Molecular Determinants of Differential Sensitivity to Docetaxel and Paclitaxel in Human Pediatric Cancer Models

Abstract

Background: The differential sensitivity of some tumors to paclitaxel and docetaxel raises questions regarding the specific mechanisms responsible for the discrepant sensitivity to these taxanes. Materials and Methods: Docetaxel and paclitaxel were evaluated and compared at maximum tolerated doses (MTD) and 0.5 MTDs against the human pediatric tumor xenograft models SK-N-MC and IMR32 (neuroblastoma), RH1 and RH30 (rhabdomyosarcoma) and KHOS/NP (osteosarcoma), with 8-10 animals per group. The drug effects on the expression of the β-tubulin isotypes, Bcl-2, Bax, Bcl-XL and proteomic profiles were evaluated by immunobloting and SELDI mass spectrometry in tumor xenografts dosed at 0.5 MTDs. Results: At MTDs, docetaxel was superior in neuroblastoma and osteosarcoma, while paclitaxel was more active in the rhabdomyosarcoma models. Docetaxel showed remarkable efficacy in KHOS/NP even at 0.5 MTD. The drugs had significantly different, yet highly heterogeneous effects on the tumor levels of β_I-tubulin (RH30), β_III-tubulin (IMR32, KHOS/NP, RH1), Bax (IMR32, SK-N-MC) and Bcl-XL (KHOS/NP). In contrast, six protein species identified by proteomic profiling were consistently and differentially regulated by docetaxel and paclitaxel in all KHOS/NP xenografts. Conclusion: Anticancer activity showed no apparent correlation with drug effects on β-tubulin isotypes and apoptotic markers. The mass spectrometry approach has potential for the discovery of proteomic biomarkers for drug sensitivity.