B. R. Abdella and J. Fischer, A chemical perspective on the anthracycline antitumour antibiotics, Environ. Health Perspect, vol.64, pp.3-18, 1985.

S. A. Akman, J. H. Doroshow, T. G. Burke, and M. Dizdaroglu, DNA base modifications induced in isolated human chromatin by NADH dehydrogenase-catalysed reduction of doxorubicin, Biochemistry, vol.31, pp.3500-3506, 1992.

R. J. Anders, J. O. Shanes, and F. P. Zeller, Lower incidence of doxorubicin-induced cardiomyopathy by once a week low-dose administration, American Heart Journal, vol.111, issue.4, pp.755-759, 1986.

S. Balanehru and B. Nagarajan, Intervention of adriamycin induced free radical damage, Biochemistry international, vol.28, issue.4, pp.735-744, 1992.

A. Bartoszek and C. R. Wolf, Enhancement of doxorubicin toxicity following activation by NADPH cytochrome-P450 reductase, Biochem. Pharmacol, vol.43, issue.7, pp.1449-1457, 1992.

W. T. Bellamy, W. S. Dalton, P. Meltzer, and R. T. Dorr, Role of glutathione and its associated enzymes in multidrug-resistant human myeloma cells, Biochem. Pharmacol, vol.38, pp.787-793, 1989.

M. N. Benchekroun, P. Catroux, D. Montaudon, and J. Robert, Development of mechanisms of protection against oxidative stress in doxorubicin-resistant rat tumoral cells in culture, Free Rad. Res. Comms, vol.11, issue.1-3, pp.137-144, 1990.

T. M. Bray and W. Bettger, The physiological role of zinc as antioxidant. Free Rad, Biot. Med, vol.8, pp.281-291, 1990.

D. E. Brenner, W. W. Grosh, R. Noone, R. Stein, F. A. Greco et al., Human plasma pharmacokinetics of doxorubicin: comparison of bolus and infusional administration, Cancer Treat. Symp, vol.3, pp.77-83, 1984.

M. R. Bristow, N. E. Kantrowitz, W. D. Harrison, W. A. Minobe, W. S. Sageman et al., Mediation of subacute anthracycline cardiotoxicity in rabbits by cardiac histamine release, J. Cardiovasc. Pharmacol, vol.5, pp.913-919, 1983.

B. Calderon, P. Praet, M. Ruysschaert, J. M. Roberfroid, and M. , Reduction of toxicity and increase antitumor effect of adriamycin by N-acyl dehydroalanines, a new family of free radical scavengers, Adv. Exp. Med. Biol, vol.264, pp.339-344, 1990.

J. Cadet and M. Weinfeld, Detecting DNA damage, Analytical Chemistry, vol.65, issue.15, pp.675-682, 1993.

C. C. Chao, Y. T. Huang, C. M. Ma, W. Y. Chou, and S. L. Chao, Overexpression of glutathione S-transferase and elevation of thiol pools in a multidrug-resistant human colon cancer cell line, Molecular Pharmacology, vol.41, pp.69-75, 1991.

J. Y. Charcosset, La résistance aux agents antitumoraux cytotoxiques, pp.163-174, 1991.

M. Chvapil, J. N. Ryan, S. L. Elias, and Y. M. Peng, Protective effect of zinc on carbon tetrachloride-induced liver injury in rats, Exp. Mol. Pharmacol, vol.19, pp.186-196, 1973.

C. Coudray, V. Charlon, J. De-leiris, and A. Favier, Effect of zinc deficiency on lipid peroxidation status and infarct size in rat hearts. /nt, J. Cardiology, vol.41, pp.109-113, 1993.

S. Crauste-manciet, P. Faure, I. Madelaine, and J. L. Saulnier, Anticancéreux: utilisation pratique. Dossier du CNIMH, hors série, 1992.

J. Cummings and J. F. Smyth, Pharmacology of adrian1ycin: the message to the clinician

, Eur. J. Cancer. Clin. Oncol, vol.24, issue.4, pp.579-582, 1987.

J. Cummings, L. Anderson, N. Willmott, and J. F. Smyth, The molecular pharmacology of Doxorubicin in vivo, Eur. J. Cancer, vol.27, issue.5, pp.532-535, 1991.

K. J. Davies, Protein damage and degradation by oxygen radicals: general aspects, J. Biot. Chem, vol.262, issue.20, pp.9895-9901, 1987.

K. J. Davies, M. E. Delsignore, and S. W. Lin, Protein damage and degradation by oxygen radicals: modification of amino acids, J. Biol. Chem, vol.262, issue.20, pp.9902-9907, 1987.

