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Published on: September 8, 2017
Molecular determinants of differential sensitivity to docetaxel and paclitaxel in human pediatric cancer models
Elzbieta Izbicka1, David Campos, Jennifer Marty
1Cancer Therapy and Research Center, The Institute for Drug Development, San Antonio, TX 78245, USA. eizbicka@idd.org
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 beta-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 betaI-tubulin (RH30), betaIII-tubulin (IMR32, KHOS/NP, RH]), 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 beta-tubulin isotypes and apoptotic markers. The mass spectrometry approach has potential for the discovery of proteomic biomarkers for drug sensitivity.
Insights
This study compared paclitaxel and docetaxel in pediatric tumor models. Proteomic profiling identified potential biomarkers for taxane sensitivity, though effects on tubulin and apoptosis markers were inconsistent.
Area of Science:
- Pharmacology
- Oncology
- Biomarker Discovery
Background:
- Tumor sensitivity to paclitaxel and docetaxel varies, prompting investigation into underlying mechanisms.
- Understanding differential taxane sensitivity is crucial for optimizing cancer therapy.
Purpose of the Study:
- To compare the efficacy of docetaxel and paclitaxel in pediatric tumor xenografts.
- To investigate the effects of these taxanes on beta-tubulin isotypes, apoptotic markers, and proteomic profiles.
- To identify potential proteomic biomarkers associated with differential drug sensitivity.
Main Methods:
- Evaluated docetaxel and paclitaxel at maximum tolerated doses (MTD) and 0.5 MTDs in neuroblastoma, rhabdomyosarcoma, and osteosarcoma xenograft models.
- Assessed drug effects on beta-tubulin isotypes, Bcl-2, Bax, and Bcl-XL expression via immunoblotting.
- Utilized SELDI mass spectrometry for proteomic profiling of tumor xenografts.
Main Results:
- Docetaxel demonstrated superior activity in neuroblastoma and osteosarcoma, while paclitaxel was more effective in rhabdomyosarcoma.
- Docetaxel exhibited significant efficacy in osteosarcoma even at 0.5 MTD.
- Proteomic profiling revealed consistent differential regulation of six protein species by both drugs in osteosarcoma xenografts.
Conclusions:
- Anticancer activity did not correlate with observed effects on beta-tubulin isotypes or apoptotic markers.
- Proteomic profiling shows promise for discovering biomarkers predictive of taxane drug sensitivity.
- Further research is needed to elucidate the mechanisms of differential taxane sensitivity.
