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Effects of 3'-(3-Cyano-4-morpholinyl)-3'-deaminoadriamycin and Structural Analogues on DNA in HT-29 Human Colon Carcinoma Cells¹

Departments of Pharmacology and Therapeutics [M. I. J., C. D. A., A. B.] and Internal Medicine [J. B. J., A. B.], University of Manitoba, and Manitoba Institute of Cell Biology [J. B. J., A. B.], Manitoba Cancer Treatment and Research Foundation, Winnipeg, Manitoba R3E 0V9, Canada

The potent Adriamycin (ADR) analogue, 3'-(3-cyano-4-morpholinyl)-3'-deaminoadriamycin (CMA), produces DNA-DNA cross-links in human and murine tumor cells. The cellular pharmacology of CMA, its derivative, 5-imino-3'-(3-cyano-4-morpholinyl)-3'-deaminoadriamycin (ICMA), 3'-(4-morpholinyl)-3'-deaminoadriamycin (MA), and ADR was evaluated in HT-29 human colon carcinoma cells to determine the structural requirements for the cross-linking activity of CMA, and the role of this activity in the antitumor effect of this agent. CMA was 50-fold more cytocidal than ICMA to HT-29 cells, 300-fold more toxic than MA, and 150-fold more potent than ADR. Both CMA and ICMA produced DNA-DNA cross-links in HT-29 cells but, consistent with its reduced cytotoxicity, the imino derivative was 30-fold less active than CMA. No DNA-DNA cross-links were observed with MA or ADR. CMA also showed cross-linking activity in isolated HT-29 nuclei, indicating that cytoplasmic activation was not required for this effect. Both CMA and ICMA produced cross-links in isolated -phage DNA with CMA being 40-fold more active than the imino derivative, and this activity was unchanged in the presence or absence of a reducing agent. While MA and ADR produced DNA strand breaks in HT-29 cells, this damage was not observed with CMA and ICMA. This study indicates that the potent antitumor activity of CMA may be related to its ability to induce DNA cross-links, which can occur without the need for metabolic activation. The cyanide group appears to be essential for cross-linking and the quinone group may also be involved, but by a mechanism unrelated to its reduction.

¹ Supported by a grant from the Medical Research Council of Canada.

² To whom requests for reprints should be addressed, at Manitoba Institute of Cell Biology, 100 Olivia St., Winnipeg, Manitoba R3E OV9, Canada.

Received 6/ 8/87. Revised 8/17/87. Accepted 8/20/87.