Bleomycin, oxidation with

Although, as stated above, we wiU mostly focus on hydrolytic systems it is worth discussing oxidation catalysts briefly [8]. Probably the best known of these systems is exemphfied by the antitumor antibiotics belonging to the family of bleomycins (Fig. 6.1) [9]. These molecules may be included in the hst of peptide-based catalysts because of the presence of a small peptide which is involved both in the coordination to the metal ion (essential co-factor for the catalyst) and as a tether for a bisthiazole moiety that ensures interaction with DNA. It has recently been reported that bleomycins will also cleave RNA [10]. With these antibiotics DNA cleavage is known to be selective, preferentially occurring at 5 -GpC-3 and 5 -GpT-3 sequences, and results from metal-dependent oxidation [11]. Thus it is not a cleavage that occurs at the level of a P-O bond as expected for a non-hydrolytic mechanism. 

Portugal J, Waring MJ (1987) Interaction of nucleosome core particles with distamycin and echinomycin analysis of the effect of DNA sequences. Nucleic Acids Res 15(3) 885-903 Povirk LF, Goldberg IH (1987) A role of oxidative DNA sugar damage in mutagenesis by neocarzino-statin and bleomycin. Biochimie 69(8) 815-823... 

LCLs derived from targeted populations have been utilized to evaluate genetic susceptibility to radiation sensitivity (9), sensitivity to mitomycin C in patients with Wilms tumor (10), and camptothecin-induced apoptosis (11). These cell lines have been useful for studying bleomycin-induced chromatid breaks and oxidant-induced apoptosis (12)... 

Oxidative stress reduces the rate of cell proliferation, and that occurring during chemotherapy may interfere with the cytotoxic effects of antineoplastic drugs, which depend on rapid proliferation of cancer cells for optimal activity. Antioxidants detoxify ROS and may enhance the anticancer effects of chemotherapy. For some supplements, activities beyond their antioxidant properties, such as inhibition of topoisomerase II or protein tyrosine kinases, may also contribute. ROS cause or contribute to certain side effects that are common to many anticancer drugs, such as gastrointestinal toxicity and muagenesis. ROS also contribute to side effects that occur only with individual agents, such as doxorubicin-induced cardiotoxicity, cisplatin-induced nephrotoxicity, and bleomycin-induced pulmonary fibrosis. Antioxidants can reduce or prevent many of these side effects, and for some supplements the protective effect results from activities other than their antioxidant properties. Certain side effects, however, such as alopecia and myelosuppression, are not prevented... 

The interaction of the anti-tumour antibiotic bleomycin with DNA under conditions of limiting oxygen results in the production of a free nucleic base and an oxidatively damaged sugar-lesion. Studies on d(CGCTGCGT) demonstrate... 

Fig. 2. Different routes for the generation of activated bleomycin. The formal oxidation state (V) of the bleomycin-iron-oxo species (perferryl complex) is two oxidant equivalents above BLM-Fe ", but one oxidant equivalent might be located on the ligand, as in Compound I of peroxidases, with an iron" -oxo-ligand radical cation structure.

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