PT  - JOURNAL ARTICLE
AU  - Mattern, Michael R.
AU  - Mong, Shau-Ming
AU  - Bartus, Henry F.
AU  - Mirabelli, Christopher K.
AU  - Crooke, Stanley T.
AU  - Johnson, Randall K.
TI  - Relationship between the Intracellular Effects of Camptothecin and the Inhibition of DNA Topoisomerase I in Cultured L1210 Cells
DP  - 1987 Apr 01
TA  - Cancer Research
PG  - 1793--1798
VI  - 47
IP  - 7
4099  - http://cancerres.aacrjournals.org/content/47/7/1793.short
4100  - http://cancerres.aacrjournals.org/content/47/7/1793.full
SO  - Cancer Res1987 Apr 01; 47
AB  - Results of filter elution assays of lesions produced in the DNA of cultured L1210 cells by the antineoplastic alkaloid camptothecin support the notion that topoisomerase I is an intracellular target of this drug. One to 10 µm camptothecin induced DNA single-strand, but not double-strand, breaks when incubated with intact cells or with their isolated nuclei. Approximately one half of the strand breakage was protein concealed, as judged by filter elution. Camptothecin-induced, protein-concealed DNA strand breaks disappeared rapidly after drug removal. DNA-protein cross-links were generated by camptothecin with frequencies approximately equal to those of protein-concealed DNA strand breaks. It is likely that camptothecin can inhibit topoisomerase I in intact cells in a manner similar to that in which other antineoplastic agents such as amsacrine or teniposide inhibit topoisomerase II. DNA-breaking lesions other than those resulting from trapped topoisomerase I-DNA complexes may also be generated by camptothecin. The yields of DNA strand breaks induced by camptothecin, amsacrine, or teniposide were approximately doubled when cells were incubated for 16 h with 3-aminobenzamide, an inhibitor of poly(ADP ribosylation) of proteins, prior to 1-h exposure to the antineoplastic compounds. 3-Aminobenzamide also enhanced the cytotoxic action of camptothecin, amsacrine, and teniposide. These results suggest that protein-concealed strand breaks can be lethal lesions and that intracellular topoisomerase I and II activity may be regulated coordinately through poly(ADP ribosylation). ©1987 American Association for Cancer Research.