Abstract
Purpose: PNU-159548 (4-demethoxy-3'-deamino-3'aziridinyl-4'-methylsulphonyl-daunorubicin), a derivative of the anticancer idarubicin, has a broad spectrum of antitumoral activity in vitro and in vivo attributable to its DNA intercalating and alkylating properties. The present study was conducted to determine the cardiotoxic activity of PNU-159548 relative to doxorubicin in a chronic rat model sensitive to anthracycline-induced cardiomyopathy. Methods: Young adult male rats were allocated to the following treatment groups: group 1, PNU-159548 vehicle control (colloidal dispersion); group 2, doxorubicin control (saline); groups 3, 4, 5, 6, and 7, PNU-159548 at 0.12, 0.25, 0.50, 0.75, and 1.0 mg/kg, respectively; and group 8, 1.0 mg/ kg doxorubicin. Treatments were administered intravenously once weekly for 4 weeks (first sacrifice time) or for 7 weeks (rats killed at weeks 8, 12, 22, 27, or 35). Body weights, organ weights, serum chemistry, hematology, serum troponin-T, and cardiac histopathology were followed throughout the study. Results: Doxorubicin caused irreversible cardiomyopathy evident at week 4 in some rats and progressing in severity in all rats by week 8. There were also marked myelotoxicity, increased liver and kidney weights, testicular atrophy, and about 20% mortality by week 27 in doxorubicin-treated rats. The deaths were attributed to cardiomyopathy and/ or nephropathy. PNU-159548 caused a dose-dependent myelotoxicity, with the dose of 0.5 mg/kg per week being equimyelotoxic to 1.0 mg/kg per week doxorubicin.
PNU-159548 also caused an increase in liver weight that was reversible and a non-reversible testicular atrophy but, unlike doxorubicin, had no effect on kidney weight. At equimyelotoxic doses, the cardiotoxicity caused by PNU-159548, expressed as the mean total score, was less than one-twentieth of that induced by doxorubicin, and much less than that predicted on the basis of its content of idarubicin, which is in turn markedly less cardiotoxic than doxorubicin. Conclusions: The novel cytotoxic antitumor derivative, PNU-159548, is significantly less cardiotoxic than doxorubicin at equimyelosuppressive doses. The combination of intercalating and alkylating activities within the same molecule without the cardiotoxic side effects of anthracyclines makes PNU-159548 an excellent candidate for clinical development in oncology.
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References
Ballerini L, Solcia E, Bellini O, Sala L, Bertazzoh C (1977) Experimental adriamycin cardiomyopathy in the rat. IRCS Med Sci 5:431
Bienvenu P, Caron L, Gasparutto D, Kergonou SF (1992) Assessing and counteracting of anticancer drugs. In: Emerit I, Chance B (eds) Free radicals and aging. Birkhauser Verlag, Basel, p 257
Billingham ME, Mason JW, Bristow MR, Daniels SR (1978) Anthracycline cardiomyopathy monitored by morphologic changes. Cancer Treat Rep 62:865
Bleuel H, Deschl U, Bertsch T, Bolz G, Rebel W (1995) Diagnostic efficiency of troponin T measurements in rats with experimental myocardial cell damage. Exp Toxicol Pathol 47:121
Borchmann P, Hubel K, Schnell R, Engert A (1997) Idarubicin: a brief overview on pharmacology and clinical use. Int J Clin Pharmacol Ther 35:80
Bower M, Brock C Gulliford T, O'Reilly SM, Smith DB, Newlands ES (1996) A weekly alternating chemotherapy regimen with low toxicity for the treatment of aggressive lymphoma. Cancer Chemother Pharmacol 38:106
Bristow MR, Sageman WS, Scott RH, Billingham ME, Bowden RE, Kernoff RS, Snidow GH, Daniels SR (1980) Acute and chrome cardiovascular effects of doxorubicin in the dog: the cardiovascular pharmacology of drug-induced histamine release. J Cardiovasc Pharmacol 2:487
Coiffier B (1996) Ifosfamide in the treatment of lymphoma. Semin Oncol 23: 2
Davies KJ, Doroshow SH (1986) Redox cycling of anthracyclines by cardiac mitochondria. I. Anthracycline radical formation by NADH dehydrogenase. J Biol Chem 261:3060
Delta Torte P, Podesta A, Pinciroli G, Iatropoulos MJ, Mazue G (1996) Long-lasting effect of dexrazoxane against anthracycline cardiotoxicity in rats. Toxicol Pathol 24:398
Delta Torte P, Mazue G, Podesta A, Moneta D, Sammartini U, Imondi AR (1999) Protection against doxorubicin induced cardiotoxicity in weanling rats by dexrazoxane. Cancer Chemother Pharmacol 43:151