K. J. Davies and M. E. Delsignore, Protein damage and degradation by oxygen radicals: modification of secondary and tertiary structure, J. Biot. Chem, vol.262, issue.20, pp.9908-9913, 1987.

K. J. Davies, S. W. Lin, and R. E. Pacifici, Protein damage and degradation by oxygen radicals: degradation of denatured protein, J. Biot. Chem, vol.262, issue.20, pp.9914-9920, 1987.

R. T. Dean and K. H. Cheeseman, Vitamin E protects proteins against free radical damage in lipid environments, Biochem. Biophys. Res. Comms, vol.148, issue.3, pp.1277-1282, 1987.

D. Maestro, R. F. Thaw, H. H. Bjork, J. Planker, M. Arfors et al., Free radicals as mediators of tissue injury, Acta Physiol. Scand, vol.492, pp.43-57, 1980.

E. J. Demant and N. Noerskov-lauritsen, Binding of transferrin-iron by adriamycin at acidic pH, Febs Lett, vol.196, pp.321-324, 1986.

E. J. Demant, Inactivation of cytochrome c oxidase activity in mitochondrial membranes during redox cycling of doxorubicin, Biochem. Pharmacol, vol.41, issue.4, pp.543-552, 1991.

D. Monte, D. Bellomo, G. Thor, H. Nicotera, P. Orrenius et al., Menadione-induced cytotoxicity is associated with protein thiol oxidation and alteration in intracellular Ca2+ homeostasis, Arch. Biochem. Biophys, vol.235, issue.2, pp.343-350, 1984.

J. H. Doroshow, G. Y. Locker, and C. E. Myers, Prevention of doxorubicin cardiac toxicity by N-acetylcysteine, J. Clin. Invest, vol.65, pp.128-135, 1981.

J. H. Doroshow, Effect of anthracycline antibiotics on oxygen radical formation in rat heart, Cancer Res, vol.43, pp.460-472, 1983.

J. H. Doroshow, Doxorubicin-induced cardiac toxicity, N. Engt. J. Med, vol.324, issue.12, pp.843-845, 1991.

H. Eliot, L. Gianni, and C. E. Myers, Oxidative destruction of DNA by the adriamycin-iron complex, Biochemistry, vol.23, pp.928-936, 1984.

J. Emerit, J. Fechner, A. Galli, J. P. Clavel, and F. Congy, Les radicaux libres dérivés de l'oxygène et la peroxydation lipidique. Rôle en biologie et en physiopathologie. Presse méd, vol.15, pp.751-754, 1986.

M. Espie, J. M. Extra, and M. Marty, Pharmacologie anticancéreuse. In Schorderet M.: Pharmacologie, des concepts fondamentaux aux applications thérapeutiques. FrisonRoche, 1992.

A. Favier, Ecole d'été de formation à la biologie des radicaux libres, Defence of the body against free radicals, 1992.

, Biological aspect of superoxyde radical and superoxide dismutases, pp.171-181, 1977.

F. 1. , The biology of oxygen radical, Science, vol.201, pp.875-880, 1978.

M. Fry and D. E. Green, Cardiolipin requirement for electron transfer in complex 1 and III of the mitochondrial respiratory chain, J. Biot. Chem, vol.256, pp.1874-1880, 1981.

L. X. Fu, F. Waagstein, and A. Hjalmarson, A new insight into adriamycin-induced cardiotoxicity. /nt, J. of Cardiology, vol.29, pp.15-20, 1990.

G. T. Gabit and B. M. Barior, The oxygen forming oxidase responsible for the respiratory burst in human neutrophils, J. Biot. Chem, vol.254, pp.9070-9074, 1979.

A. Geetha and C. S. Shyamala-devi, Effect of doxorubicin on heart mitochondrial enzymes in rats: a protective role for alpha-tocopherol, Indian J. Experimentat Biology, vol.30, pp.615-618, 1992.

L. Gianni, J. Corden, and C. E. Myers, The biochemical basis of anthracycline toxicity and antitumor activity, Rev. Biochem. Toxicot, vol.5, pp.1-82, 1983.

J. Goodman and P. Hochstein, Generation of free radicals and lipid peroxidation by redox cycling of adriamycin and daunomycin, Biochem. Biophys. Res. Commun, vol.77, pp.797-803, 1977.

M. D. Green, J. L. Speyer, and F. M. Muggia, Cardiotoxicity of anthracyclines, Eur. J. Cancer Clin. Oncol, vol.20, issue.2, pp.293-296, 1984.

