A critical evaluation of the mechanisms of action proposed for the antitumor effects of the anthracycline antibiotics adriamycin and daunorubicin

Biochemical Pharmacology

Volumn 57, Issue 7, 1999, Pages 727-741

  Gewirtz, David A ^a  

^a VIRGINIA COMMONWEALTH UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

Adriamycin (doxorubicin); Daunomycin (daunorubicin); DNA biosynthesis; Free radical mechanisms; Inhibition of topoisomerase II

Indexed keywords

ANTHRACYCLINE ANTIBIOTIC AGENT; DAUNORUBICIN; DNA TOPOISOMERASE (ATP HYDROLYSING); DOXORUBICIN; FREE RADICAL; HELICASE;

ANTINEOPLASTIC ACTIVITY; DNA ALKYLATION; DNA BINDING; DNA CROSS LINKING; DNA DAMAGE; DNA SYNTHESIS INHIBITION; DRUG CYTOTOXICITY; DRUG MECHANISM; ENZYME INHIBITION; LIPID PEROXIDATION; PRIORITY JOURNAL; REVIEW;

EID: 0033006172     PISSN: 00062952     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0006-2952(98)00307-4     Document Type: Article

References (198)

1. Murphy GP, Lawrence Jr W and Lenhard RE (Eds.), American Society Textbook of Clinical Oncology. 2nd Edn. American Cancer Society, Atlanta, GA, 1995.
2. Wiernik P.H., Dutcher J.P. Clinical importance of anthracyclines in the treatment of acute myeloid leukemia. Leukemia. 6:(Suppl 1):1992;67-69.
3. Di Marco A., Silverstrini R., Di Marco S., Dasdia T. Inhibiting effect of the new cytotoxic antibiotic daunomycin on nucleic acids and mitotic activity of HeLa cells. J Cell Biol. 27:1965;545-550.
4. Calendi E., Di Marco A., Reggiani M., Scarpinato B., Valentini L. On physico-chemical interactions between daunomycin and nucleic acids. Biochim Biophys Acta. 103:1965;25-49.
5. Bremerskov V., Linnemann R. Some effects of daunomycin on the nucleic acid synthesis in synchronized L-cells. Eur J Cancer. 5:1969;317-330.
6. Dano K., Frederiksen S., Hellung-Larsen P. Inhibition of DNA and RNA synthesis by daunorubicin in sensitive and resistant Ehrlich ascites tumor cells in vitro. Cancer Res. 32:1972;1307-1314.
7. Kim S.H., Kim J.H. Lethal effects of adriamycin on the division cycle of HeLa cells. Cancer Res. 32:1972;323-325.
8. Meriwether W.D., Bachur N.R. Inhibition of DNA and RNA metabolism by daunorubicin and adriamycin in L1210 mouse leukemia. Cancer Res. 32:1972;1137-1142.
9. Wang J.J., Chervinsky D.S., Rosen J.M. Comparative biochemical studies of adriamycin and daunomycin in leukemic cells. Cancer Res. 32:1972;511-515.
10. Zunino F., Gambetta R., Di Marco A., Zaccara A. Interaction of daunomycin and its derivatives with DNA. Biochim Biophys Acta. 277:1972;489-498.
11. Goodman M.F., Bessman M.J., Bachur N.R. Adriamycin and daunorubicin inhibition of mutant T4 DNA polymerase. Proc Natl Acad Sci USA. 71:1974;1193-1196.
12. Zunino F., Gambetta R., Di Marco A. The inhibition in vitro of DNA polymerase and RNA polymerases by daunomycin and adriamycin. Biochem Pharmacol. 24:1975;309-311.
13. Momparler R.L., Karon M., Siegel S.E., Avila F. Effect of adriamycin on DNA, RNA and protein synthesis in cell-free systems and intact cells. Cancer Res. 36:1976;2891-2895.
14. Goodman M.F., Lee G.M. Adriamycin interactions with T4 DNA polymerase. J Biol Chem. 252:1977;2670-2674.
15. Supino R., Necco A., Dasdia T., Casazza A.M., Di Marco A. Relationship between effects on nucleic acid synthesis in cell cultures and cytotoxicity of 4-demethoxy derivatives of daunorubicin and adriamycin. Cancer Res. 37:1977;4523-4528.
16. Phillips D.R., DiMarco A., Zunino F. The interaction of daunomycin with polydeoxynucleotides. Eur J Biochem. 85:1978;487-492.
