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Effects of the Antitumor Agent 8-Carbamoyl-3-(2-chloroethyl)imidazo[5,1-d]-1,2,3,5-tetrazin-4(3H)-one on the DNA of Mouse L1210 Cells

Cancer Research Campaign Experimental Chemotherapy Group, Department of Pharmacy, University of Aston, Birmingham B4 7ET, England [N. W. G., J. A. H.], and Laboratory of Molecular Pharmacology, Developmental Therapeutics Program, Division of Cancer Treatment, National Cancer Institute, NIH, Bethesda, Maryland 20205 [L. C. E.]

L1210 murine leukemia cells were treated in vitro with the novel antineoplastic agent 8-carbamoyl-3-(2-chloroethyl)imidazo[5,1-d]-1,2,3,5-tetrazin-4(3H)-one (M&B 39565), and its interaction with cellular DNA was assessed by alkaline elution. DNA interstrand cross-link and DNA-protein cross-link formation was quantified with regard to drug concentration and length of incubation time after a 2-hr incubation period with drug. Cytotoxicity, as measured by colony formation assays, and DNA damage caused by M&B 39565 were compared with those caused by a breakdown product of M&B 39565, 5-[3-(2-chloroethyl)triazen-1-yl]imidazole-4-carboxamide (MCTIC) and also with 1-(2-chloroethyl)-1-nitrosourea (CNU). Both MCTIC and CNU decompose to yield a 2-chloroethyldiazo species which is capable of alkylating DNA. At equimolar concentrations, all three drugs possessed similar in vitro cytotoxicities; at equitoxic concentrations, they produced similar levels of DNA interstrand cross-linking. The time course for cross-link formation was different for CNU when compared with MCTIC and M&B 39565, with peaks at 6 hr (CNU) and 9 hr (M&B 39565 and MCTIC). This study suggests that M&B 39565 is cytotoxic against L1210 leukemia cells as a consequence of DNA interstrand cross-link formation, probably via its breakdown product MCTIC.

¹ Recipient of a research studentship from the Science and Engineering Research Council (United Kingdom) and a travel scholarship from the British Association of Cancer Research. Present address: Laboratory of Molecular Pharmacology, National Cancer Institute, Bethesda, MD 20205.

² Present address: Section of Oncology, Loyola University, Stritch School of Medicine, Maywood, Illinois 60153.

³ To whom requests for reprints should be addressed.

Received 7/12/83. Accepted 1/27/84.

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