E. A. Griffin-green and M. Zaleska, Adriamycin induced lipid peroxidation in mitochondria and microsomes, Biochem. Pharmacol, vol.37, pp.3071-3077, 1988.

J. M. Gutteridge, Antioxidant properties of caeruloplasmin toward copper and iron dependant oxygen radical formation, Febs Lett, vol.172, pp.245-249, 1984.

B. Halliwell and C. H. Foyer, Ascorbic acid, metal ions and the superoxide radical, Biochem. J, vol.155, pp.697-700, 1976.

B. Halliwell and J. M. Gutteridge, Free radicals in biology and medicine, 1989.

R. N. Harris and J. H. Doroshow, Effect of doxorubicin-enhanced hydrogen peroxide and hydroxyl radical formation on calcium sequestration by cardiac sarcoplasmic reticulum, Biochem. Biophys. Res. Commun, vol.130, pp.739-745, 1985.

B. B. Hasinoff and J. P. Davey, Adriamycin and its iron(III) and copper(II) complexes, Biochem. Pharmacol, vol.37, issue.19, pp.3663-3669, 1988.

H. Hida, Etude de l'effet des antioxydants sur la peroxydation microsomale induite par l'adriamycine. Mémoire du DES de pharmacie hospitalière et des collectivités 1993, Anticancereux et especes reactives de l'oxygene, vol.1

P. C. Jocelyn, Spectrophotometric assay of thiols, Methods in enzymotogy, vol.143, pp.44-67, 1987.

H. G. Keizer, H. M. Pinedo, G. J. Schuurhuis, and H. Joenje, Doxorubicin (Adriamycin): a critical review of free radical-dependent mechanisms of cytotoxicity, vol.47, pp.219-231, 1990.

C. D. Klaasen and G. L. Plaa, Comparaison of the biological alteration elicited in li ver from rats treated with carbon tetrachloric acid, chloroform, 1 '1 '2-trichloroethane and 1 '1 '1-trichloroethane, Biochem. Pharmacol, vol.15, pp.374-384, 1969.

D. J. Kombrust and R. D. Mavis, Relative susceptibility of microsomes from lung, heart, liver, kidney, brain and testes to lipid peroxidation: correlation with vitamin E content, Lipids, vol.15, issue.5, pp.315-322, 1979.

N. I. Krinsky, Antioxidant functions of carotenoids. Free Rad, Biol. Med, vol.7, pp.617-635, 1989.

V. Lee, A. K. Randhawa, and P. K. Singal, Adriamycin-induced myocardial dysfunction in vitro is mediated by free radicals, Am. J. Physiol, vol.261, pp.989-995, 1991.

S. S. Legha, Y. M. Wang, B. Mackay, M. Ewer, G. N. Hortobagyi et al., Clinical and pharmacologie investigation of the effects of a-tocopherol on adriamycin cardiotoxicity, Annals New-York Academy of Sciences, pp.411-416, 1982.

T. J. Lin, G. Y. Liu, and G. Z. Xu, Protection by salvianolic acid A against adriamycin toxicity on rat heart mitochondria

, Biol. Med, vol.12, pp.347-351, 1992.

S. F. Llesuy, J. Milei, B. S. Gonzalez-flecha, and A. Boveris, Myocardial damage induced by doxorubicins: Hydroperoxide-initiated chemiluminescence and morphology. Free Rad, Biot. Med, vol.8, pp.259-264, 1990.

W. Lown, H. Chen, and J. A. Plambeck, Further studies on the generation of reactives oxygen species from activated anthracyclines and the relationship to cytotoxic action and cardiotoxic effects, Biochem. Pharmacol, vol.31, issue.4, pp.575-581, 1982.

O. H. Lowry, N. J. Rosbrough, A. L. Farr, and R. J. Randal, J. Biot. Chem, vol.193, pp.265-275, 1951.

F. P. Mettler, D. M. Young, and J. M. Ward, Adriamycin-induced cardiotoxicity (cardiomyopathy and congestive heart failure) in rats, Cancer Res, vol.37, pp.2705-2713, 1977.

E. G. Mimnaugh, M. A. Trush, and T. E. Gram, Stimulation by adriamycin of rat heart and liver microsomal NADPH-dependent lipid peroxidation, Biochem. Pharmacol, vol.30, issue.20, pp.2797-2804, 1981.

G. Minotti and S. D. Aust, The role of iron on the initiation of lipid peroxidation, Chem. Phys. Lipids, vol.44, pp.191-208, 1987.

