Relevance of interstrand DNA crosslinking induced by anthracyclines for their biological activity

doi:10.1016/0006-2952(94)90266-6

Biochemical Pharmacology

Volume 47, Issue 12, 15 June 1994, Pages 2279-2287

https://doi.org/10.1016/0006-2952(94)90266-6 Get rights and content

Abstract

The relevance of interstrand DNA crosslinking induced by anthracyclines for their cytotoxic action was studied in several biological systems with cells differing in sensitivity towards these compounds. It was done by establishing the correlation between DNA crosslinking and cytotoxic activity of anthracyclines. The study showed that there is a strong positive correlation between cytotoxic activity of anthracyclines and their DNA crosslinking potency in HeLa S₃ cells for a group of six Daunomycin derivatives (r = 0.97) as well as for all the studied 13 anthracyclines of divergent chemical structure (r = 0.95). Similar relationships between cytotoxic activity and DNA crosslinking ability was found for Adriamycin® and Daunomycin in three other cellular systems: (i) in LoVo and about 20-fold Adriamycinresistant LoVo/DX human colon adenocarcinoma cells, (ii) CHO-K1 and its Adriamycin-hypersensitive mutant CHO-ADR5 Chinese hamster ovary cells and (iii) HeLa S₃ cells sensitized about 3-fold to cytotoxic action of Adriamycin and Daunomycin by lowering intracellular glutathione content, to about 10% of normal level, by buthionine sulfoximine treatment. The presented results show that DNA crosslinking induced by anthracyclines may be responsible for the cytotoxic activity of these compounds.

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The mechanism of action, antitumor activity, and cardiotoxicity of anthracyclines and anthracenediones have been extensively discussed and depend on many factors [12–14]. The biological activity of these compounds results from the possibility of the DNA intercalation leading to the inhibition of many cellular processes [15], interstrand DNA cross-linking [16,17], free radical formation leading to DNA damage [18], DNA alkylation [19], and inhibition of the enzyme topoisomerase II [20]. Taking into consideration the above-mentioned factors, one can conclude that the antitumor activity of anthraquinone derivatives strongly depends on the chemical structure and redox activities.
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Relevance of interstrand DNA crosslinking induced by anthracyclines for their biological activity

Abstract

Biochem Biophys Res Commun

Biochem Pharmacol

Biochimie

Pharmacol Ther

Pharmacol Ther

Biochem Pharmacol

Biochem Pharmacol

Biochem Pharmacol

Depedence on treatment time of melphalan resistance and DNA cross-linking in human melanoma cell lines

Cancer Res

A fluorimetric method for determination of oxidized and reduced glutathione in tissues

Anal Biochem

An Introduction to Statistical Methods and Data Analysis

Structure-activity relations of anthracyclines relative to effects on macromolecular synthesis

Mol Pharmacol

DNA topoisomerase II as intracellular target in anthracycline treatment of cancer

Relationship of Adriamycin concentrations to the DNA lesions induced in hypoxic and euoxic L1210 cells

Cancer Res