CELLULAR PHARMACOLOGY OF 3'-(3-CYANO-4-MORPHOLINYL)-3'-DEAMINOADRIAMYCIN AND STRUCTURAL ANALOGS IN HUMAN-COLON CARCINOMA HT-29 CELLS-INVITRO

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  • 1 August 1987
    • journal article
    • research article
    • Vol. 47  (15) , 4076-4080
Abstract
The new Adriamycin (ADR) analogue, 3''(3-cyano-4-morpholinyl)-3''-deaminoadriamycin (CMA), is the most potent anthracycline yet developed. The cellular pharmacology of CMA and 3''-(4-morpholinyl)-3''-deaminoadriamycin (MA), and their 5-imino derivatives, ICMA and IMA, were compared with ADR in a human colon carcinoma (HT-29) cell line in vitro. In a soft agar clonogenic assay, the order of antitumor activity was CMA>ICMA>ADR>MA>IMA, for both 2- and 24-h drug exposure periods, indicating a requirement for the cyainde group and an intact quinone ring for the potent antitumor effect of CMA. The cellular uptake of CMA was 2-fold less than that of MA, although, consistent with its greater nuclear binding, the degree of efflux of CMA was less than that of MA. The order of cytotoxicity of the analogues correlated approximately with their effects on cellular DNA synthesis, indicating that this feature may contribute to the antitumor effect. Using isolated nuclei, the order of inhibition of DNA transcription by the analogues was CMA>MA>ADR, which was similar to their nuclear affinities, suggesting that their effects on cellular nucleic acid synthesis were due to a direct interaction of drug with DNA. However, CMA did not appear to differ from the other drugs in its base specificity as all the analogues preferentially inhibited Escherichia coli RNA polymerase activity directed by poly(dAdT) .cntdot. poly(dAdT) compared to poly(dGdC) .cntdot. poly(dGdC).