This Article Abstract Free Full Text (Free PDF) Free Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Saved Citations Download to citation manager Request Permissions Request Reprints Add to My Marked Citations Citing Articles Citing Articles via Google Scholar Citing Articles via Scopus Google Scholar Articles by Zima, T. Articles by Preedy, V. R. Search for Related Content PubMed PubMed Citation Articles by Zima, T. Articles by Preedy, V. R. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Hazardous Substances DB DOXORUBICIN Social Bookmarking                         What's this?

Acute Dosage With Dexrazoxane, but not Doxorubicin, Is Associated With Increased Rates of Hepatic Protein Synthesis in vivo

1st Institute of Clinical Chemistry and Biochemistry, First Faculty of Medicine, Charles University, Prague 2, Czech Republic

Vladimir Tesar

1st Institute of Clinical Chemistry and Biochemistry, First Faculty of Medicine, Charles University, Prague 2, Czech Republic

Roy Sherwood

Department of Clinical Biochemistry Guy's, King's and St Thomas' Medical School, King's College London, London

Alka Sood

Department of Clinical Biochemistry Guy's, King's and St Thomas' Medical School, King's College London, London

Lai-Chong Au

Department of Clinical Biochemistry Guy's, King's and St Thomas' Medical School, King's College London, London

Peter J. Richardson

Department of Cardiology, Guy's, King's and St Thomas' Medical School, King's College London, London

Victor R. Preedy

Department of Nutrition and Dietetics, King's College London, London, victor.preedy{at}kcl.ac.uk

An investigation was carried out into the effects of dexrazoxane and doxorubicin on hepatic protein synthesis in vivo. The protocol included 8 groups of rats and involved a pretreatment stage of 30 min followed by a treatment stage of either 2.5 or 24 h. Male Wistar rats (0.15-0.20 kg) were pretreated with either dexrazoxane (100 mg/kg; 5 ml/kg) or saline (0.15 mol/l NaCl; 5 ml/kg). At 30 min after the pretreatment, rats were again injected with either doxorubicin (5 mg/kg; 10 ml/kg) or saline (0.15 mol/l NaCl; 10 ml/kg) in the treatment phase. Rats were sacrifi ced at either 2.5 or 24 h after the last doxorubicin or saline injection. Rate of protein synthesis were measured 10 min prior to sacrifi cing rats, with a fl ooding dose of L-[4-³H]phenylalanine. Liver was analyzed for the protein synthetic capacity (C_s , mg RNA/g protein), the fractional rate of protein synthesis (k_s, %/d), and the RNA activity (k_RNA mg protein/d/mg RNA). Complementary analysis included plasma albumin, total protein and activities of alkaline phosphatase, and aspartate aminotransferase. In the 2.5-h study, doxorubici n alone had no effect on any of the above variables. Dexrazoxane alone increased C_s, k_s and k_RNA at 2.5 h. Combined dexrazoxane + doxorubicin increased hepatic C_S and k_s with concomitant reductions in total plasma protein. In the 24-h study, doxorubicin alone had no effect on any of the variables. Dexrazoxane alone had no effect on either C_S, k_s , or k_RNA but raised plasma activities of alkaline phosphatase and aspartate aminotransferase. Combined dexrazoxane + doxorubicin increased C_s and k_s and decreased total plasma protein and increased plasma aspartate aminotransferase activities at 24 h. In conclusion, there is no evidence that acutely doxorubicin per se has measurable effects on hepatic protein synthesis in vivo in an acute period. However, acutely dexrazoxane increases hepatic protein synthesis, which may represent its putative cytotoxic effects, as indicated by raised serum activities of liver enzymes. A combination of both dexrazoxane + doxorubicin appears to have a greater effect in increasing liver protein synthesis than dexrazoxane alone.

Key Words: Liver • rat • fl ooding dose • protein synthesis • doxorubicin • dexrazoxane • liver function • cytotoxicity.