17. Tanaka M., Yoshida S. Mechanism of the inhibition of calf thymus DNA polymerases α and β by daunomycin and adriamycin. J Biochem (Tokyo). 87:1980;911-918.
18. Glazer R.I., Hartmann K.D., Richardson C.L. Cytokinetic and biochemical effects of 5-iminodaunorubicin in human colon carcinoma in culture. Cancer Res. 42:1982;117-121.
19. Fritzsche H., Wahnert U. Anthracycline antibiotics. Interaction with DNA and nucleosomes and inhibition of DNA synthesis. Biochemistry. 26:1987;1996-2000.
20. Wasserman K., Zwelling L.A., Mullins T.D., Silberman L.E., Andersson B.S., Bakic M., Acton E.M., Newman R.A. Effects of 3′-deamino-3′-(3-cyano-4-morpholinyl) doxorubicin and doxorubicin on the survival, DNA integrity, and nucleolar morphology of human leukemia cells in vitro. Cancer Res. 46:1986;4041-4046.
21. Munger C., Ellis A., Woods K., Randolph J., Yanovich S., Gewirtz D. Evidence for inhibition of growth related to compromised DNA synthesis in the interaction of daunorubicin with H-35 rat hepatoma. Cancer Res. 48:1988;2404-2411.
22. Schott B., Robert J. Comparative cytotoxicity, DNA synthesis inhibition and drug incorporation of eight anthracyclines in a model of doxorubicin-sensitive and -resistant rat glioblastoma cells. Biochem Pharmacol. 38:1989;167-172.
23. Fornari F.A. Jr, Jarvis W.D., Grant S., Orr M.S., Randolph J.K., White F.K.H., Gewirtz D.A. Growth arrest and non-apoptotic cell death associated with the suppression of c-myc expression in MCF-7 breast tumor cells following acute exposure to doxorubicin. Biochem Pharmacol. 51:1996;931-940.
24. Lown J.W., Sim S.-K., Majumdar K.C., Chang R.-Y. Strand scission by DNA bound adriamycin and daunorubicin in the presence of reducing agents. Biochem Biophys Res Commun. 76:1977;705-710.
25. Bachur N.R., Gordon S.L., Gee M.V. Anthracycline antibiotic augmentation of microsomal electron transport and free radical formation. Mol Pharmacol. 13:1977;901-910.
26. Berlin V., Haseltine W.A. Reduction of adriamycin to a semiquinone free radical by NADPH cytochrome P-450 reductase produces DNA cleavage in a reaction mediated by molecular oxygen. J Biol Chem. 256:1981;4747-4756.
27. Bachur N.R., Gordon S.L., Gee M.V. A general mechanism for microsomal activation of quinone anticancer agents. Cancer Res. 38:1978;1745-1750.
28. 2: Evidence for hydroxyl radical participation. FEBS Lett. 145:1982;137-142.
29. Eliot H., Gianni L., Myers C. Oxidative destruction of DNA by the adriamycin-iron complex. Biochemistry. 23:1984;928-936.
30. Muindi J.R.F., Sinha B.K., Gianni L., Myers C.E. Hydroxyl radical production and DNA damage induced by anthracycline-iron complex. FEBS Lett. 172:1984;226-230.
31. 2 by iron-adriamycin. J Biol Chem. 259:1984;6056-6058.
32. Gianni L., Zweier J., Levy A., Myers C.E. Characterization of the cycle of iron-mediated electron transfer from adriamycin to molecular oxygen. J Biol Chem. 260:1985;6820-6826.
33. Gutteridge J.M.C., Quinlan G.J. Free radical damage to deoxyribose by anthracycline, aureolic acid and aminoquinone antitumour antibiotics. An essential requirement for iron, semiquinones and hydrogen peroxide. Biochem Pharmacol. 34:1985;4099-4103.
34. Graham M.A., Newell D.R., Butler J., Hoey B., Patterson L.H. The effect of the anthrapyrazole antitumour agent C1941 on rat liver microsome and cytochrome P-450 reductase mediated free radical processes. Inhibition of doxorubicin activation in vitro. Biochem Pharmacol. 36:1987;3345-3351.
35. Sinha B.K. Free radicals in anticancer drug pharmacology. Chem Biol Interact. 69:1989;293-317.
36. Sinha B.K., Mimnaugh E.G., Rajagopalan S., Myers C.E. Adriamycin activation and oxygen free radical formation in human breast tumor cells: Protective role of glutathione peroxidase in adriamycin resistance. Cancer Res. 49:1989;3844-3848.