Demant EJ, Sensen PK (1983) Destruction of phospholipids and respiratory-chain activity in pig-heart submitochondrial particles induced by an adriamycin-iron complex. Fur J Biochem 132:551
Farm YE, Ho WK, So I (1994) Effects of adriamycin on ionic currents in single cardiac myocytes of the rabbit. J Mot Cell Cardiol 26:163
Fisher B, Brown A, Mamounas E, Wieand S, Robidoux A, Margolese RG, Cruz AB Sr, Fisher ER, Wickerham DL, Wolmark N, DeCillis A, Hoehn SL, Lees AW, Dimitrov NV (1997) Effect of preoperative chemotherapy on local-regional disease in women with operable breast cancer: findings from National Surgical Adjuvant Breast and Bowel Project B-18. J Clin Oncol 15:2483
Friedenberg WR, Spencer SK, Musser C Hogan TF, Rodvold KA, Rushing DA, Mazza JJ, Tewksbury DA, Marx JJ (1999) Multidrug resistance in chronic lymphocytic leukemia. Leuk Lymphoma 34:171
Geroni C, Ripamonti M, Pennella G, Capolongo L, Marsigho A, Caruso M, Suarato A, Marchini S, Grandi M (1998) PNU159548(4-demethoxy-3'-deamino-3'-aziridinyl-4'-methylsulphonyl-DNR) a novel cytotoxic compound active in vitro and in vivo against tumors with different resistance mechanisms (abstract). Proc Am Assoc Cancer Res 39:222
Geroni C Ripamonti M, Marsigho A, Paston A, Caruso M, Bargiotti A, Moneta D, Grandi M (1998) PNU-159548(4demethoxy-3'-deamino-3'-aziridinyl-4'-methylsulphonyl-DNR) a novel cytotoxic agent with wide spectrum antitumor activity (abstract). Proc Am Assoc Cancer Res 39:222
Gianni L, Corden BJ, Myers CE (1983) The biochemical basis of anthracycline toxicity and antitumor activity. Rev Biochem Toxicol 5:1
Gutteridge SM (1984) Lipid peroxidation and possible hydroxyl radical formation stimulated by the self-reduction of a doxorubicin-iron (III) complex. Biochem Pharmacol 33:1725
Herman EH, Schein P, Farmar RM (1969) Comparative cardiac toxicity of daunomycin in three rodent species. Proc Soc Exp Biol Med 130:1098
Herman EH, Lipshultz SE, Rifai N, Zhang J, Papoian T, Yu ZX, Takeda K, Ferrans VS (1998) Use of cardiac troponin T levels as an indicator of doxorubicin-induced cardiotoxicity. Cancer Res 58:195
Imondi AR (1998) Preclinical models of cardiac protection and testing for effects of dexrazoxane on doxorubicin antitumor effects. Semin Oncol 25:22
Imondi AR, Delta Torte P, Mazue G, Sullivan TM, Robbins TL, Hagerman LM, Podesta A, Pinciroli G (1996) Doseresponse relationship of dexrazoxane for prevention of doxo rubicin-induced cardiotoxicity in mice, rats, and dogs. Cancer Res 56:4200
Saenke RS (1976) Delayed and progressive myocardial lesions after adriamycin administration in the rabbit. Cancer Res 36:2958
Marchini S, Gonzalez Paz O, Ripamonti M, Geroni C Bargiotti A, Caruso M, Todeschi S, D 'Incalci M, Broggini M (1995) Sequence-specific DNA interactions by novel alkylating anthracycline derivatives. Anticancer Drug Des 10:641
Mariani M, Capolongo L, Suarato A, Bargiotti A, Mongelli N, Grandi M, Beck WT (1994) Growth-inhibitory properties of novel anthracyclines in human leukemic cell fines expressing either Pgp-MDR or at-MDR. Invest New Drugs 12:93
Plosker GL, Faulds D (1993) Epirubicin. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in cancer chemotherapy. Drugs 45:788
Podesta A, Delta Torre P, Pinciroli G, Iatropoulos MJ, Brughera M, Mazue G (1994) Evaluation of 4'-iodo-0' deoxydoxorubicin-induced cardiotoxicity in two experimental rat models. Toxicol Pathol 22:68
Solcia E, Ballerini L, Bellini O, Magrini U, Bertazzofi C Tosana G, Sala L, Balconi F, Rallo F (1981) Cardiomyopathy of doxorubicin in experimental animals. Factors affecting the severity, distribution and evolution of myocardial lesions. Tumori 67:461
Solem LE, Henry TR, Wallace KB (1994) Disruption of mitochondrial calcium homeostasis following chronic doxorubicin administration. Toxicol Appl Pharmacol 129:214
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Della Torre, P., Podestà, A., Imondi, A. et al. PNU-159548, a novel cytotoxic antitumor agent with a low cardiotoxic potential. Cancer Chemother Pharmacol 47, 355–360 (2001). https://doi.org/10.1007/s002800000240
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DOI: https://doi.org/10.1007/s002800000240