Bleomycin factors

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. 

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... 

Kurten S, Obe, G (1975) Premature chromosome condensation in the bone marrow of Chinese hamster after pUcation of bleomycin in vivo. Mutat Res 27(2) 285—294 Lee DY, Hayes JJ, Pruss D, Wolffe AP (1993) A positive role for histone acetylation in transcription factor access to nucleosomal DNA. Cell 72 73—84... 

The anthracycline antibiotics, which include doxorubicin, daunorubicin, bleomycin, and mitomycin C, inhibit DNA and RNA synthesis. Doxorubicin also interfers with topoisomerase II (a DNA gyrase), the activity of which is markedly increased in proliferating cells. Structurally related to doxorubicin are epirubicin and mitozantrone. The cytotoxic antibiotics are used to treat leukaemias and lymphomas and also for solid tumours in the breast, lung, thyroid and ovary. Cardiotoxicity is the major dose-limiting factor, with arrhythmias and myocardial depression (Bacon and Nuzzo 1993). The chronic phase of cardiotoxicity is a dose-dependent cardiomyopathy that leads to congestive heart failure in 2-10% of patients. Myocardial injury is the result of oxygen free radical formation. Children are particularly sensitive to these cardiotoxic reactions and may require a heart transplant in their later years. Epirubicin is less cardiotoxic than doxorubicin. 

Acute febrile interstitial pneumonitis occurred within less than 48 hours after the second to fourth cycles of chemotherapy (doxorubicin, cyclophosphamide, bleomycin, methotrexate, plus methylprednisolone) in five patients with non-Hodgkin s lymphoma who were receiving prophylactic G-CSF n — 3) or GM-CSF (n = 2) (23). Lymphocytic alveolitis was confirmed in four of these patients and all three patients tested had an increased number of CD8+ T cells. Even though all the patients received high-dose methylprednisolone, two died as a result of diffuse and extensive interstitial pulmonary fibrosis, demonstrated at postmortem. Although both G-CSF and GM-CSF can cause acute pneumonitis in patients with cancers, it is still unknown to what extent hemopoietic growth factors are involved in this complication. 

Bleomycins and their analogues occur naturally as blue copper chelates. Removal of the copper by chemical reduction or complexing agents affords the antibiotics as white solid.s. Copper-free bleomycin is the active. species for chemotherapy, and it has lower toxicity. Bleomycin complexes readily with metal ion.s. which is a key factor in its mode of action. In.sidc the cell, bleomycin forms a chclatc with Fe(ll) that has square pyramidal gcomctiy. Nitrogen atoms from bleomycin occupy five of the po.sitions in this structure. The sixth position may be occupied by the carboxyl group of the carhamate function, but this group is... 

Denholm, E.M. and Rollins, S.M. (1993). Expression and secretion of transforming growth factor /3 by bleomycin-stimulated rat alveolar macrophages. Am. J. Physiol. 264 (Lung. Cell. Mol. Physiol. 8), L36-L42. 

Giri, S.N., Hyde, D.M. and HoUinger, M.A. (1993). Effect of antibody to transforming growth factor 0 on bleomycin induced accumulation of lung collagen in mice. Thorax 48, 959-966. 

Hoyt, D.G. and Lazo, J.S. (1988). Alteration of pulmonary mRNA encoding procollagens, fibronectin and transforming growth factor b precede bleomycin-induced pulmonary fibrosis in mice. J. Pharmacol. Exp. Ther. 246, 765-771. 

Phan, S.H., Gharaee-Kermani, M., Wolber, F. and Ryan, U.S. (1991). Stimulation of rat endothelial cell transforming growth factor production by bleomycin. J. Clin. Invest. 87, 148-154. 

Piguet, P.F., CoUart, M.A., Grau, G.E., Kapanci, Y. and Vas-salli, P. (1989). Tumour necrosis factor/cachectin plays a key role in bleomycin-induced pneumopathy and fibrosis. J. Exp. Med. 170, 655-663. 

Lasky JA, Ortiz LA, Tonthat B, Hoyle GW, Corti M, et al. 1998. Connective tissue growth factor mRNA expression is up-regulated in bleomycin-induced lung fibrosis. Am. Physiol. Soc. 275 L365-71... 

Gurujeyalakshmi G, Wang Y, Giri SN. 2000. Taurine and niacin block lung injury and fibrosis by down-regulating bleomycin-induced activation of transcription nuclear factor-kB in mice. J. Pharmacol. Exp. Ther. 293 82-90... 

Effects of pirfenidone on transforming growth factor-/ gene expression at the transcriptional level in bleomycin hamster model of lung fibrosis. J. Pharmacol. Exp. Ther. 291 367-73... 

Wang Q, Wang Y, Hyde DM, Gotwals PJ, Koteliansky VE, et al. 1999. Reduction of bleomycin induced lung fibrosis by transforming factor p soluble receptor in hamsters. Thorax 54 805-12... 

Wang Q, Hyde DM, Gotwals PJ, Giri. SN. 2002. Effects of delayed treatment with transforming growth factor-/ soluble receptor in a three-dose bleomycin model of... 

Giri SN, Sharma AK, Hyde DM, Wild JS. 1995. Amelioration of bleomycin-induced lung fibrosis by treatment with the platelet activating factor receptor antagonist WEB 2086 in hamsters. Exp. Lung Res. 21 287-307... 

Keerthisingam CB, Jenkins RG, Harrison NK, Hemandez-Rodriguez NA, Booth H, et al. 2001. Cyclooxygenase-2 deficiency results in a loss of the anti-proliferative response to transforming growth factor-f i in human fibrotic lung fibroblasts and promotes bleomycin-induced pulmonary fibrosis in mice. Hot. J. Pathol. 158 1411— 22... 

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