37. Bustamante J., Galleano M., Medrano E.E., Boveris A. Adriamycin effects on hydroperoxide metabolism and growth of human breast tumor cells. Breast Cancer Res Treat. 17:1990;145-153.
38. Benchekroun N.B., Sinha B.K., Robert J. Doxorubicin-induced oxygen free radical formation in sensitive and doxorubicin resistant variants of rat glioblastoma cells. FEBS Lett. 322:1993;295-298.
39. Feinstein E., Canaani E., Weiner L.M. Dependence of nucleic acid degradation on in situ free-radical production by adriamycin. Biochemistry. 32:1993;13156-13161.
40. Abdella B.R.J., Fisher J. A chemical perspective on the anthracycline antitumor antibiotics. Environ Health Perspect. 64:1995;3-18.
41. Potmesil M., Israel M., Silber R. Two mechanisms of adriamycin-DNA interactions in L1210 cells. Biochem Pharmacol. 33:1984;3137-3142.
42. Griffin-Green E.A., Zaleska M.M., Erecinska M. Adriamycin-induced lipid peroxidation in mitochondria and microsomes. Biochem Pharmacol. 37:1988;3071-3077.
43. Banfi P., Parolini O., Lanzi C., Gambetta R.A. Lipid peroxidation, phosphoinositide turnover, and protein kinase C activation in human platelets treated with anthracyclines and their complexes with Fe(III). Biochem Pharmacol. 43:1992;1521-1527.
44. Benchekroun M.N., Robert J. Measurement of doxorubicin-induced lipid peroxidation under the conditions that determine cytotoxicity in cultured cells. Anal Biochem. 201:1992;326-330.
45. Fukuda F., Kitada M., Horie T., Awazu S. Evaluation of adriamycin-induced lipid peroxidation. Biochem Pharmacol. 44:1992;755-760.
46. Sinha B.K., Chignell C.F. Binding modes of chemically activated semiquinone free radicals from quinone anticancer agents to DNA. Chem Biol Interact. 28:1979;301-308.
47. Sinha B.K., Trush M.A., Kennedy K.A., Mimnaugh E.G. Enzymatic activation and binding of adriamycin to nuclear DNA. Cancer Res. 44:1984;2892-2896.
48. Wallace K.B., Johnson J.A. Oxygen-dependent effect of microsomes on the binding of doxorubicin to rat hepatic nuclear DNA. Mol Pharmacol. 31:1986;307-311.
49. Phillips D.R., White R.J., Cullinane C. DNA sequence-specific adducts of adriamycin and mitomycin C. FEBS Lett. 246:1989;233-240.
50. Cullinane C., Phillips D.R. Induction of stable transcriptional blockage sites by adriamycin GpC specificity of apparent adriamycin-DNA adducts and dependence on iron(III) ions . Biochemistry. 29:1990;5638-5646.
51. Cummings J., Bartoszek A., Smyth J.F. Determination of covalent binding to intact DNA, RNA and oligonucleotides by intercalating anticancer drugs using high-performance liquid chromatography. Studies with doxorubicin and NADPH cytochrome P450 reductase. Anal Biochem. 194:1991;146-155.
52. Cummings J., Willmott N., Hoey B.M., Marley E.S., Smyth J.F. The consequences of doxorubicin quinone reduction in vivo in tumour tissue. Biochem Pharmacol. 44:1992;2165-2174.
53. Cullinane C., Cutts S.M., van Rosmalen A., Phillips D.R. Formation of adriamycin-DNA adducts in vitro. Nucleic Acids Res. 22:1994;2296-2303.
54. Skladanowski A., Konopa J. Interstrand DNA crosslinking induced by anthracyclines in tumour cells. Biochem Pharmacol. 47:1994;2269-2278.
55. Skladanowski A., Konopa J. Relevance of interstrand DNA crosslinking induced by anthracyclines for their biologic activity. Biochem Pharmacol. 47:1994;2279-2287.
56. Fornari F.A., Randolph J.K., Yalowich J.C., Ritke M.K., Gewirtz D.A. Interference by doxorubicin with DNA unwinding in MCF-7 breast tumor cells. Mol Pharmacol. 45:1994;649-656.
57. Montecucco A., Pedrali-Noy G., Spadari S., Zanolin E., Ciarrochi G. DNA unwinding and inhibition of T4 DNA ligase by anthracyclines. Nucleic Acids Res. 16:1988;3907-3918.