References

• Anderson H., Roberge M. (1996). Topoisomerase II inhibitors affect entry into mitosis and chromosome condensatio n in BHK cells. Cell Growth Differ 7: 83—90.[Abstract]
• Bagchi D., Bagchi M., Hassoun EA, Kelly J., Stohs SJ (1995). Adriamycin-induced hepatic and myocardial lipid peroxidation and DNA damage, and enhanced excretion of urinary lipid metabolites in rats. Toxicology 95: 1—9.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• Davis TA, Fiorotto ML, Nguyen HV, Burrin DG (1999). Amino-tRNA and tissue free amino acid pools are equilibriated after a fl ooding dose of phenylalanine. Am J Physiol 277: E103—E109.[Web of Science][Medline] [Order article via Infotrieve]
• Della Torre P., Mazue G., Podesta A., Moneta D., Sammartini U., Imondi AR (1999). Protection against doxorubicin-induce d cardiotoxicity in weanling rats by dexrazoxane. Cancer Chemother Pharmacol 43: 151—156.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• El Hage AN, Herman EH, Ferrans VJ (1983). Examination of the protective effect of ICRF-187 and dimethyl sulfoxide against acetaminophen-induce d hepatotoxicity in Syrian golden hamsters. Toxicology 28: 295—303.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• Fardel O., Lecureur V., Daval S., Corlu A., Guillouzo A. (1997). Up-regulation of P-glycoprotein expression in rat liver cells by acute doxorubicin treatment. Eur J Biochem 246: 186—192.[Web of Science][Medline] [Order article via Infotrieve]
• Fattman CL, Allan WP, Hasinoff BB, Yalowich JC (1996). Collateral sensitivity to the bisdioxopiperazine dexrazoxane (ICRF-187) in etoposide (VP-16)-resistant human leukemia K562 cells. Biochem Pharmacol 52: 635—642.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• Ferrans VJ, Clark JR, Zhang J., Yu ZX, Herman EH (1997). Pathogenesis and prevention of doxorubicin cardiomyopathy. Tsitologiia 39: 928—937.[Medline] [Order article via Infotrieve]
• Garlick PJ, McNurlan MA, Preedy VR (1980). A rapid and convenient technique for measuring the rate of protein synthesis in tissues by injection of [3H]phenylalanine. Biochem J 192: 719—723.[Web of Science][Medline] [Order article via Infotrieve]
• Gornall HG, Bardawill CJ, David MM (1949). Determination of serum proteins by means of the Biuret reaction. J Biol Chem 177: 751—766.[Free Full Text]
• Hasinoff BB (1989). The interaction of the cardioprotective agent ICRF-187 [ + )-1,2-bis(3,5-dioxopiperazinyl-1-yL)propane ); its hydrolysis product (ICRF-198); and other chelating agents with the Fe(III) and Cu(II) complexes of adriamycin. Agents Actions 26: 378—385.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• Hasinoff BB (1998). Chemistry of dexrazoxane and analogues. Semin Oncol 25: 3—9.[Web of Science][Medline] [Order article via Infotrieve]
• Hasinoff BB, Abram ME, Chee GL, Huebner E., Byard EH, Barnabe N., Ferrans VJ, Yu ZX, Yalowich JC (2000). The catalytic DNA topoisomeras e II inhibitor dexrazoxane (ICRF-187) induces endopolyploidy in Chinese hamster ovary cells. J Pharmacol Exp Ther 295: 474—483.[Abstract/Free Full Text]
• Hasinoff BB, Aoyama RG (1999). Stereoselective metabolism of dexrazoxane (ICRF-187) and levrazoxane (ICRF-186). Chirality 11: 286—290.[Medline] [Order article via Infotrieve]
• Hasinoff BB, Kuschak TI, Yalowich JC, Creighton AM (1995). A QSAR study comparing the cytotoxicity and DNA topoisomerase II inhibitory effects of bisdioxopiperazine analogs of ICRF-187 (dexrazoxane). Biochem Pharmacol 50: 953—958.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• Hasinoff BB, Reinders FX, Clark V. (1991). The enzymatic hydrolysis-activation of the adriamycin cardioprotective agent ( + )-1,2-bis(3,5dioxopiperazinyl-1-yl)propane. Drug Metab Dispos 19: 74—80.[Abstract]
