Bleomycin mechanisms

Natrajan A, Hecht SM (1994) Bleomycins mechanism of polynucleotide recognition and oxydative degradation. In Neidle S, Waring M (eds) Molecular aspects of anticancer drug-DNA interactions. MacMillan, London, pp 197-242... 

Chemotherapeutic agents are grouped by cytotoxic mechanism. The alkylating agents, such as cyclophosphamide [50-18-0] and melphalan [148-82-3] interfere with normal cellular activity by alkylation deoxyribonucleic acid (DNA). Antimetabohtes, interfering with complex metaboHc pathways in the cell, include methotrexate [59-05-2] 5-fluorouracil [51-21-8] and cytosine arabinoside hydrochloride [69-74-9]. Antibiotics such as bleomycin [11056-06-7] and doxombicin [23214-92-8] h.a.ve been used, as have the plant alkaloids vincristine [57-22-7] and vinblastine [865-21-4]. 

Bleomycin sulfate is used alone or in combination with other antineoplastic dmgs. Using this DNA-cleaving dmg, disease-free (possibly cured) survivors of some cancers have been seen, especially with the use of bleomycin in multidmg regimens. General reviews of bleomycin (234,242—245) and its mechanism of action (246—249) are available. 

In general, the mechanisms of action are not cell cycle specific, although some members of the class show greatest activity at certain phases of the cell cycle, such as S-phase (anthracyclins, mitoxantrone), Gl- and early S-phases (mitomycin C) and G2- and M-phases (bleomycins). 

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. 

Cooperative work with Prof. Nobuo Tanaka (Professor Emeritus of the University of Tokyo) in 1969 showed the mechanism of action of bleomycin to involve DNA strand-scission. The difficult total synthesis of bleomycin was accomplished (1981) in cooperation with Takita and others, including Hamao s son, Yoji Umezawa. H. Umezawa was very satisfied with the success of this total synthesis, and his sustained enthusiasm for improved bleomycins led to peplomycin (1978 used clinically since 1981) and libro-mycin(1985). 

All of Hamao U mezawa s work was closely connected with carbohydrates. The principal compounds that he developed, namely, kanamycin, dibekacin (with the elucidation of the resistance mechanism), kasugamycin, formycin, bleomycin, and anthracyclines, are all glycosides. The l.m.w. enzyme-inhibitors, exemplified by bestatin, are mostly oligopeptides, and are the only exceptions. 

Studies on the mechanism of antitumor elfect of bleomycin on squamous cell carcinoma, H. Umezawa, T. Takeuchi, S. Hori, T. Sawa, M. Ishizuka, T. Ichikawa, and T. Komai, J. Antibiot., 25 (1972) 409-420. 

A 34-year-old male with Hodgkin s disease is treated with the adri-amycin, bleomycin, vinblastine, and decarbazine (ABVD) regimen. What is the mechanism of action of vinblastine ... 

GUoni, L., Takeshita, M., Johnson, F., Iden, C., and Grollman, A. P., 1981, Bleomycin-induced strand-scission ofDNA. Mechanism of deoxyiibose cleavage,/. Biol. Chem. 256 8608-8615. 

Giloni L, Takeshita M, Johnson F, Iden C, Grollman AP (1981) Bleomycin induced strand-scission of DNA. Mechanism of deoxyribose cleavage. J Biol Chem 256(16) 8608-8615 Gniazdowski M, Czyz M (1999) Transcription factors as targets of anticancer drugs. Acta Biochim Pol 46(2) 255-262... 

Steighner RJ, Povirk LF (1990) Bleomycin-induced DNA lesions at mutational hot spots imphcations for the mechanism of double-strand cleavage. Proc Natl Acad Sci USA 87(21) 8350-8354 Straney DC, Crothers DM (1987) Effect of drug-DNA interactions upon transcription initiation at the lac promoter. Biochemistry 26(7) 1987-1995... 