58. Bachur N.R., Yu F., Johnson R., Hickey R., Wu Y., Malkas L. Helicase inhibition by anthracycline anticancer agents. Mol Pharmacol. 41:1992;993-998.
59. Ciarrochi G., Lestingi M., Fontana M., Spadari S., Montecucco A. Correlation between anthracycline structure and human DNA ligase inhibition. Biochem J. 279:1992;141-146.
60. Bachur N.R., Johnson R., Yu F., Hickey R., Applegren N., Malkas L. Antihelicase action of DNA-binding anticancer agents Relationship to guanosine-cytidine intercalator binding . Mol Pharmacol. 44:1993;1064-1069.
61. Tuteja N., Phan T.-N., Tuteja R., Ochem A., Falaschi A. Inhibition of DNA unwinding and ATPase activities of human DNA helicase II by chemotherapeutic agents. Biochem Biophys Res Commun. 236:1997;636-640.
62. Bachur N.R., Lun L., Sun P.M., Trubey C.M., Elliott E.E., Egorin M.J., Malkas L., Hickey R. Anthracycline antibiotic blockade of SV40 T antigen helicase action. Biochem Pharmacol. 55:1998;1025-1034.
63. Goormaghtigh E., Ruysschaert J.M. Anthracycline glycoside-membrane interactions. Biochim Biophys Acta. 779:1984;271-288.
64. Murphree S.A., Tritton T.R., Smith P.L., Sartorelli A.C. Adriamycin-induced changes in the surface membrane of sarcoma 180 ascites cells. Biochim Biophys Acta. 649:1981;317-324.
65. Tritton T.R., Yee G. The anticancer agent adriamycin can be actively cytotoxic without entering cells. Science. 217:1982;248-250.
66. Tokes Z.A., Rogers K.E., Rembaum A. Synthesis of adriamycin-coupled polyglutaraldehyde microspheres and evaluation of their cytostatic activity. Proc Natl Acad Sci USA. 79:1982;2026-2030.
67. Rogers K.E., Carr B.I., Tokes Z.A. Cell surface mediated cytotoxicity of polymer bound adriamycin against drug-resistant hepatocytes. Cancer Res. 43:1983;2741-2748.
68. Lane P., Vichi P., Bain D.L., Tritton T.R. Temperature dependence studies of adriamycin uptake and cytotoxicity. Cancer Res. 47:1987;4038-4042.
69. Vichi P., Robison S., Tritton T.R. Temperature dependence of adriamycin-induced DNA damage in L1210 cells. Cancer Res. 49:1989;5575-5580.
70. Vichi P., Tritton T.R. Adriamycin Protection from cell death by removal of extracellular drug . Cancer Res. 52:1992;4135-4138.
71. Tewey K.M., Chen G.L., Nelson E.M., Liu L.F. Intercalative antitumor drugs interfere with the breakage-reunion reaction of mammalian DNA topoisomerase II. J Biol Chem. 259:1984;9182-9187.
72. Tewey K.M., Rowe T.C., Yang L., Halligan B.D., Liu L.F. Adriamycin-induced DNA damage mediated by mammalian topoisomerase II. Science. 226:1984;466-468.
73. Zwelling L.A., Kerrigan D., Michaels S. Cytotoxicity and DNA strand breaks by 5-iminodaunorubicin in mouse leukemia L1210 cells Comparison with adriamycin and 4′-(9-acridinylamino) methanesulfon-m-anisidide . Cancer Res. 42:1982;2687-2691.
74. Capranico G., Dasdia T., Zunino F. Comparison of doxorubicin-induced DNA damage in doxorubicin-sensitive and -resistant P388 murine leukemia cells. Int J Cancer. 37:1986;227-231.
75. Capranico G., Riva A., Tinelli S., Dasdia T., Zunino F. Markedly reduced levels of anthracycline-induced DNA strand breaks in resistant P388 leukemia cells and isolated nuclei. Cancer Res. 47:1987;3752-3756.
76. Bellamy W.T., Dalton W.S., Kailey J.M., Gleason M.C., McCloskey T.M., Dorr R.T., Alberts D.S. Verapamil reversal of doxorubicin resistance in multidrug-resistant human myeloma cells and association with drug accumulation and DNA damage. Cancer Res. 48:1988;6303-6308.
77. Bellamy W.T., Dorr R.T., Dalton W.S., Alberts D.S. Direct relation of DNA lesions in multidrug-resistant human myeloma cells to intracellular doxorubicin concentration. Cancer Res. 48:1988;6360-6364.