• Hasinoff BB, Yalowich JC, Ling Y., Buss JL ( 1996). The effect of dexrazoxane (ICRF-187) on doxorubicin- and daunorubicin-mediate dgrowth inhibition of Chinese hamster ovary cells. Anticancer Drugs 7: 558—567.[Medline] [Order article via Infotrieve]
• Herman EH, Zhang J., Chadwick DP, Ferrans VJ (2000). Comparison of the protective effects of amifostine and dexrazoxan e against the toxicity of doxorubicin in spontaneously hypertensive rats. Cancer Chemother Pharmacol 45: 329—334.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• Herman EH, Zhang J., Ferrans VJ (1994). Comparison of the protective effects of desferrioxamine and ICRF-187 against doxorubicin-induced toxicity in spontaneously hypertensive rats. Cancer Chemother Pharmacol 35: 93—100.[Web of Science][Medline] [Order article via Infotrieve]
• Holm B., Jensen PB, Sehested M. (1996). ICRF-187 rescue in etoposide treatment in vivo. A model targeting high-dose topoisomeras e II poisons to CNS tumors. Cancer Chemother Pharmacol 38: 203—209.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• Imondi AR (1998). Preclinical model s of cardiac protection and testing for effects of dexrazoxane on doxorubicin antitumor effects. Semin Oncol 25: 22—30.[Web of Science][Medline] [Order article via Infotrieve]
• Imondi AR, Della Torre P., Mazue G., Sullivan TM, Robbins TL, Hagerman LM, Podesta A., Pinciroli G. (1996). Dose-response relationship of dexrazoxane for prevention of doxorubicin-induced cardiotoxicity in mice, rats, and dogs. Cancer Res 56: 4200—4204.[Abstract/Free Full Text]
• Khelifa T., Beck WT ( 1999). Induction of apoptosis by dexrazoxane (ICRF-187) through caspases in the absence of c-jun expression and c-Jun NH2-terminal kinase 1 (JNK1) activation in VM-26-resistantCEM cells. Biochem Pharmacol 58: 1247—1257.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• Kirby GM, Bach PH ( 1995). Enhanced hexachloro-1:3-butadien e nephrotoxicity in rats with a preexisting adriamycin-induced nephrotic syndrome. Toxicologic Pathology 23: 303—312.[Abstract/Free Full Text]
• Koyama I., Arai K., Sakagishi Y., Ikezawa H., Komoda T. (1987). Blood appearance of rat alkaline phosphatas e originating from the duodenu m in vitro. J Chromatogr 420: 275—286.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• Kvetina J., Grossmann V., Svoboda Z., Safarova M. (1997). Preclinical comparison of bis-diketopiperazine-propan e (dexrazoxane) and bis-diketopiperazine-ethane (antimet) on the adriamycin-cardiotoxi c effect. Neoplasma 44: 97—99.[Web of Science][Medline] [Order article via Infotrieve]
• Lear L., Nation RL, Stupans I. (1992). Effects of cyclophosphamid e and adriamycin on rat hepatic microsomal glucuronidation and lipid peroxidation. Biochem Pharmacol44: 747—753.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• Leo E., Arletti R., Forni F., Cameroni R. (1997). General and cardiac toxicity of doxorubicin-loade d gelatin nanoparticles. Farmaco 52: 385—388.[Web of Science][Medline] [Order article via Infotrieve]
• Merski JA, Daskal I., Busch H. (1976). Effects of adriamycin on ultrastructure of nucleoli in the heart and liver cells of the rat. Cancer Res 36: 1580— 1584.[Abstract/Free Full Text]
• Monti E., Sinha BK (1990). Potentiation of doxorubicin cytotoxicity by ( + )-1,2-bis-(3,5-dioxopiperazinyl-1-yl) propane (ICRF-187) in human leukemic HL-60 cells. Cancer Commun 2: 145—149.[Web of Science][Medline] [Order article via Infotrieve]
• MorganSE, Beck WT ( 2001). Role of an inverted CCAAT element inhuman topoisomeras e II alpha gene expression in ICRF-187-sensitive and -resistant CEM leukemic cells. Mol Pharmacol 59: 203—211.[Abstract/Free Full Text]
