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.
ARTICLES|
May 15, 1995
In vitro and in vivo activity of topotecan against human B-lineage acute lymphoblastic leukemia cells
FM Uckun,
FM Uckun
Department of Therapeutic Radiology-Radiation Oncology, University of Minnesota, Minneapolis 55455, USA.
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CF Stewart,
CF Stewart
Department of Therapeutic Radiology-Radiation Oncology, University of Minnesota, Minneapolis 55455, USA.
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G Reaman,
G Reaman
Department of Therapeutic Radiology-Radiation Oncology, University of Minnesota, Minneapolis 55455, USA.
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LM Chelstrom,
LM Chelstrom
Department of Therapeutic Radiology-Radiation Oncology, University of Minnesota, Minneapolis 55455, USA.
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J Jin,
J Jin
Department of Therapeutic Radiology-Radiation Oncology, University of Minnesota, Minneapolis 55455, USA.
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M Chandan-Langlie,
M Chandan-Langlie
Department of Therapeutic Radiology-Radiation Oncology, University of Minnesota, Minneapolis 55455, USA.
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KG Waddick,
KG Waddick
Department of Therapeutic Radiology-Radiation Oncology, University of Minnesota, Minneapolis 55455, USA.
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J White,
J White
Department of Therapeutic Radiology-Radiation Oncology, University of Minnesota, Minneapolis 55455, USA.
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WE Evans
WE Evans
Department of Therapeutic Radiology-Radiation Oncology, University of Minnesota, Minneapolis 55455, USA.
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Blood (1995) 85 (10): 2817–2828.
Citation
FM Uckun, CF Stewart, G Reaman, LM Chelstrom, J Jin, M Chandan-Langlie, KG Waddick, J White, WE Evans; In vitro and in vivo activity of topotecan against human B-lineage acute lymphoblastic leukemia cells. Blood 1995; 85 (10): 2817–2828. doi: https://doi.org/10.1182/blood.V85.10.2817.bloodjournal85102817
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