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Mechanism of Cellular Drug Resistance

Abstract

CELLULAR resistance to drugs or chemicals, which can be “natural”1–4 or “acquired”5,6, is important particularly in the treatment of infectious diseases by antibiotics and of tumour cells by cancer chemotherapeutic drugs. I have investigated the mechanism of cellular drug resistance using mammalian cell lines resistant to actinomycin D. In murine leukaemias7, HeLa cells8 and bacteria9 this resistance has been related to membrane permeability barriers which prevent the interaction of actinomycin D with deoxyguanosine residues in DNA, stopping its pharmacological action. Earlier I had found that L5178Y (mouse lymphoma cell line) and L5178Y/D (actinomycin D-resistant subline) glycosidase10 and glycoprotein: glycosyl transferase11 activities, which are important in membrane glycoprotein catabolism and anabolism, were altered in the resistant lines. I have now shown that surface membranes are affected, particularly the glycoproteins and glycolipids and their synthesis in the cells resistant to actinomycin D. In this article I shall develop the hypothesis that acquired drug resistance occurs through selection of cells with altered membranes and altered membrane synthetic apparatus, and that such membrane changes decrease drug permeability and thus increase drug resistance.

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BOSMANN, H. Mechanism of Cellular Drug Resistance. Nature 233, 566–569 (1971). https://doi.org/10.1038/233566a0

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