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  • Review Article
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Bleomycins: towards better therapeutics

Nature Reviews Cancer volume 5, pages 102–112 (2005)Cite this article

Key Points

  • Bleomycins are a family of glycopeptide antibiotics with antitumour activity. They are used clinically in combination chemotherapy against lymphomas, squamous-cell carcinomas and germ-cell tumours.

  • The side effects of the bleomycins are dose-dependent and involve lung inflammation that often proceeds to lung fibrosis.

  • Bleomycins bind transition metals (Fe(II) or Cu(I)) and oxygen and, in the presence of a one-electron reductant, can catalyse formation of single-stranded (ss) and double-stranded (ds) DNA lesions. The damage is similar to that generated by ionizing radiation.

  • In vitro studies indicate that a single molecule of bleomycin is sufficient to generate lesions on both strands of DNA, the proposed source of cytotoxicity. Hot spots for dsDNA cleavage have been identified and have led to empirical rules about the sequences leading to dsDNA lesions.

  • Studies on a large number of bleomycin analogues, made possible by total synthesis of bleomycin, have indicated that the whole molecule is much greater than the sum of its parts. The linker between the metal and the bithiazole DNA-binding domain and the flexibility of the bithiazole moiety itself are essential for efficient dsDNA cleavage.

  • The cellular responses to bleomycin treatment are complex and are cell-line- and genotype-dependent. Extended cell-cycle arrest, apoptosis and mitotic cell death are the most common outcomes of bleomycin treatment.

  • Bleomycins are hydrophilic molecules that are unable to cross cell membranes by free diffusion. Studies indicate that the positively charged tail of bleomycin might be key to cellular uptake.

  • Biosynthetic genes for bleomycin have been identified and some of the proteins in the pathway have been characterized. These studies, in concert with chemical synthesis, open the door to making libraries of bleomycin analogues.

Abstract

Bleomycins are a family of glycopeptide antibiotics that have potent antitumour activity against a range of lymphomas, head and neck cancers and germ-cell tumours. The therapeutic efficacy of the bleomycins is limited by development of lung fibrosis. The cytotoxic and mutagenic effects of the bleomycins are thought to be related to their ability to mediate both single-stranded and double-stranded DNA damage, which requires the presence of specific cofactors (a transition metal, oxygen and a one-electron reductant). Progress in understanding the mechanisms involved in the therapeutic efficacy of the bleomycins and the unwanted toxicity and elucidation of the biosynthetic pathway of the bleomycins sets the stage for developing a more potent, less toxic therapeutic agent.

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Figure 1: Structure of metallobleomycins and their domain organization.
Figure 2: Formation of 'activated' bleomycin and cleavage of DNA.
Figure 3: Products of bleomycin-induced double-stranded DNA cleavage and a proposed model for this process.
Figure 4: Putative base-excision repair pathway for bleomycin-induced single-stranded DNA breaks.
Figure 5: Intracellular response network to bleomycin damage.
Figure 6: Proposed mechanisms for generation of 'activated bleomycin' in vivo.

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Acknowledgements

This research has been supported by the National Institutes of Health.

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Authors and Affiliations

  1. Department of Chemistry, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, 02139, Massachusetts, USA

    Jingyang Chen & JoAnne Stubbe

  2. Department of Biology, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, 02139, Massachusetts, USA

    JoAnne Stubbe

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Correspondence to JoAnne Stubbe.

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DATABASES

Entrez Gene

APE1

ATM

bleomycin hydrolase

p53

POLβ

TDP1

XRCC4

National Cancer Institute

testicular cancer

Glossary

RADICAL

An atom or group of atoms with at least one unpaired electron. This feature makes a radical very chemically reactive.

OMICS

Refers to the study of biological systems, and includes genomics (DNA), proteomics (proteins) and metabolomics (small molecules).

INTERCALATION

Intercalation is a form of reversible interaction of drugs with the DNA double helix. Intercalating agents share common structural features such as the presence of planar polyaromatic systems which bind by insertion between DNA base-pairs in the minor or major groove of DNA, with a marked preference for 5′-pyrimidine-purine-3′ steps.

DICENTRIC CHROMOSOME

An abnormal chromosome with two centromeres.

RING CHROMOSOME

An abnormal chromosome in which the end of each chromosome arm has been deleted and the broken arms reunite to form a ring.

MITOTIC CELL DEATH

The type of cell death that results from failure to arrest the cell cycle before or during mitosis in response to DNA damage with hallmarks including nuclear fragmentation and multiple micronuclei.

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Chen, J., Stubbe, J. Bleomycins: towards better therapeutics. Nat Rev Cancer 5, 102–112 (2005). https://doi.org/10.1038/nrc1547

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