Activity of Oral and Intravenous 9-Aminocamptothecin in SCID Mice Engrafted with Human Leukemia

Abstract

The intravenous (IV) 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, IV; group 3, 1.33 mg/kg/dose, orally (PO); group 4, 2.0 mg/kg/dose IV and group 5, 2.0 mg/kg/dose PO. 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 HI trials. Oral and intravenous routes are equally effective.

Key Words:

• 9-AC
• SCID Mouse
• AML
• acute myeloblastic leukemia
• aminocamptothecin