Bone marrow CFU-GM and human tumor xenograft efficacy of three antitumor nucleoside analogs

  • Authors:
    • Rebecca G. Bagley
    • Stephanie Roth
    • Leslie S. Kurtzberg
    • Cecile Rouleau
    • Min Yao
    • Jennifer Crawford
    • Roy Krumbholz
    • Dennis Lovett
    • Steven Schmid
    • Beverly A. Teicher
  • View Affiliations

  • Published online on: May 1, 2009     https://doi.org/10.3892/ijo_00000260
  • Pages: 1329-1340
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Abstract

Nucleoside analogs are rationally designed anticancer agents that disrupt DNA and RNA synthesis. Fludarabine and cladribine have important roles in the treatment of hematologic malignancies. Clofarabine is a next generation nucleoside analog which is under clinical investigation. The bone marrow toxicity, tumor cell cytotoxicity and human tumor xenograft activity of fludarabine, cladribine and clofarabine were compared. Mouse and human bone marrow were subjected to colony forming (CFU-GM) assays over a 5-log concentration range in culture. NCI-60 cell line screening data were compared. In vivo, a range of clofarabine doses was compared with fludarabine for efficacy in several human tumor xenografts. The IC90 concentrations for fludarabine and cladribine for mouse CFU-GM were >30 and 0.93 µM, and for human CFU-GM were 8 and 0.11 µM, giving mouse to human differentials of >3.8- and 8.5-fold. Clofarabine produced IC90s of 1.7 µM in mouse and 0.51 µM in human CFU-GM, thus a 3.3-fold differential between species. In the NCI-60 cell line screen, fludarabine and cladribine showed selective cytotoxicity toward leukemia cell lines while for clofarabine there was no apparent selectivity based upon origin of the tumor cells. In vivo, clofarabine produced a dose-dependent increase in tumor growth delay in the RL lymphoma, the RPMI-8226 multiple myeloma, and HT-29 colon carcinoma models. The PC3 prostate carcinoma was equally responsive to clofarabine and fludarabine. Bringing together bone marrow toxicity data, tumor cell line cytotoxicity data, and human tumor xenograft efficacy provides valuable information for the translation of preclinical findings to the clinic.

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May 2009
Volume 34 Issue 5

Print ISSN: 1019-6439
Online ISSN:1791-2423

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Spandidos Publications style
Bagley RG, Roth S, Kurtzberg LS, Rouleau C, Yao M, Crawford J, Krumbholz R, Lovett D, Schmid S, Teicher BA, Teicher BA, et al: Bone marrow CFU-GM and human tumor xenograft efficacy of three antitumor nucleoside analogs. Int J Oncol 34: 1329-1340, 2009
APA
Bagley, R.G., Roth, S., Kurtzberg, L.S., Rouleau, C., Yao, M., Crawford, J. ... Teicher, B.A. (2009). Bone marrow CFU-GM and human tumor xenograft efficacy of three antitumor nucleoside analogs. International Journal of Oncology, 34, 1329-1340. https://doi.org/10.3892/ijo_00000260
MLA
Bagley, R. G., Roth, S., Kurtzberg, L. S., Rouleau, C., Yao, M., Crawford, J., Krumbholz, R., Lovett, D., Schmid, S., Teicher, B. A."Bone marrow CFU-GM and human tumor xenograft efficacy of three antitumor nucleoside analogs". International Journal of Oncology 34.5 (2009): 1329-1340.
Chicago
Bagley, R. G., Roth, S., Kurtzberg, L. S., Rouleau, C., Yao, M., Crawford, J., Krumbholz, R., Lovett, D., Schmid, S., Teicher, B. A."Bone marrow CFU-GM and human tumor xenograft efficacy of three antitumor nucleoside analogs". International Journal of Oncology 34, no. 5 (2009): 1329-1340. https://doi.org/10.3892/ijo_00000260