• Mungikar AM, Gothoskar BP (1985). Depression of mouse liver microsomal mixed function oxidase enzymes by adriamycin. Toxicol Lett 29: 17—23.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• Munro HN, Fleck A. (1969). Analysis of tissues and body fl uids for nitrogenous constituents. In: Mammalian Protein Metabolism, Anonymous Academic Press, New York, pp 423—586.
• O'Leary M., Ferguson J., Hinds C., Coakley J., Preedy VR (1998). Fractional rates of liver protein synthesis (PS) in sepsis in the rat: relation to glutamine (Gln) levels. Intensive Care Med 24 (Supplement 1): S74.
• Ogura R., Sugiyama M., Haramaki N., Hidaka T. (1991). Electron spin resonance studies on the mechanism of Adriamycin-induced heart mitochondria l damages. Cancer Res 51: 3555—3558.[Abstract/Free Full Text]
• Pierscinski G., Drzewoski J., Nowak D. (1994). The infl uence of doxorubicin and 4'-epi-doxorubicin on lipid peroxidation in mouse heart, lungs and liver. Part II. Pol J Pharmacol 46: 55—59.
• Preedy VR, Marway JS, Baldwin D., Paice AG, Jones J., Wassif WS, Scott D. (1996). Experimental D-penicillamine-induced myopathy. Biochem Soc Trans 24: 266S.[Medline] [Order article via Infotrieve]
• Preedy VR, McIntosh A., Bonner AB, Peters TJ (1996). Ethanol dosage regimens in studies of ethanol toxicity: infl uence of nutrition and surgical interventions. Addict Biol 1: 255—262.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• Preedy VR, Why H., Paice AG, Reilly ME, Ansell H., Patel VB, Richardson PJ (1995). Protein synthesi s in the heart in vivo, its measurement and pathophysiologica l alterations. Int J Cardiol 50: 95—106.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• . Rajagopalan S., Politi PM, Sinha BK, Myers CE (1988). Adriamycin-induced free radical formation in the perfused rat heart: implications for cardiotoxicity. Cancer Res 48: 4766—4769.[Abstract/Free Full Text]
• Rapozzi V., Comelli M., Mavelli I., Sentjurc M., Schara M., Perissin L., Giraldi T. (1999). Melatonin and oxidative damage in mice liver induced by the prooxidant antitumor drug, adriamycin. In Vivo 13: 45—50.[Web of Science][Medline] [Order article via Infotrieve]
• Samelis GF, Stathopoulos GP, Kotsarelis D., Dontas I., Frangia C., Karayannacos PE (1998). Doxorubicin cardiotoxicity and serum lipid increase is prevented by dextrazoxane (ICRF-187). Anticancer Res 18: 3305— 3309.[Web of Science][Medline] [Order article via Infotrieve]
• Sehested M., Jensen PB (1996). Mapping of DNA topoisomerase II poisons (etoposide, clerocidin) and catalytic inhibitors (aclarubicin, ICRF-187) to four distinct steps in the topoisomerase II catalytic cycle. Biochem Pharmacol 51: 879—886.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• Seymour L., Bramwell V., Moran LA (1999). Use of dexrazoxane as a cardioprotectant in patients receiving doxorubici n or epirubicin chemotherapy for the treatment of cancer. The Provincial Systemic Treatment Disease Site Group. Cancer Prev Control 3: 145—159.[Medline] [Order article via Infotrieve]
• Shinozawa S., Gomita Y., Araki Y. (1991). Effect of aclarubicin and doxorubicin on rat liver mitochondrial oxidative phosphorylation. Physiol Chem Phys Med NMR 23: 101—106.[Web of Science][Medline] [Order article via Infotrieve]
• Siddiq T., Richardson PJ, Hashim IA, Preedy VR (1991). Effect of acute anaesthesi a on synthesis of contractile and non-contractile proteins of heart muscle and mixed proteins of types I and II fi bre rich skeletal muscles of rat. Cardiovasc Res 25: 314—318.[Abstract/Free Full Text]
• Siddiq T., Richardson PJ, Sherwood RA, Preedy VR (1992). Protein synthesis in pulmonary, cardiac, and skeletal muscle in acute hypertension induced by aortic constriction in the rat. Cardiovasc Res 26: 72—81.[Abstract/Free Full Text]
