Bone marrow CFU-GM and human tumor xenograft efficacy of three tubulin binding agents
In: Cancer chemotherapy and pharmacology, Jg. 64 (2009), Heft 5, S. 1029-1038
Online
academicJournal
- print, 58 ref
Zugriff:
Purpose The dynamic instability of microtubules in cells is one of the key targets of anticancer therapeutics. Micro-tubule-disrupting agents such as vinca alkaloids and micro-tubule-stabilizing agents such as taxanes are important antitumor agents. The bone marrow toxicity and human tumor xenograft activity of three tubulin-binding compounds, vincristine, paclitaxel, and tasidotin were compared. Methods Mouse and human bone marrow were subjected to colony-forming (CFU-GM) assays over a 5-log concentration range in culture. In vivo, a range of tasidotin doses was compared with vincristine, paclitaxel, and docetaxel for efficacy in several human tumor xenografts. Results The IC90 concentrations for vincristine and paclitaxel for mouse CFU-GM were 30 and 27 nM, and for human CFU-GM were 3 and 9 nM, giving mouse to human differentials of ten- and threefold. Tasidotin produced IC90s of >300 nM in mouse and 65 nM in human CFU-GM, thus a >4.6-fold differential between species. In vivo, tasidotin resulted in a dose-dependent increase in tumor growth delay in the RL lymphoma, the RPMI 8226 multiple myeloma, and MX-1 breast carcinoma models. Vincristine and tasidotin were also very effective against these tumors. The PC-3 prostate carcinoma was very responsive to full-dose paclitaxel and docetaxel while tasidotin generated a dose dependent effect. Conclusions Bringing together bone marrow toxicity data, pharmacokinetic parameters, and human tumor xenograft efficacy provides valuable information for the translation of preclinical findings to the clinic.
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Bone marrow CFU-GM and human tumor xenograft efficacy of three tubulin binding agents
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Autor/in / Beteiligte Person: | KURTZBERG, Leslie S ; ROTH, Stephanie D ; BAGLEY, Rebecca G ; ROULEAU, Cecile ; MIN, YAO ; CRAWFORD, Jennifer L ; KRUMBHOLZ, Roy D ; SCHMID, Steven M ; TEICHER, Beverly A |
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Zeitschrift: | Cancer chemotherapy and pharmacology, Jg. 64 (2009), Heft 5, S. 1029-1038 |
Veröffentlichung: | Heidelberg: Springer, 2009 |
Medientyp: | academicJournal |
Umfang: | print, 58 ref |
ISSN: | 0344-5704 (print) |
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