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INTRODUCTION

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Natural product research has yielded many active anticancer compounds acting as inhibitors of topoisomerases (Chapter 4) and as antimitotics (Chapter 4). Others, such as bleomycin and trabectedin, interact directly with DNA and exhibit unusual mechanisms of action.

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BLEOMYCIN

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Traditional fermentation research has been the backbone of efforts to discover anti-infective and antitumor agents. From this research has come bleomycin, a drug important in the curative combination therapy of Hodgkin disease and testicular germ cell tumors. Among the exquisite cytotoxics designed by nature, the most unique is bleomycin, which was isolated from the broth of the fungus, Streptomyces verticillus. The clinical bleomycin preparation consists of a family of peptides that share a common C-terminal metal binding core, attached to a variable DNA binding portion with different substitutions on the amino-terminal end of the molecule (Figure 7-1). The various bleomycin peptides have a molecular weight of about 1500, and differ in their potency for DNA cleavage, but share a common chemistry. The predominant peptide, bleomycin A2, comprises 70% of the clinical preparation.

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MECHANISM OF ACTION

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The bleomycin peptides function as carriers for a catalytic metal that undergoes rapid cycles of oxidation/reduction (1). The metal may be copper, iron, cobalt, zinc, or others. The metal ligand is bound in a coordination complex of amine groups contributed by the unusual amino acids of the peptide. All metals but the cobalt species are readily exchangeable; thus 57-Co (II) bleomycin is sufficiently stable to be used as a tumor-imaging agent. The clinical preparation of bleomycin is metal free, but upon administration rapidly acquires Cu (II) or Fe (II), the latter probably representing the active form of the drug. Bleomycin binds to DNA by intercalation of its C-terminal bithiazole groups between guanine bases in adjacent DNA strands. Intercalation brings the bleomycin metal group into proximity with the deoxyribose backbone of DNA. The radicals released by cycles of oxidation/reduction of the metal core oxidize adjacent deoxyribose groups at the 3′-4′ bond, releasing propenal or propenal-thymine as its most frequent products (Figure 7-2). DNA single and double strand breaks (in the ratio of 10:1) result and must be repaired if the cell is to survive. If double strand breaks are sufficient in number, the cell undergoes apoptosis. Cells deficient in double strand break repair, such as those from tumors with BRCA1 mutation, are highly sensitive to bleomycin (2).

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FIGURE 7-2

Intercalation of bithiazole groups between DNA strands in which one strand has the preferred sequence of GpT or GpC. The Fe++–O2 complex bound to bleomycin comes in opposition to the deoxyribose of DNA, abstracting a proton and cleaving the deoxyribose phosphate bond.

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