Bone marrow CFU-GM and human tumor xenograft efficacy of three tubulin binding agents
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The dynamic instability of microtubules in cells is one of the key targets of anticancer therapeutics. Microtubule-disrupting agents such as vinca alkaloids and microtubule-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.
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.
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.
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.
KeywordsTasidotin Vincristine Paclitaxel Bone marrow CFU-GM Tumor xenografts
- 7.Corbett TH, Polin L, Roberts BJ (2002) Transplantable syngeneic rodent tumors. In: Teicher BA et al (eds) Tumor models in cancer research. Humana Press, Totowa, pp 41–71Google Scholar
- 17.Guo P, Wang X, Zhou F, Gallo JM (2004) Determination of vincristine in mouse plasma and brain tissues by liquid chromatography–electrospray mass spectrometry. J Chromatogr B 809:273–278Google Scholar
- 23.Johnson IS, Armstrong JG, Gorman M et al (1967) The vinca alkaloids: a new class of oncolytic agents. Cancer Res 23:1390–1427Google Scholar
- 26.Kaighn ME, Narayan KS, Ohnuki Y et al (1979) Establishment and characterization of a human prostatic carcinoma cell line (PC-3). Investig Urol 17:16–23Google Scholar
- 27.Kaur KK, Verschraegen C (2005) Tasidotin HCl. Curr Opin Invest Drugs 6:631–638Google Scholar
- 41.Ovejera AA, Houchens DP (1981) Human tumor xenografts in athymic nude mice as a preclinical screen for anticancer agents. Sem Oncol 8:386–393Google Scholar
- 42.Perez EA (2007) Novel enhanced delivery taxanes: an update. Semin Oncol 34:Suppl 1–5Google Scholar
- 49.Rowinsky EK, Donehower RC (1996) Antimicrotubule agents. In: Chabner BA, Longo DL (eds) Cancer chemotherapy and biotherapy. Lippincott-Raven, New York, pp 263–296Google Scholar