78. Covey J.M., Kohn K.W., Kerrigan D., Tilchen E.J., Pommier Y. Topoisomerase II mediated DNA damage produced by 4′-(9-acridinylamino)methanesulfon-m-anisidide and related acridines in L1210 cells and isolated nuclei Relation to cytotoxicity . Cancer Res. 48:1988;860-865.
79. Davies S.M., Robson C.M., Davies S.L., Hickson I.D. Nuclear topoisomerase II levels correlate with the sensitivity of mammalian cells to intercalating agents and epipodophyllotoxins. J Biol Chem. 263:1988;17724-17729.
80. Epstein R.J., Smith P.J. Estrogen-induced potentiation of DNA damage and cytotoxicity in human breast cancer cells treated with topoisomerase II interactive antitumor drugs. Cancer Res. 48:1988;297-303.
81. Lawrence T.S. Reduction of doxorubicin cytotoxicity by ouabain Correlation with topoisomerase-induced DNA strand breakage in human and hamster cells . Cancer Res. 48:1988;725-730.
82. Maniar N., Krishan A., Israel M., Samy T.S.A. Anthracycline-induced DNA breaks and resealing in doxorubicin-resistant murine leukemic P388 cells. Biochem Pharmacol. 37:1988;1763-1772.
83. Deffie A.M., Batra J.K., Goldenberg G.J. Direct correlation between DNA topoisomerase II activity and cytotoxicity in adriamycin-sensitive and resistant P388 leukemia cell lines. Cancer Res. 49:1989;58-62.
84. Capranico G., Kohn K.W., Pommier Y. Local sequence requirements for DNA cleavage by mammalian topoisomerase II in the presence of doxorubicin. Nucleic Acids Res. 18:1990;6611-6619.
85. Binaschi M., Caparanico G., De Isabella P., Mariani M., Supino R., Tinelli S., Zunino F. Comparison of DNA cleavage induced by etoposide and doxorubicin in two human small-cell lung cancer cell lines with different sensitivities to topoisomerase II inhibitors. Int J Cancer. 45:1990;347-352.
86. Friche E., Danks M.K., Schmidt C.A., Beck W.T. Decreased DNA topoisomerase II in daunorubicin-resistant Ehrlich ascites tumor cells. Cancer Res. 51:1991;4213-4218.
87. Webb C.D., Latham M.D., Lock R.B., Sullivan D.M. Attenuated topoisomerase II content directly correlates with a low level of drug resistance in Chinese hamster ovary cells. Cancer Res. 51:1991;6543-6549.
88. Glisson B.S., Killary A.M., Merta P., Ross W.E., Siciliano J., Siciliano M.J. Dissociation of cytotoxicity and DNA cleavage activity induced by topoisomerase II-reactive intercalating agents in hamster-human somatic cell hybrids. Cancer Chemother Pharmacol. 31:1992;131-138.
89. Ramachandran C., Samy T.S.A., Huang X.L., Yuan Z.K., Krishan A. Doxorubicin-induced DNA breaks, topoisomerase II activity and gene expression in human melanoma cells. Biochem Pharmacol. 45:1993;1367-1371.
90. Pommier Y, DNA topoisomerases and their inhibition by anthracyclines. In: Anthracycline Antibiotics: New Analogs, Methods of Delivery and Mechanisms of Action (Ed. Priebe W), ACS Symposium Series No. 574, pp. 183-203. American Chemical Society, Washington, DC, 1995.
91. Ling Y.-H., Priebe W., Perez-Solar R. Apoptosis induced by anthracycline antibiotics in P388 parent and multidrug resistant cells. Cancer Res. 53:1993;1845-1852.
92. Skladanowski A., Konopa J. Adriamycin and daunomycin induce programmed cell death (apoptosis) in tumour cells. Biochem Pharmacol. 46:1993;375-382.
93. Zaleskis G., Berleth E., Verstovek S., Ehrke M.J., Mihich E. Doxorubicin-induced DNA degradation in murine thymocytes. Mol Pharmacol. 46:1994;901-908.
94. Bose R., Verheij M., Haimovitz-Friedman A., Scotto K., Fuks Z., Kolesnick R. Ceramide synthase mediates daunorubicin-induced apoptosis An alternative mechanism for generating death signals . Cell. 82:1995;405-414.
95. Jaffrezou J.-P., Levade T., Bettaieb A., Andrieu N., Bezombes C., Maestre N., Vermeersch S., Rousse A., Laurent G. Daunorubicin-induced apoptosis Triggering of ceramide generation through sphingomyelin hydrolysis . EMBO J. 15:1996;2417-2424.
