Interaction of trans-diamminedichloroplatinum(II) with DNA: Formation of monofunctional adducts and their reaction with glutathione

Alan Eastman, Michael A Barry

Research output: Contribution to journalArticle

135 Citations (Scopus)

Abstract

Bifunctional reactions with DNA are responsible for the toxic action of the cancer chemotherapeutic drug cis-diamminedichloroplatinum(II) (cis-DDP). Thiourea has previously been used to trap transient monofunctional adducts in DNA before they rearrange to the toxic lesions. In these studies, thiourea was used to quantify the monofunctional adducts produced by the ineffective isomer trans-DDP. Rather than trapping monofunctional adducts, thiourea labilized them from DNA. At short time periods, 85% of trans-DDP bound to double-stranded DNA as monofunctional adducts of deoxyguanosine. Rearrangement to bifunctional adducts in double-stranded DNA was 50% complete in 24 h but was much more rapid in single-stranded DNA with 100% complete rearrangement in 24 h. The ineffectiveness of trans-DDP therefore results from ε high proportion of monofunctional adducts in DNA that rearrange very slowly to toxic bifunctional adducts. The persistent monofunctional adducts react rapidly with glutathione, which would further reduce their potential toxicity by preventing them from rearranging to more toxic bifunctional adducts.

Original languageEnglish (US)
Pages (from-to)3303-3307
Number of pages5
JournalBiochemistry
Volume26
Issue number12
StatePublished - 1987
Externally publishedYes

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Thiourea
Glutathione
Poisons
DNA Adducts
DNA
Toxic Actions
Deoxyguanosine
Single-Stranded DNA
Cisplatin
Isomers
Toxicity
transplatin
Pharmaceutical Preparations
Neoplasms

ASJC Scopus subject areas

  • Biochemistry

Cite this

Interaction of trans-diamminedichloroplatinum(II) with DNA : Formation of monofunctional adducts and their reaction with glutathione. / Eastman, Alan; Barry, Michael A.

In: Biochemistry, Vol. 26, No. 12, 1987, p. 3303-3307.

Research output: Contribution to journalArticle

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