In vitro and in vivo activity of topotecan against human B-lineage acute lymphoblastic leukemia cells

Uckun, F.M.; Stewart, C.F.; Reaman, G.; Chelstrom, L.M.; Jin, J.; Chandan-Langlie, M.; Waddick, K.G.; White, J.; Evans, W.E.

Blood 85(10): 2817-2828

1995


ISSN/ISBN: 0006-4971
PMID: 7742543
DOI: 10.1182/blood.v85.10.2817.bloodjournal85102817
Accession: 008833500

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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.