of human cancer xenografts as a tool for preclinical assessment: example of in-vivo evaluation of topotecan-based chemotherapy in a panel of human small-cell lung cancer xenografts.

摘要

Prediction of human tumor response based on preclinical data could reduce the failure rates of subsequent new anticancer drugs clinical development. Human small-cell lung carcinomas (SCLC) are characterized by high initial sensitivity to chemotherapy but a low median survival time because of drug resistance. The aim of this study was to evaluate the therapeutic relevance of a panel of human SCLC xenografts established in our laboratory using one compromising drug in SCLC, topotecan (TPT). Six SCLC xenografts derived from six patients were used: three were sensitive to a combination of etoposide (VP16), cisplatin (CDDP), and ifosfamide (IFO), and three were resistant, as published earlier. Growth inhibition was greater than 84% for five xenografts at doses of 1-2 mg/kg/day. TPT was combined with IFO, etoposide (VP16), and CDDP. IFO improved the efficacy of TPT in three of the five xenografts and complete responses were obtained even with the less TPT-sensitive xenograft. VP16 increased the efficacy of two of four xenografts and complete responses were obtained. The combination of TPT and CDDP did not improve TPT responses for any of the xenografts tested. Semiquantitative reverse transcriptase-PCR of genes involved in drug response, such as topoisomerase I, topoisomerase IIalpha, multidrug resistance 1 (MDR1), multidrug resistance-associated protein (MRP), lung resistance-related protein (LRP), and glutathione S-transferase pi (GSTpi), did not explain the variability in drug sensitivity between SCLC xenografts. In conclusion, these preclinical data mirror those from published clinical studies suggesting that our panel of SCLC xenografts represents a useful tool for preclinical assessment of new treatments.