G. Minotti, Adriamycin-dependent release of iron from microsomal membranes, Arch. Biochem. Biophys, vol.268, pp.398-403, 1989.

O. Minotti, Reactions of adriamycin with microsomal iron and lipids. Free Rad, Res. Comms, vol.7, issue.3-6, pp.143-148, 1989.

O. Minotti, M. Di-gennaro, D. Granone, and P. , Possible sources of iron for lipid peroxidation, Free Rad. Res. Comms, pp.99-106, 1991.

H. P. Monteiro, G. F. Vile, and C. C. Winterboum, Release of iron from ferritin by semiquinone, anthracycline, bipyridyl and nitroaromatic radicals. Free Radie, vol.6, pp.587-591, 1989.

E. Monti, L. Paracchini, O. Perletti, and F. Piccinini, Protective effects of spin-trapping agents on adriamycin-induced cardiotoxicity in isolated rat atria, Free Rad. Res. Comms, vol.14, issue.1, pp.41-45, 1991.

J. R. Muindi, B. K. Sinha, L. Gianni, and C. E. Myers, Hydroxyl radical production and DNA damage induced by anthracycline-iron complex, Febs Lett, vol.172, issue.2, pp.226-230, 1984.

C. E. Myers, W. Mc-guire, and R. Young, Adriamycin: amelioration of toxicity by alphatocopherol, Cancer Treatment Reports, vol.60, issue.7, pp.961-962, 1976.

A. L. Odom, C. A. Hatwig, J. S. Stanley, and A. M. Benson, Biochemical determinants of adriamycin toxicity in mouse liver, heart, and intestine, Biochem. Pharmacol, vol.43, issue.4, pp.831-836, 1992.

R. D. Olson and P. S. Mushlin, Doxorubicin cardiotoxicity: analysis of prevailing hypotheses, Faseb J, vol.4, pp.3076-3086, 1990.

P. Palozza and N. I. Krinsky, The inhibition of radical-initiated peroxidation of microsomal lipids by both alpha-tocopherol and B-carotène. Free Rad, vol.11, pp.407-414, 1991.

O. Paradies and F. M. Ruggiero, The effect of doxorubicin on the transport of pyruvate in rat-heart mitochondria, Biochem. Biophys. Res. Comms, vol.156, pp.1302-1307, 1988.

O. Powis, Anthracycline metabolism and free radical formation, Metabolism and action of anticancer drugs, pp.211-260, 1987.

O. Powis, Free radical formation by antitumor quinones. Free Rad, Biol. Med, vol.6, pp.63-101, 1989.

S. R. Powell and P. B. Mc-cay, Inhibition of doxorubicin-initiated membrane damage by Nacetylcysyeine: possible mediation by a thiol-dependent, cytosolic inhibitor of lipid peroxidation, Toxicol. Appt. Pharmacol, vol.96, pp.175-184, 1988.

C. A. Pritsos, M. Sokoloff, and D. L. Gustaf-son, PZ-51 (Ebselen) in vivo protection against adriamycin-induced mouse cardiac and hepatic lipid peroxidation and toxicity, Biochem. Pharmacol, vol.44, issue.4, pp.839-841, 1992.

A. Ramu, L. Cohen, and D. Glaubiger, Oxygen radical detoxification enzymes in doxorubicin-sensitive and -resistant P388 murine leukemia cells, Cancer Res, vol.44, 1976.

C. C. Reddy and E. T. Massaro, Biochemistry of selenium. A brief overview, Fundam. Appl. Toxicol, vol.3, pp.431-436, 1983.

C. C. Winterbourn, J. M. Gutteridge, and B. Halliwell, Doxorubicin-dependent lipid peroxidation at low partial pressures of 02, J. Free Rad. Biot. Med, vol.1, pp.43-49, 1985.

C. C. Winterboum, G. F. Vile, and H. P. Monteiro, Ferritin, lipid peroxidation and redoxcycling xenobiotics, Free Rad. Res. Comms, pp.107-114, 1991.

. Liste-des-abreviations-adr:-adriamycine, A. Doxorubicine, and . Sq, Adriamycine Semiquinone AGPI: Acides gras polyinsaturés AR: Acide 13-cis rétinoïque CA T: Catalase ERO: Espèces réactives oxygénées GPX: Glutathion peroxydase H202: Peroxyde d'hydrogène MDA: Malondialdehyde NA C: N-acétylcystéine NADPH: Nicotinamide adénine dinucléotide phosphate 0 0H: Radical hydroxyle RLO: Radicaux libres oxygénés SOD: Superoxyde dismutase Abréviations