96. Brenner D.E., Galloway S., Cooper J., Noone R., Hande K.R. Improved high performance liquid chromatographic assay of doxorubicin Detection of circulating aglycones in human plasma and comparison with thin-layer chromatography . Cancer Chemother Pharmacol. 14:1985;139-145.
97. Greene R.F., Collins J.M., Jenkins J.F., Speyer J.L., Meyers C.E. Plasma pharmacokinetics of adriamycin and adriamycinol Implications for the design of in vitro experiments and treatment protocols . Cancer Res. 43:1983;3417-3421.
98. Kokenberg E., Sonneveld P., Sizoo W., Hagenbeek A., Lowenberg B. Cellular pharmacokinetics of daunorubicin Relationship with response to treatment in patients with acute myeloid leukemia . J Clin Oncol. 6:1988;802-812.
99. Muller C., Chatelut E., Gualano V., De Forni M., Huguet F., Attal M., Canal P., Laurent G. Cellular pharmacokinetics of doxorubicin in patients with chronic lymphocytic leukemia Comparison of bolus administration and continuous infusion . Cancer Chemother Pharmacol. 32:1993;379-384.
100. Speth P.A.J., Linssen P.C.M., Boezeman J.B.M., Wessels H.M.C., Haanen C. Cellular and plasma adriamycin concentrations in long-term infusion therapy of leukemia patients. Cancer Chemother Pharmacol. 20:1987;305-310.
101. Speth P.A.J., Linssen P.C.M., Boezeman J.B.M., Wessels H.M.C., Haanen C. Leukemic cell and plasma daunomycin concentrations after bolus injection and 72 h infusion. Cancer Chemother Pharmacol. 20:1987;311-315.
102. Benjamin R.S., Riggs C.E., Bachur N.R. Pharmacokinetics and metabolism of adriamycin in man. Clin Pharmacol Ther. 14:1993;592-600.
103. Creasey W.A., McIntosh L.S., Brescia T., Odujinrin O., Aspnes G.T., Murray E., Marsh J.C. Clinical effects and pharmacokinetics of different dosage schedules of adriamycin. Cancer Res. 36:1976;216-221.
104. Camaggi C.M., Comparsi R., Strocchi E., Testoni F., Angelelli B., Pannuti F. Epirubicin and doxorubicin comparative metabolism and pharmacokinetics. A cross-over study. Cancer Chemother Pharmacol. 21:1988;221-228.
105. Siegfried J.M., Sartorelli A.C., Tritton T.R. Evidence for the lack of relationship between inhibition of nucleic acid synthesis and cytotoxicity of adriamycin. Cancer Biochem Biophys. 6:1983;137-142.
106. Kastan M.B., Onyekwere O., Sidransky D., Vogelstein B., Craig R.W. Participation of p53 in the cellular response to DNA damage. Cancer Res. 51:1991;6304-6311.
107. Sheikh M.S., Li X.-S., Chen J.-C., Shao Z.-M., Ordonez J.V., Fontana J.A. Mechanisms of regulation of WAf1/Cip 1 gene expression in human breast carcinoma Role of p53-dependent and independent signal transduction pathways . Oncogene. 9:1994;3407-3415.
108. Kelman Z. PCNA, Structure, functions and interactions. Oncogene. 14:1997;629-640.
109. Dimri G.P., Nakanishi M., Desprez P.-Y., Smith J.R., Campisi J. Inhibition of E2F activity by the cyclin dependent protein kinase p21 in cells expressing or lacking a functional retinoblastoma protein. Mol Cell Biol. 16:1996;2987-2997.
110. Farnham P.J., Slansky J.E., Kollmer R. The role of E2F in the mammalian cell cycle. Biochim Biophys Acta. 1155:1993;125-131.
111. Goodman J., Hochstein P. Generation of free radicals and lipid peroxidation by redox cycling of adriamycin and daunomycin. Biochem Biophys Res Commun. 77:1977;797-803.
112. Doroshow J.H. Anthracycline antibiotic-stimulated superoxide, hydrogen peroxide and hydroxyl radical production by NADH dehydrogenase. Cancer Res. 43:1983;4543-4551.
113. Pan S.-S., Pederson L., Bachur N.R. Comparative flavoprotein catalysis of anthracycline antibiotic. Reductive cleavage and oxygen consumption. Mol Pharmacol. 19:1980;184-186.
