Summary
Compared to doxorubicin, equimolar epirubicin toxicity is reduced by about 50% by the epimerization of a hydrogen and hydroxyl group at the 4′ position of the anthracycline sugar moeity. The circadian timing of doxorubicin administration markedly affects its lethal and sub-lethal bone marrow and gut toxicities in mice, as well as the severity of its clinical toxicity. We tested whether the timing of administration of equitoxic epirubicin doses similarly affected the toxicological response in female CD2F1 mice. A large and highly reproducible effect of the circadian stage of administration was documented with best drug tolerance occurring during the first half of the daily rest (light) span of the animals. In addition to this circadian rhythm, a significant seasonal effect was found with significantly fewer deaths occurring after epirubicin was given in the Summer, as compared to the Winter. Safest circadian timing for epirubicin is statistically significantly earlier in the day than for doxorubicin, while their seasonal patterns are quite similar.
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References
Carter SK: Adriamycin: a review. J Natl Cancer Inst 1975, 55:1265–1267
Blum RH, Carter SK: Adriamycin, a new anticancer drug with significant clinical activity. Ann Intern Med 80:249–259, 1974
Lefrak EA, Pitha J, Rosenheim S, Gottlieb JA: A clinicopathologic analysis of Adriamycin cardiotoxicity. Cancer 32:302–314, 1973
Von Hoff DD, Layard MW, Basa P, Davis H, Von Hoff AL, Rozencweig M, Muggia FM: Risk factors for doxorubicin-induced congestive heart failure. Ann Intern Med 91:710–717, 1979
Sothern RB, Nelson WL, Halberg F: A circadian rhythm in susceptibility of mice to the anti-tumor drug, Adriamycin. In: Proc. XII Intl. Conf. Intl. Soc. Chronobiology, Washington, DC, II Ponte, Milan, 1977, pp. 433–438
Sothern RB, Halberg F, Hrushesky WJ, Doe RP: Circadian optimization of cis-diamminedichloroplatinum and adriamycin combination therapy of an immunocytoma gauged by complete remission or cure. Clin Res 26:712A, 1978
Good RA, Sothern RB, Stoney PJ, Simpson H, Halberg E, Halberg F: Circadian stage dependence of adriamyc-ininduced tumor regression and recurrence rates in immunocytoma-bearing LOU rats. Chronobiologia 4:174, 1977
Haus E, Halberg F, Scheving LE, Cardoso SS, Kühl JFW, Sothern R, Shiotsuka RN, Hwang DS, Pauly JE: Increased tolerance of leukemic mice to arabinosyl cytosine given on schedule adjusted to circadian system. Science 177:80–82, 1972
Scheving LE, Cardoso SS, Pauly JE, Halberg F, Haus E: Variation in susceptibility of mice to the carcinostatic agent arabinosyl cytosine. In: Chronobiology, L.E. Scheving, F. Halberg, J.E. Pauly, Eds., Igaku Shoin Ltd., Tokyo, 1974, pp. 213–217
Scheving LE: Chronobiological aspects of comparative experimental chemotherapy of neoplasma. In: Neoplasms-Comparative Pathology of Growth in Animals, Plants and Man. H.E. Kaiser, Ed., Williams and Wilkins, Baltimore, 1981, pp. 317–332
Halberg F, Haus E, Cardoso SS, Scheving LE, Kühl JFW, Shiotsuka R, Rosene G, Pauly JE, Runge W, Spalding JF, Lee JK, Good RA: Toward a chronotherapy of neoplasia. Experientia 29:909–934, 1973
Levi F, Halberg F, Nesbit M, Haus E, Levine H: Chronooncology. In: Neoplasms — Comparative Pathology of Growth in Animals, Plants and Man, H.E. Kaiser, Ed., Williams and Wilkins, Baltimore, 1981, pp. 267–316
Legha SS, Benjamin RS, Mackay B, Ewer M, Wallace S, Valdvivieso M, Rasmussen SL, Blumenschein GR, Freireich E: Reduction of doxorubicin cardiotoxicity by prolonged continuous intravenous infusion. Ann Intern Med 96:133–139, 1982
Garnick MB, Wiess GR, Steel GD Jr, Israel M, Schade D, Sack MJ, Frei E III: Clinical evaluation of long-term continuous infusion doxorubicin. Cancer Treat Rep 67:133–142, 1983
Lokich J, Bothe A, Zipoli T, Green R, Sonneborn H, Paul S, Philips D: Constant infusion schedule for Adriamycin: a phase I–II clinical trial of a 30-day schedule by ambulatory pump delivery system. J Clin Oncol 1:24–28, 1983
Benjamin RS, Chowla SP, Hortobagyi GN, Ewer MS, Mackay B, Legha SS, Carrasco H, Wallace S: Continuous-infusion adriamycin. In: Clinical Applications of Continuous Infusion Chemotherapy and Concomitant Radiation Therapy, C.J. Rosenthal and M. Rotman, Eds., Plenum Press, New York, 1986, pp. 19–26
Chlebowski RT, Paroly WS, Pugh RP, Hueser J, Jacobs EM, Pajak TF, Bateman JR: Adriamycin given as a weekly schedule without a loading course: clinically effective with reduced incidence of cardiotoxicity. Cancer Treat Rep 64:47–51, 1980
Torti FM, Bristow MR, Howes AE, Aston D, Stockdale FE, Carter SK, Kohler M, Brown BW, Billingham ME: Reduced cardiotoxicity of doxorubicin delivered on a weekly schedule. Ann Intern Med 99:745–749, 1983
