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Laboratory of Molecular Pharmacology, Division of Basic Sciences,
National Cancer Institute, National Institutes of Health, Bethesda,
Maryland 20892-4255 (M.V., W.N.-N., G.K., K.W.K, Y.P.), and
Chemistry
and Life Sciences, Research Triangle Institutes, Research Triangle
Park, North Carolina 27709-2194 (M.E.W., M.C.W.)
An alkylating camptothecin (CPT) derivative,
7-chloromethyl-10,11-methylenedioxy-camptothecin (7-CM-MDO-CPT) was
recently shown to produce irreversible topoisomerase I (top1) cleavage complexes by binding to the +1 base of the scissile strand of a top1
cleavage site. We demonstrate that 7-CM-EDO-CPT
(7-chloromethyl-10,11-ethylenedioxy-camptothecin) also induces
irreversible top1-DNA complexes. 7-CM-MDO-CPT, 7-CM-EDO-CPT, and the
nonalkylating derivative 7-ethyl-10,11-methylenedioxy-camptothecin (7-E-MDO-CPT) also induced reversible top1 cleavable complexes, which
were markedly more stable to salt-induced reversal than those induced
by 7-ethyl-10-hyroxy-CPT, the active metabolite of CPT-11. This greater
stability of the top1 cleavable complexes was contributed by the
7-alkyl and the 10,11-methylene- (or ethylene-) dioxy substitutions.
Studies in SW620 cells showed that 7-E-MDO-CPT, 7-CM-MDO-CPT, and
7-CM-EDO-CPT are more potent inducers of cleavable complexes and more
cytotoxic than CPT. The reversal of the cleavable complexes induced by
7-E-MDO-CPT, 7-CM-MDO-CPT, and 7-CM-EDO-CPT was markedly slower after
drug removal than that for CPT, which is consistent with the data with
purified top1. By contrast to CPT, 7-E-MDO-CPT, 7-CM-MDO-CPT, and
7-CM-EDO-CPT were cytotoxic irrespective of the presence of 10 µM aphidicolin. These results suggest that 7-E-MDO-CPT,
7-CM-MDO-CPT, and 7-CM-EDO-CPT are more potent top1 poisons than CPT
and produce long lasting top1 cleavable complexes and greater
cytotoxicity than CPT in cells.
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