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Hypothetical Mechanism of Therapeutic Synergism Induced by the Combination of 6-Thioguanine and 3-[(4-Amino-2-methyl-5-pyrimidinyl)methyl]-1-(2-chloroethyl)-1-nitrosourea Hydrochloride¹

Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Kami-Ikebukuro 1-37-1, Toshima-ku, Tokyo 170, Japan

Comparative studies were carried out using various antimetabolites in order to determine whether the synergistic cell-killing effect on L1210 murine leukemia cells induced by a treatment combining 6-thioguanine (6-TG) and 3-[(4-amino-2-methyl-5-pyrimidinyl)methyl]-1-(2-chloroethyl)-1-nitrosourea hydrochloride (ACNU) resulted from "complementary inhibition." The combinations of ACNU plus 5-fluorouracil and ACNU plus 5-bromo-2'-deoxyuridine induced 31- and 18-fold greater cell killing of L1210 cells in vitro over the expected additive survival (the product of the observed survival for each drug), respectively, whereas the cytocidal activity of the combinations of ACNU plus methotrexate and ACNU plus 6-methylmercaptopurine riboside was less than 2-fold greater. Moreover, therapeutic synergism defined by two parameters (survival time and/or cure incidence) against iv. L1210 leukemia was clearly elicited only by the combinations of ACNU plus 5-fluorouracil, 5-bromo-2'-deoxyuridine, or 6-mercaptopurine. As a result, the following possibility that the 6-TG incorporated into the DNA in place of guanine increases the amount of the DNA interstrand cross-linking by ACNU was considered and examined using the DNAs isolated from 6-day-old L1210 cells in the peritoneal cavity untreated or treated with 30, 3, and 0.3 mg of 6-TG per kg for 5 hr. Significant increases in the amount of binding of [ethylene-}su14}/suC]ACNU to the DNA and in the amount of the DNA interstrand cross-linking determined by the hydroxylapatite technique were observed with the increase in the 6-TG dose and, maximally, approximately 6-fold greater binding and 6- to 12-fold increases in the double-stranded DNA fraction over those of control DNA were obtained by 4- and 2-hr incubations at 37°, respectively.

¹ This study was supported in part by Grants-in-Aid for Cancer Research from the Ministry of Health and Welfare (52-12) and from the Ministry of Education, Science and Culture, Japan, and by Contract NO1-CM-22054 from the National Cancer Institute. Bethesda, Md. This is Paper 5 in a series concerning the combination of 6-thioguanine and 3-[(4-amino-2-methyl-5-pyrimidinyl)methyl]-1-(2-chloroethyl)-1-nitrosourea hydrochloride.

² To whom requests for reprints should be addressed.

Received 8/25/81. Accepted 6/ 3/82.

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