Cellular pharmacology of 3'-(3-cyano-4-morpholinyl)-3'-deaminoadriamycin and structural analogues in human colon carcinoma HT-29 cells in vitro.
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 greater than ICMA greater than ADR greater than MA greater than IMA, for both 2- and 24-h drug exposure periods, indicating a requirement for the cyanide 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 greater than MA greater than 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).poly(dAdT) compared to poly(dGdC).poly(dGdC).
Johnston
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Pugh
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Begleiter
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D000230:Adenocarcinoma / Q000378:metabolism / Q000473:pathology*; D001426:Bacterial Proteins / Q000378:metabolism; D001692:Biological Transport; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D003110:Colonic Neoplasms / Q000378:metabolism / Q000473:pathology*; D004261:DNA Replication / Q000187:drug effects; D003630:Daunorubicin / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D004317:Doxorubicin / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D004926:Escherichia coli / Q000201:enzymology; D006801:Humans; D012318:RNA Polymerase I / Q000378:metabolism; D013329:Structure-Activity Relationship; D014158:Transcription, Genetic / Q000187:drug effects; D014410:Tumor Stem Cell Assay
D001426:Bacterial Proteins; C034844:3'-(4-morpholinyl)-3'-deaminodaunorubicin; D004317:Doxorubicin; C038555:3'-deamino-3'-(3-cyano-4-morpholinyl)doxorubicin; D012318:RNA Polymerase I; D003630:Daunorubicin