114. Takanashi S., Bachur N.R. Adriamycin metabolism in man. Evidence from urinary metabolites. Drug Metab Dispos. 4:1976;79-87.
115. 2. FEBS Lett. 136:1981;89-94.
116. Gewirtz D.A., Yanovich S. Metabolism of adriamycin in hepatocytes isolated from the rat and the rabbit. Biochem Pharmacol. 36:1987;1793-1798.
117. Speth P.A.J., van Hoesel Q.G.C.M., Haanen C. Clinical pharmacokinetics of doxorubicin. Clin Pharmacokinet. 15:1988;15-31.
118. Ubezio P., Civoli F. Flow cytometric detection of hydrogen peroxide production induced by doxorubicin in cancer cells. Free Radic Biol Med. 16:1994;509-516.
119. Kharasch E.D., Novak R.F. Inhibitory effects of anthracenedione antineoplastic agents on hepatic and cardiac lipid peroxidation. J Pharmacol Exp Ther. 226:1983;500-506.
120. Babson J.R., Abell N.S., Reed D.J. Protective role of the glutathione redox cycle against adriamycin-mediated toxicity in isolated hepatocytes. Biochem Pharmacol. 30:1981;2299-2304.
121. Hamilton T.C., Winker M.A., Louie K.G., Batist G., Behrens B.C., Tsuruo T., Grotzinger K.R., McKoy W.M., Young R.C., Ozols R.F. Augmentation of adriamycin, melphalan and cisplatin toxicity in drug-resistant and -sensitive human ovarian carcinoma cell lines by buthionine sulfoximine mediated glutathione depletion. Biochem Pharmacol. 34:1985;2583-2586.
122. Dusre L., Mimnaugh E.G., Myers C.E., Sinha B.K. Potentiation of doxorubicin cytotoxicity by buthionine sulfoximine in multidrug-resistant human breast tumor cells. Cancer Res. 49:1989;511-515.
123. Raghu G., Pierre-Jerome M., Dordal M.S., Simonian P., Bauer K.D., Winter J.N. P-glycoprotein and alterations in the glutathione/glutathione peroxidase cycle underlie doxorubicin resistance in HL-60-R, a subclone of the HL-60 human leukemia cell line. Int J Cancer. 53:1993;804-811.
124. Lai G.-M., Moscow J.A., Alvarez M.G., Fojo A.T., Bates S.E. Contribution of glutathione and glutathione-dependent enzymes in the reversal of adriamycin resistance in colon carcinoma cell lines. Int J Cancer. 49:1991;688-695.
125. Nair S., Singh S.V., Samy T.S.A., Krishan A. Anthracycline resistance in murine leukemic P388 cells. Role of drug efflux and glutathione related enzymes. Biochem Pharmacol. 39:1990;723-728.
126. Ford J.M., Yang J.-M., Hait W.N. Effect of buthionine sulfoximine on toxicity of verapamil and doxorubicin in multidrug resistant cells and to mice. Cancer Res. 51:1991;67-72.
127. Bellamy W.T., Dalton W.S., Meltzer P., Dorr R.T. Role of glutathione and its associated enzymes in multidrug-resistant human myeloma cells. Biochem Pharmacol. 38:1989;787-793.
128. Benchekroun M.N., Catroux P., Montaudon D., Robert J. Development of mechanisms of protection against oxidative stress in doxorubicin-resistant rat tumoral cells in culture. Free Radic Res Commun. 11:1990;137-144.
129. Keizer H.G., van Rijn J., Pinedo H.M., Joenje H. Effect of endogenous glutathione, superoxide dismutases, catalase and glutathione peroxidase on adriamycin tolerance of Chinese hamster ovary cells. Cancer Res. 48:1988;4493-4497.
130. Liebmann J., Fisher J., Lipschultz C., Kuno R., Kaufman D.C. Enhanced glutathione peroxidase expression protects cells from hydroperoxides but not from radiation or doxorubicin. Cancer Res. 55:1995;4465-4470.
131. Leyland-Jones B.R., Townsend A.J., Tu C.-P.D., Cowan K.H., Goldsmith M.E. Antineoplastic drug sensitivity of human MCF-7 breast cancer cells stably transfected with a human α class glutathione S-transferase gene. Cancer Res. 51:1991;587-594.
132. Lenehan P.F., Gutierrez P.L., Wagner J.L., Milak N., Fisher G.R., Ross D.D. Resistance to oxidants associated with elevated catalase activity in HL-60 leukemia cells that overexpress multidrug-resistance protein does not contribute to resistance to daunorubicin manifested by these cells. Cancer Chemother Pharmacol. 35:1995;377-386.
