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• W2565796763 abstract "The antitumor properties of anthracyclines were discovered in 1963, when daunomycin was found to be cytotoxic to leukemic cells [1]. Adriamycin, a closely related anthracycline, was discovered in 1969 and also showed potent antitumor activity [2,3]. Today, daunorubicin and doxorubicin are used extensively in cancer chemotherapy, although severe side effects and development of drug resistance continue to place limits on the effectiveness of these agents. The anthracyclines are believed to cause cytotoxicity by one or more of several mechanisms: a) direct DNA interaction b) reactivity with cellular enzymes like topoisomerase II c) formation of reactive free radicals or d) membrane damage. Brief considerations on each of these mechanisms include: a) Adriamycin within the cell is found to be extensively bound to DNA. Modelling studies show insertion of the planar heterocyclic ring structure into the DNA helix parallel to the base pairs [4,5]. Binding of anthracyclines to DNA disrupts the nucleic acid's ability to function as a template for polymerases [4,6-9]. Anthracyclines also cause single-stranded scission of DNA [10,11]. Because of DNA interaction anthracyclines are both mutagenic [12,13] and carcinogenic [14]. b) Adriamycin is also capable of stabilizing the topoisomerase II-DNA cleavage complex, which can lead to the formation of DNA breaks and DNA-protein crosslinks [15]. There is still uncertainty about the detailed mechanism of this process, including whether the nucleic acid or the enzyme is the direct target for the drug. c) An electron spin resonance signal indicative of a free radical has been found when anthracyclines were reacted with rat liver microsomes under anaerobic conditions [13,16-20]. The anthracycline radical may react either with cellular targets, damaging their function, or with molecular oxygen, producing superoxide and hydroxyl radicals, as well as hydrogen peroxide [21 ]. d) With any of the above intracellular mechimisms of drug action, the initial event must be the transport of the drug across the plasma membrane. However, is also possible that the plasma membrane itself may be the" @default.
• W2565796763 created "2017-01-06" @default.
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• W2565796763 date "1989-01-01" @default.
• W2565796763 modified "2023-09-24" @default.
• W2565796763 title "5. Anthracycline resistance" @default.
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