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Blood, 1 February 2005, Vol. 105, No. 3, pp. 1231-1236.
Prepublished online as a Blood First Edition Paper on September 21, 2004; DOI 10.1182/blood-2004-05-1709.
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Submitted May 4, 2004
Accepted September 14, 2004
Combination therapy of adult T-cell leukemia xenografted mice with flavopiridol and an anti-CD25 monoclonal antibody
Meili Zhang, Zhuo Zhang, Carolyn K Goldman, John Janik, and Thomas A Waldmann*
Metabolism Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
* Corresponding author; email: tawald{at}helix.nih.gov.
Adult T-cell leukemia (ATL) develops in a small proportion of human T-cell lymphotrophic virus-I infected individuals. The leukemia consists of an overabundance of activated T cells, which express CD25 on their cell surfaces. Presently, there is no accepted curative therapy for ATL. Flavopiridol, an inhibitor of cyclin dependent kinases, has potent antiproliferative effects and antitumor activity. We investigated the therapeutic efficacy of flavopiridol alone and in combination with humanized anti-Tac antibody (HAT), which recognizes CD25, in a murine model of human ATL. The ATL model was established by intraperitoneal injection of MET-1 leukemic cells into nonobese diabetic/severe combined immunodeficient mice. Either flavopiridol, given 2.5 mg/kg body weight daily for 5 days, or HAT, given 100 µg weekly for 4 weeks, inhibited tumor growth as monitored by serum levels of human  -2-microglobulin (2µ) (p<0.01), and prolonged survival of the leukemia-bearing mice (p<0.05) as compared with the control group. Combination of the two agents dramatically enhanced the antitumor effect, as shown by both 2µ levels and survival of the mice, when compared with those in flavopiridol or HAT alone group (p<0.01). The significantly improved therapeutic efficacy by combining flavopiridol with HAT provides support for a clinical trial in the treatment of ATL.
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