Weiss AJ: Studies on cardiotoxicity and antitumor effect of doxorubicin administered weekly. Cancer Treat Symposia 3:91–94, 1984
Hrushesky WJM: Chemotherapy timing: an important variable in toxicity and response. In: Toxicity of Chemotherapy, M.C. Perry and J.W. Yarbro, Eds., Grune and Stratton, Inc., New York, 1984, pp. 449–477
Hrushesky WJM: Circadian timing of cancer chemotherapy. Science 228:73–75, 1985
Hrushesky WJM: Circadian scheduling of chemotherapy increases ovarian patient survival and cancer responses significantly. Proc ASCO 6:120, 1987
Levi F, Bailleul F, Chevelle C, Benavides M, Misset JL, Le Saunier F, Despax R, Ribaud P, Machover D, Jasmin C, Regensberg C, Reinberg A, Mathe G: Chronotherapy of ovarian cancer with 4′ tetrahydropyranyl adriamycin (THP) and cisdichlorodiammine platinum (CDDP). Proc ASCO 6:119, 1987
Benavides M, Levi F, Bailleui F, Chevelle C, Misset JL, Le Saunier F, Despax R, Ribaud P, Machover D, Jasmin C, Regensberg C, Reinberg A, Mathe G: Chronotherapy of ovarian cancer with 4′ tetrahydropyranyl adriamycin (THP) and cisdichlorodiammine platinum (CDDP). A phase I–II trial. Satellite Symp Proc ECCO 4:43, 1987
Sothern RB, Halberg F, Good RA, Simpson HW, Grage TB: Difference in timing of circadian susceptibility rhythm in murine tolerance of chemically related antimalignant antibiotics: Adriamycin and Daunomycin. In: Chronopharmacology and Chronotherapeutics, C.A. Walker, C.M. Winget, K.F.A. Soliman, Eds., Florida A&M University Foundation, Tallahassee, Florida, 1981, pp. 247–256
Halberg F, Johnson EA, Nelson W, Runge W, Sothern R: Autorhythmometry — procedures for physiologic self-measurements and their analysis. Physiol Teacher 1:1–11, 1972
Hrushesky WJM: Bone marrow suppression from doxorubicin and cis-diamminedichloroplatinum is substantially dependent upon both circadian and circannual stages of administration. Ann New York Acad Sci 397:293–295, 1982
Laerum OD, Aardal NP: Chronobiological aspects of bone marrow and blood cells. Prog Clin Biol Res 59:87–97, 1981
Scheving LE, Burns ER, Pauly JE, Tsai TH: Circadian variation in cell division of the mouse alimentary tract, bone marrow, and corneal epithelium, and its possible implication in cell kinetics and cancer chemotherapy. Anat Rec 191:479–485, 1978
Haus E, Lakatua DJ, Sackett-Lundeen L, White M: Circannual variation of intestinal cell proliferation in BDF1 male mice on three lighting regimens. Chronobiol Intl 1:185–194, 1984
Hrushesky WJM, Olshefski R, Wood P, Meshnick S, Eaton JW: Modifying intracellular redox balance: an approach to improving therapeutic index. Lancet i:565–567, 1985
Sinha BK, Trush MA, Kennedy KA, Mimnaugh EG: Enzymatic activation and binding of Adriamycin to nuclear DNA. Cancer Res 44:2892–2896, 1984
Pearlman LF, Chuang RY, Israel M, Simpkins H: Interaction of three second generation anthracyclines with polynucleotides, RNA, DNA, and nucleosomes. Cancer Res 46:341–346, 1986
Hill BT, Whelan RDH: A comparison of the lethal and kinetic effects of doxorubicin and 4′-epi-doxorubicin in vitro. Tumori 68:29–37, 1982
Arcamone F, Penco S, Vigenvani A, Redaelli S, Franchi S, Di Marco A, Casazza AM, Dasdia T, Formelli F, Necco A, Soranzo C: Synthesis and antitumor properties of new glycosides of daunomycinone and adriamycinone. J Med Chem 18:703–707, 1975
Cassinelli G, Configliacchi E, Penco S, Rivola G, Arcamone F, Pacciarini A, Ferrari L: Separation, characterization, and analysis of Epirubicin (4′-epi-doxorubicin) and its metabolites from human urine. Drug Metab Dispos 12:506–510, 1984
Weenen H, Van Maanen JMS, de Planque MM: Metabolism of 4′-modified analogs of doxorubicin. Unique glucuronidation pathway for 4′-epidoxorubicin. Eur J Cancer Clin Oncol 20:919–927, 1984
Broggini M, Colombo T, Martini A, Donelli MG: Studies on the comparative distribution and biliary excretion of doxorubicin and 4′-epi-doxorubicin in mice and rats. Cancer Treat Rep 64:897–904, 1980
Weenen H, Lankelma J, Penders PGM, McVie JG, Ten Bokkel Huinink WW, de Planque MM, Pinedo HM: Pharmacokinetics of 4′-epi-doxorubicin in man. Invest New Drugs 1:59–64, 1983
von Roemeling R, Mormont MC, Walker K, Olshefski R, Langevin T, Rabatin J, Wick M, Hrushesky W: Cancer control depends upon the circadian shape of continuous FUDR infusion. Proc AACR 28:293, 1987
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Mormont, M.C., von Roemeling, R., Sothern, R.B. et al. Circadian rhythm and seasonal dependence in the toxicological response of mice to Epirubicin. Invest New Drugs 6, 273–283 (1988). https://doi.org/10.1007/BF00173645
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DOI: https://doi.org/10.1007/BF00173645