Bleomycin pharmacology: Mechanism of action and resistance, and clinical pharmacokinetics

Research output: Contribution to journalArticle

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Abstract

Bleomycin is a glycopeptide antibiotic with a unique mechanism of antitumor activity. The drug binds to guanosine-cytosine-rich portions of DNA via association of the "S" tripeptide and by partial intercalation of the bithiazole rings. A group of five nitrogen atoms arranged in a square-pyramidal conformation binds divalent metals including iron, the active ligand, and copper, an inactive ligand. Molecular oxygen, bound by the iron, can produce highly reactive free radicals and Fe(III). The free radicals produce DNA single-strand breaks at 3′-4′ bonds in deoxyribose. This yields free base propenals, especially of thymine: cytotoxicity is cell-cycle-phase specific for G2 phase. In humans, bleomycin is rapidly eliminated primarily by renal excretion. This accounts for approximately half of a dose. In patients with renal compromise or extensive prior cisplatin therapy, the drug half-life can extend from 2 to 4 hours up to 21 hours. Thus, dose adjustments are needed when creatinine clearance is ≤35 mL/min. Finally, resistance to bleomycin in normal tissues can be correlated with the presence of a bleomycin hydrolase enzyme, which is in the cysteine proteinase family. The enzyme replaces a terminal amine with a hydroxyl, thereby inhibiting iron binding and cytotoxic activity. The low concentration of enzyme in the skin and lung may explain the unique sensitivity of these tissues to bleomycin toxicity. However, correlation of hydrolase levels with tumor cell sensitivity has thus far been negative.

Original languageEnglish (US)
Pages (from-to)3-8
Number of pages6
JournalSeminars in Oncology
Volume19
Issue number2 SUPPL. 5
StatePublished - 1992

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Bleomycin
Iron
Pharmacokinetics
Pharmacology
Free Radicals
Enzymes
Ligands
Deoxyribose
Single-Stranded DNA Breaks
Thymine
Cysteine Proteases
Glycopeptides
Guanosine
G2 Phase
Cytosine
Hydrolases
Hydroxyl Radical
Cisplatin
Amines
Half-Life

ASJC Scopus subject areas

  • Oncology

Cite this

Bleomycin pharmacology : Mechanism of action and resistance, and clinical pharmacokinetics. / Dorr, Robert T.

In: Seminars in Oncology, Vol. 19, No. 2 SUPPL. 5, 1992, p. 3-8.

Research output: Contribution to journalArticle

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