title: The topoisomerase I inhibitor DX-8951f is active in a severe combined immunodeficient mouse model of human acute myelogenous leukemia.
abstract: The severe combined immunodeficient (SCID) mouse model of human acute myelogenous leukemia (AML) is a unique system for preclinical in vivo evaluation of the activity and toxicity of new agents. The topoisomerase I (topo I) inhibitor topotecan is active in patients with AML and myelodysplastic syndromes. DX-8951f is a novel topo I inhibitor with more potent antitumor effects than topotecan or CPT-11 in vitro. To study the in vivo activity of DX-8951f, 6-week-old female SCID mice received injections into the tail vein with 2 x 10(7) exponentially growing KBM-3 cells. In each experiment, three to five sets of five mice were treated with DX-8951f doses ranging from 7.5 to 80 mg/kg and at schedules of 1, 3, and 5 days; a control set of five mice was treated with the drug vehicle alone. One group received DX-8951f on day 7 of the inoculation with KBM-3 (early-treatment group). To study the activity of DX-8951f in advanced disease, a second group was treated 1 month after the inoculation, when the animals were developing symptoms (late-treatment group). The study end point was the duration of survival until death from leukemia, which was assessed clinically and by the presence of the human DQ alpha gene in tissue samples by PCR. Six experiments were conducted with 170 animals. Survival was higher in both the early- and late-treatment groups than in untreated controls, and the treated groups had significantly less central nervous system disease. Significantly improved survival was observed in animals treated early with 60 and 80 mg/kg as a single injection, with 15 and 20 mg/kg over 3 days, and with 7.5 and 10 mg/kg over 5 days. In the late-disease model (treatment starting on days 28-35), improved survival was observed with a single dose of 80 or 20 mg/kg over 5 days. Dose escalation was limited by dilution problems at the 1-day schedule and by toxicity (mainly gastrointestinal) of the prolonged schedules. Both efficacy and toxicity were dose schedule dependent, increasing with higher doses and prolonged exposure. By establishing the antileukemic activity of DX-8951f against human AML transplanted into SCID mice at doses below the LD10, our data provide a rationale for clinical evaluation of the drug in patients with AML and favor the use of prolonged administration.
authors.affiliation: Department of Leukemia, University of Texas M. D. Anderson Cancer Center, Houston 77030, USA.
authors.forename: N
authors.initials: N
authors.lastname: Vey
authors.forename: F J
authors.initials: FJ
authors.lastname: Giles
authors.forename: H
authors.initials: H
authors.lastname: Kantarjian
authors.forename: T L
authors.initials: TL
authors.lastname: Smith
authors.forename: M
authors.initials: M
authors.lastname: Beran
authors.forename: S
authors.initials: S
authors.lastname: Jeha
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000627:therapeutic use* / Q000633:toxicity; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000627:therapeutic use / Q000633:toxicity; D005260:Female; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy*; D051379:Mice; D016513:Mice, SCID; D016019:Survival Analysis; D013997:Time Factors; D059004:Topoisomerase I Inhibitors; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D059004:Topoisomerase I Inhibitors; C095887:exatecan; D002166:Camptothecin