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Comutagenic Effects of 3-Aminobenzamide in Chinese Hamster Ovary Cells¹

Department of Cancer Biology, Harvard School of Public Health, Boston, Massachusetts 02115 [J. L. S., R. R. W.], and Laboratory of Radiobiology and Environmental Health, University of California, San Francisco, California 94143 [W. F. M., P. B-L., V. A., S. W.]

Inhibition of poly (ADP-ribose) synthesis by agents such as 3-aminobenzamide (3-AB) potentiates the cytotoxic, carcinogenic, and clastogenic effects of certain DNA-damaging agents. Experiments were carried out in Chinese hamster ovary cells to compare chromosome aberration production and cytotoxicity with the induction of somatic mutations at the hypoxanthine-guanine phosphoribosyltransferase (HGPRT) and sodium-potassium ATPase loci after treatment with 3-AB in combination with certain monofunctional alkylating agents. On its own, 1 to 10 mM concentrations of 3-AB were not mutagenic, reduced plating efficiencies only slightly, and produced a small elevation in the frequency of chromatid aberrations. In combination with ethyl methanesulfonate (EMS), 3-AB increased cytotoxicity and the frequency of alkylation-induced chromatid aberrations. 3-AB also increased the frequency of EMS and N-methyl-N'-nitro-N-nitrosoguanidine-induced 6-thioguanine-resistant cells (a marker for the HGPRT^- phenotype). It had no effect on the frequency of EMS-induced ouabain-resistant cells (a marker for ATPase mutations). All the effects were dose dependent. Larger absolute increases were found with 10 mM 3-AB as compared with 1 mM 3-AB and with 2 mM EMS as compared to 1 mM EMS. The 3-AB-mediated increases in 6-thioguanine-resistant cells, which are often deletion mutations, and the lack of any increase in the frequency of ouabain-resistant cells, which can only arise through point mutation induction, along with the increases in chromosome aberration frequency, suggests that 3-AB increases the frequency of deletion mutations by increasing the frequency and duration of DNA strand breaks.

¹ This work was supported by the US Department of Energy (DE-AM03-76-SF-010102) and by Grant CA 29883 from the NIH.

² Present address: Department of Radiation Oncology, University of Chicago Medical Center, Box 440, 5841 South Maryland Avenue, Chicago, IL 60637. To whom requests for reprints should be addressed.

Received 8/20/84. Revised 12/14/84. Accepted 12/28/84.