• Sparano JA (1998). Use of dexrazoxane and other strategies to prevent cardiomyopathy associated with doxorubicin-taxane combinations. Semin Oncol 25: 66—71.[Web of Science][Medline] [Order article via Infotrieve]
• Swain SM (1998). Adult multicenter trials using dexrazoxane to protect against cardiac toxicity. Semin Oncol 25: 43—47.[Web of Science][Medline] [Order article via Infotrieve]
• Vats T., Kamen B., Krischer JP (1991). Phase II trial of ICRF-187 in children with solid tumors and acute leukemia. Invest New Drugs 9: 333— 337.[Web of Science][Medline] [Order article via Infotrieve]
• Villani F., Galimberti M., Monti E., Cova D., Lanza E., Rozza-Dionigi A., Favalli L., Poggi P. (1990). Effect of ICRF-187 pretreatment against doxorubicin-induce d delayed cardiotoxicity in the rat. Toxicol and Appl Pharmacol 102: 292—299.[CrossRef]
• Weiss G., Kastner S., Brock J., Thaler J., Grunewald K. (1997). Modulation of transferrin receptor expression by dexrazoxane (ICRF-187) via activation of iron regulatory protein. Biochem Pharmacol 53: 1419—1424.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• Wexler LH, Andrich MP, Venzon D., Berg SL, Weaver-McClure L., Chen CC, Dilsizian V., Avila N., Jarosinski P., Balis FM, Poplack DG, Horowitz ME (1996). Randomized trial of the cardioprotective agent ICRF-187 in pediatric sarcoma patients treated with doxorubicin. J Clin Oncol 14: 362— 372.[Abstract/Free Full Text]
• Yeung TK, Jaenke RS, Wilding D., Creighton AM, Hopewell JW (1992). The protective activity of ICRF-187 against doxorubicin-induce d cardiotoxicity in the rat. Cancer Chemother Pharmacol 30: 58—64.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• Zhang J., Clark JR, Jr, Herman EH, Ferrans VJ (1996). Doxorubicin-induce d apoptosis in spontaneously hypertensive rats: differential effects in heart, kidney and intestine, and inhibition by ICRF-187. J Mol Cell Cardiol 28: 1931—1943.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• Zhang J., Herman EH, Ferrans VJ (1994). Effects of ICRF-186 [(L)1,2bis(3,5-dioxopiperazinyl-1-yl)propane] on the toxicity of doxorubicin in spontaneously hypertensive rats. Toxicology 92: 179—192.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• Zhang Y., Hua HY, Zhang TM (1993). Inhibitory effect of dioxopiperazine compounds on malondialdehyde formation induced by doxorubicin in rat liver mitochondria in vitro. Chung Kuo Yao Li Hsueh Pao 14: 340— 343.[Medline] [Order article via Infotrieve]
• Zima T., Tesar V., Crkovska J., Stejskalova A., Platenik J., Teminova J., Nemecek K., Janebova M., Stipek S. (1998). ICRF-187 (dexrazoxan) protects from adriamycin-induce d nephrotic syndrome in rats. Nephrol Dial Transplant 13: 1975—1979.[Abstract/Free Full Text]
• Zima T., Tesar V., Richardson PJ, Mantle D., Preedy VR (2001). Effects of doxorubicin (adriamycin) and [( + )-1,2-bis(3,5-dioxopiperazinyl1-yl)]propane (ICRF-187) on skeletal muscle protease activities. Toxicol Appl Pharmacol. In press.

Toxicologic Pathology, Vol. 29, No. 6, 591-599 (2001)
DOI: 10.1080/019262301753385915


CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    Twitter    What's this?

This Article Abstract Free Full Text (Free PDF) Free Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Saved Citations Download to citation manager Request Permissions Request Reprints Add to My Marked Citations Citing Articles Citing Articles via Google Scholar Citing Articles via Scopus Google Scholar Articles by Zima, T. Articles by Preedy, V. R. Search for Related Content PubMed PubMed Citation Articles by Zima, T. Articles by Preedy, V. R. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Hazardous Substances DB DOXORUBICIN Social Bookmarking                         What's this?