Activity of oral and intravenous 9-aminocamptothecin in SCID mice engrafted with human leukemia.
The intravenous (i.v.) injection of the human acute myelogenous leukemia cell line KBM-3 into severe combined immune deficient (SCID) mice results in disseminated multi-organ human disease involvement in these animals which leads to their death over a defined period of time. We utilized this model of human leukemia to investigate the in vivo therapeutic efficacy of the topoisomerase I inhibitor 9-aminocamptothecin (9-AC) given by two different routes. Mice injected with KBM-3 were divided into five groups. Group 1 received only diluent and served as control. The four remaining groups were treated with 9-AC four days a week for three consecutive weeks as follows: group 2 received 1.33 mg/kg/dose, i.v.; group 3, 1.33 mg/kg/dose, orally (p.o.); group 4, 2.0 mg/kg/dose i.v. and group 5, 2.0 mg/kg/dose p.o.. All animals in the control group died from disseminated human leukemia by day 64 from grafting, with a median survival of 59 days. Eleven out of 20 treated mice survived with no evidence of disease and were sacrificed at the termination of the experiment on day 128. PCR-assisted tissue analysis for the presence of human DNA showed no evidence of human leukemia. In conclusion, 9-AC is an active agent in SCID mice engrafted with human myelogenous leukemia and should be explored in phase I-II trials. Oral and intravenous routes are equally effective.
Department of Pediatrics, The University of Texas, M.D. Anderson Cancer Center, Houston 77030, USA.
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Jeha
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Kantarjian
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O'Brien
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Vitek
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Beran
D000208:Acute Disease; D000284:Administration, Oral; D000818:Animals; D002166:Camptothecin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D006683:HLA-DQ Antigens / Q000378:metabolism; D059848:HLA-DQ alpha-Chains; D006801:Humans; D007275:Injections, Intravenous; D007942:Leukemia, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality; D007951:Leukemia, Myeloid / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality; D051379:Mice; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D015996:Survival Rate
D006683:HLA-DQ Antigens; D059848:HLA-DQ alpha-Chains; C069050:HLA-DQA1 antigen; C080125:9-aminocamptothecin; D002166:Camptothecin