title: In vitro and in vivo activity of topotecan against human B-lineage acute lymphoblastic leukemia cells.
abstract: Topotecan [(S)-9-dimethylaminomethyl-10-hydroxycamptothecin hydrochloride; SK&F 104864-A, NSC 609699], a water soluble semisynthetic analogue of the alkaloid camptothecin, is a potent topoisomerase I inhibitor. Here we show that topotecan stabilizes topoisomerase I/DNA cleavable complexes in radiation-resistant human B-lineage acute lymphoblastic leukemia (ALL) cells, causes rapid apoptotic cell death despite high-level expression of bcl-2 protein, and inhibits ALL cell in vitro clonogenic growth in a dose-dependent fashion. Furthermore, topotecan elicited potent antileukemic activity in three different severe combined immunodeficiency (SCID) mouse models of human poor prognosis ALL and markedly improved event-free survival of SCID mice challenged with otherwise fatal doses of human leukemia cells at systemic drug exposure levels that can be easily achieved in children with leukemia.
authors.affiliation: Department of Therapeutic Radiology-Radiation Oncology, University of Minnesota, Minneapolis 55455, USA.
authors.forename: F M
authors.initials: FM
authors.lastname: Uckun
authors.forename: C F
authors.initials: CF
authors.lastname: Stewart
authors.forename: G
authors.initials: G
authors.lastname: Reaman
authors.forename: L M
authors.initials: LM
authors.lastname: Chelstrom
authors.forename: J
authors.initials: J
authors.lastname: Jin
authors.forename: M
authors.initials: M
authors.lastname: Chandan-Langlie
authors.forename: K G
authors.initials: KG
authors.lastname: Waddick
authors.forename: J
authors.initials: J
authors.lastname: White
authors.forename: W E
authors.initials: WE
authors.lastname: Evans
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000627:therapeutic use; D017209:Apoptosis; D002051:Burkitt Lymphoma / Q000188:drug therapy*; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D002648:Child; D002675:Child, Preschool; D004249:DNA Damage; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2; D016019:Survival Analysis; D059004:Topoisomerase I Inhibitors; D019772:Topotecan
chemical_list: D000970:Antineoplastic Agents; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D059004:Topoisomerase I Inhibitors; D019772:Topotecan; D002166:Camptothecin