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In vitro and in vivo activity of topotecan against human B-lineage acute
lymphoblastic leukemia cells
FM Uckun, CF Stewart, G Reaman, LM Chelstrom, J Jin, M Chandan-Langlie, KG Waddick, J White and WE Evans
Department of Therapeutic Radiology-Radiation Oncology, University of
Minnesota, Minneapolis 55455, USA.
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.
Volume 85,
Issue 10,
pp. 2817-2828,
05/15/1995
Copyright © 1995 by The American Society of Hematology
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