Molecular determinants of differential sensitivity to docetaxel and paclitaxel in human pediatric cancer models.
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.


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.


CONCLUSIONS
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.
Izbicka
Elzbieta
E
Cancer Therapy and Research Center, The Institute for Drug Development, San Antonio, TX 78245, USA. eizbicka@idd.org
Campos
David
D
Marty
Jennifer
J
Carrizales
Gilbert
G
Mangold
Gina
G
Tolcher
Anthony
A
D000818:Animals; D014408:Biomarkers, Tumor / Q000378:metabolism*; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D002648:Child; D000077143:Docetaxel; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009447:Neuroblastoma / Q000188:drug therapy* / Q000378:metabolism; D012516:Osteosarcoma / Q000188:drug therapy* / Q000378:metabolism; D017239:Paclitaxel / Q000494:pharmacology*; D040901:Proteomics; D012208:Rhabdomyosarcoma / Q000188:drug therapy* / Q000378:metabolism; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D043823:Taxoids / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
D014408:Biomarkers, Tumor; D043823:Taxoids; D000077143:Docetaxel; D017239:Paclitaxel