Combination therapy for adult T-cell leukemia-xenografted mice: flavopiridol and anti-CD25 monoclonal antibody.
Adult T-cell leukemia (ATL) develops in a small proportion of individuals infected with human T-cell lymphotrophic virus-1. 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 microg weekly for 4 weeks, inhibited tumor growth as monitored by serum levels of human beta-2-microglobulin (beta2mu; P < .01), and prolonged survival of the leukemia-bearing mice (P < .05) as compared with the control group. Combination of the 2 agents dramatically enhanced the antitumor effect, as shown by both beta2mu levels and survival of the mice, when compared with those in the flavopiridol or HAT alone group (P < .01). The significantly improved therapeutic efficacy by combining flavopiridol with HAT provides support for a clinical trial in the treatment of ATL.
Zhang
Meili
M
Metabolism Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bldg 10, Rm 4N115, 10 Center Dr, Bethesda, MD 20892, USA.
Zhang
Zhuo
Z
Goldman
Carolyn K
CK
Janik
John
J
Waldmann
Thomas A
TA
D000328:Adult; D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D005419:Flavonoids / Q000008:administration & dosage; D006801:Humans; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D010880:Piperidines / Q000008:administration & dosage; D015375:Receptors, Interleukin-2 / Q000276:immunology*; D001613:beta 2-Microglobulin / Q000032:analysis
D000911:Antibodies, Monoclonal; D005419:Flavonoids; D010880:Piperidines; D015375:Receptors, Interleukin-2; D001613:beta 2-Microglobulin; C077990:alvocidib