EFFECTS OF 3'-(3-CYANO-4-MORPHOLINYL)-3'-DEAMINOADRIAMYCIN AND STRUCTURAL ANALOGS ON DNA IN HT-29 HUMAN-COLON CARCINOMA-CELLS

  • 15 November 1987
    • journal article
    • research article
    • Vol. 47  (22) , 5935-5938
Abstract
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 .lambda.-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.

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