Fig. 2. Mechanisms causing resistance to antitumor treatment. ATM. ataxia telangiectasia gene, (Westphal et al., 1998 Xu and Baltimore, 1996), bcl-2/bax (Farrow and Brown, 1996, Zunino et al., 1997 Haq and Zanke, 1998), bcr/abl (McGahon et al., 1994), BCRP, breast cancer resistance protein (Doyle et d., 1998 Ross et al, 1999) bleomycin hydrolase (El-Deiry, 1997), BRCAl (Husain et al., 1998 Chen et al., 1998), BRCA2 (Chen et al., 1998 Chen et 1999), c-abl (White and Prives, 1999), c-jun (Sanchez-Perez and Perona, 1999), cytidine deaminase (El-Deiry, 1997), DNA poip, DNA polymerase p (Ochs et al., 1999), dihydrofolate reductase (Schimke, 1986), DT-diaphorase (Riley and Workman, 1992 Fitzsimmons et al., 1996 El-Deiry, 1997), EGR-1 (Ahmed et al., 1996), fos (Niimi et al., 1991), glucosylceramide synthase...

Burger RM, Projan SJ, Horwitz SB, Peisach J (1986) The DNA cleavage mechanism of iron-bleomycin. J Biol Chem 261 15955-15959... 

Dedon PC, Goldberg IH (1992) Free-radical mechanisms involved in the formation of sequence-de-pendent bistranded DNA lesions by the antitumor antibiotics bleomycin, neocarzinostatin, and calicheamicin. Chem Res Toxicol 5 311 -332... 

Hecht SM, Long EC, van Atta RB, De Vroom E, Carter BJ (1990) On the mechanism of bleomycin activation and polynucleotide strand scission. In Bleasdale C, Golding BT (eds) Mol. Mech. Bioorg. Processes, Conference Proceedings. Royal. Soc. Chem., London, pp 100-114 Held AM, Halko DJ, Hurst JK (1978) Mechanisms of chlorine oxidation of hydrogen peroxide. J Am Chem Soc 100 5732-5740... 

McGall GFI, Rabow LE, Ashley GW, Wu SH, Kozarich JW, Stubbe J (1992) New insight into the mechanism of base propenal formation during bleomycin-mediated DNA degradation. J Am Chem Soc 114 4958-4967... 

OwaT, Sugiyama T, Otsuka M, Ohno M (1990) A model study on the mechanism of theautoxidation of bleomycin. Tetrahedron Lett 31 6063-6066... 

Stillman MJ, Shaw CF III, Suzuki KT (1992) Metallothioneins. Synthesis, structure, and properties of metallothioneins, phytochelatins and metal-thiolate complexes. VCH Publishers, New York Stratford IJ, Hoe S, Adams GE, Hardy C, Williamson C (1983) Abnormal radiosensitizing and cytotoxic properties of ortho-substituted nitroimidazoles. Int J Radiat Biol 43 31-43 Stubbe J, Kozarich JW (1987) Mechanisms of bleomycin-induced DNA degradation. Chem Rev 87 1107-1136... 

Wojcik A, Opalka B, Obe G (1999) Analysis of inversions and sister chromatide exchanges in chromosome 3 of human lymphocytes exposed to X-rays. Mutagenesis 14 633-637 Wojcik A, von Sonntag C, Obe G (2003) Application of the biotin-dUTP chromosome-labelling tech-nigue to study the role of 5-bromo-2 -deoxyuridine in the formation of UV-induced sister chromatid exchanges in CHO cells. J Photochem Photobiol B Biol 69 139-144 Wu JC, Kozarich JW, Stubbe J (1983) The mechanism of free base formation from DNA by bleomycin. J Biol Chem 258 4694-4697... 

Wu JC, Kozarich JW, Stubbe J (1985a) Mechanism of bleomycin evidence for a rate-determining 4 -hydrogen abstraction from poly(dA-dU) association with the formation of both free base and base propenal. Biochemistry 24 7562-7568... 

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