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Studies on the Mechanism of Action of 5-Aziridinyl-2,4-dinitrobenzamide in Tumor Cells¹

Chester Beatty Research Institute, Institute of Cancer Research, Royal Cancer Hospital, Fulham Road, London SW3, 6JB England

Studies have been carried out to elucidate the mechanism of the selective antitumor action of 5-aziridinyl-2,4-dinitrobenzamide (CB 1954) against the British line of Walker 256 tumor. This drug, at a concentration of 1 µg/ml, produced biochemical effects in ascites tumor cells, which appear to be identical to those of the difunctional alkylating agent, melphalan. The incorporation of thymidine-³H into DNA was inhibited progressively and, after 4 to 12 hr of incubation of tumor cells with the drug, proceeded at about one-half the normal rate. The utilization of radioactivity from uridine-6-³H for DNA synthesis was also diminished by drug treatment, whereas no corresponding effect on de novo purine, RNA, or protein synthesis was noted. Increased concentrations of CB 1954 produced only a slightly greater effect on thymidine incorporation into DNA. In contrast, thymidine incorporation into the DNA of six other rodent tumors, including a U. S. line of the Walker tumor, which were resistant to the carcinostatic effects of CB 1954, was unaffected by drug treatment at the usual concentrations. However, in a line of the British Walker tumor that had acquired resistance to CB 1954, thymidine incorporation was depressed by CB 1954, suggesting that the initial damage produced by drug treatment was readily reversible. In a survey comparing incorporation of isotopically labeled precursors into the 3 lines of the Walker tumor, the rate of thymidine incorporation into the DNA's of tumors resistant to CB 1954 was increased.

¹ This work was supported by grants to the Chester Beatty Research Institute (Institute of Cancer Research, Royal Cancer Hospital) from the Medical Research Council and the Cancer Research Campaign. Support from USPHS Research Grant CA 02978 from the National Cancer Institute, NIH, Bethesda, Md., is also acknowledged.

² Recipient of American Cancer Society—Eleanor Roosevelt International Cancer Fellowship, awarded by the International Union Against Cancer, while on sabbatical leave from the Department of Pharmacology. The George Washington University School of Medicine, Washington, D. C. To whom reprint requests should be sent—at the Department of Pharmacology, George Washington University School of Medicine, 2300 Eye Street, N. W. Washington, D. C. 20037.

Received 7/19/73. Accepted 10/ 3/73.