Abstract
NB-506 is a topoisomerase I (top1) inhibitor in clinical trials. In this study, we used a series of camptothecin (CPT)-resistant cell lines with known top1 alterations. We show that three mutations in different domains of the top1 enzyme that confer CPT resistance also confer cross-resistance to NB-506. The CPT-resistant cell lines and corresponding mutations were: human prostate carcinoma cells DU-145/RC1 (mutation R364H), Chinese hamster fibroblasts DC3F/C10 (mutation G503S), and human leukemia CEM/C2 cells (N722S). This result suggests that NB-506 and CPT share a common binding site in the top1-DNA complex. We next used these three cell lines and their parental cells to study the relationship between top1 poisoning by NB-506 and antiproliferative activity. We found that the CPT-resistant cells were only 2–10-fold resistant to NB-506, which suggests that NB-506 targets other cellular processes/pathways besides top1. This conclusion was further supported by the limited cross-resistance of top1-deficient murine leukemia P388/CPT45 cells (2-fold). Cross-resistance was also limited for J-109,382, an isomer of NB-506 that does not intercalate into DNA, indicating that the non-top1-mediated antiproliferative activity of NB-506 is not attributable to DNA intercalation. Together, these data indicate that NB-506 and indolocarbazoles are promising agents to overcome CPT resistance.
Footnotes
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The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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↵1 Present address: Institute of Development, Aging and Cancer, Tohoku University, Sendai 980-8575, Japan.
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↵2 Present address: INSERM U 524, Institut de Recherche sur le Cancer, Place de Verdun, 59045 Lille Cedex, France.
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↵3 To whom requests for reprints should be addressed, at Laboratory of Molecular Pharmacology, Building 37, Room 4E28, National Cancer Institute, NIH, Bethesda, MD 20892-4255. Fax: (301) 402-0752; E-mail: pommier{at}nih.gov
- Received August 7, 2000.
- Accepted November 29, 2000.
- ©2001 American Association for Cancer Research.
Volume 61, Issue 2