133. Doroshow J.H. Prevention of doxorubicin-induced killing of MCF-7 human breast cancer cells by oxygen radical scavengers and iron chelating agents. Biochem Biophys Res Commun. 135:1986;330-335.
134. Doroshow J.H. Role of hydrogen peroxide and hydroxyl radical formation in the killing of Ehrlich ascites tumor cells by anticancer quinones. Proc Natl Acad Sci USA. 83:1986;4514-4518.
135. Doroshow J.H., Akman S., Esworthy S., Chu F.F., Burke T. Doxorubicin resistance conferred by selective enhancement of intracellular glutathione peroxidase or superoxide dismutase content in human MCF-7 breast cancer cells. Free Radic Res Commun. 12-13:1991;779-781.
136. Cervantes A., Pinedo H.M., Lankelma J., Schuurhuis G.J. The role of oxygen-derived free radicals in the cytotoxicity of doxorubicin in multidrug resistant and sensitive human ovarian cancer cells. Cancer Lett. 41:1988;169-177.
137. Sinha B.K., Katki A., Batist G., Cowan K.H., Myers C.E. Differential formation of hydroxyl radicals by adriamycin in sensitive and resistant MCF-7 human breast tumor cells Implications for the mechanisms of action . Biochemistry. 26:1987;3776-3781.
138. Fornari F.A. Jr, Jarvis W.D., Grant S., Orr M.S., Randolph J.K., White F.K.H., Mumaw V.R., Lovings E.T., Freeman R.H., Gewirtz D.A. Induction of differentiation and growth arrest associated with nascent (nonoligosomal) DNA fragmentation and reduced c-myc expression in MCF-7 human breast tumor cells after continuous exposure to a sublethal concentration of doxorubicin. Cell Growth Differ. 5:1994;723-733.
139. Keizer H.G., Pinedo H.M., Schuurhuis G.J., Joenje H. Doxorubicin (adriamycin) A critical review of free radical-dependent mechanisms of cytotoxicity . Pharmacol Ther. 47:1990;219-231.
140. DeGraff W., Hahn S.M., Mitchell J.B., Krishna M.C. Free radical modes of cytotoxicity of adriamycin and streptonigrin. Biochem Pharmacol. 48:1994;1427-1435.
141. Peters J.H., Gordon G.R., Kashiwase D., Acton E.M. Metabolic disposition of 5-iminodaunorubicin in the rat. Cancer Res. 44:1984;1453-1459.
142. Buzdar A.U., Marcus C., Smith T.L., Blumenschein G.R. Early and delayed clinical cardiotoxicity of doxorubicin. Cancer. 55:1985;2761-2765.
143. Ferrans V.J. Overview of cardiac pathology in relation to anthracycline cardiotoxicity. Cancer Treat Rep. 62:1978;955-961.
144. Doroshow J.H. Effect of anthracycline antibiotics on oxygen radical formation in rat heart. Cancer Res. 43:1983;460-472.
145. Davies K.J.A., Doroshow J.H. Redox cycling of anthracycline by cardiac mitochondria. I. Anthracycline radical formation by NADH dehydrogenase. J Biol Chem. 261:1986;3060-3067.
146. Doroshow J.H., Davies K.J.A. Redox cycling of anthracycline by cardiac mitochondria. II. Formation of superoxide anion, hydrogen peroxide and hydroxyl radical. J Biol Chem. 261:1986;3068-3074.
147. Demant E.J.F. Inactivation of cytochrome c oxidase activity in mitochondrial membranes during redox cycling of doxorubicin. Biochem Pharmacol. 41:1991;543-552.
148. Sokolove P.M. Interactions of adriamycin aglycones with mitochondria may mediate adriamycin cardiotoxicity. Int J Biochem. 12:1994;1341-1350.
149. Myers C.E., McGuire W.P., Liss R.H., Ifrim I., Grotzinger K., Young R.C. Adriamycin, The role of lipid peroxidation in cardiac toxicity and tumor response. Science. 197:1977;165-167.
150. Rajagopalan S., Politi P., Sinha B.K., Myers C.E. Adriamycin induced free radical formation in the perfused rat heart Implications for cardiotoxicity . Cancer Res. 48:1988;4766-4769.
151. Paracchini L., Jotti A., Bottiroli G., Prosperi E., Supino R., Piccinini F. The spin trap α-phenyl-tert-butyl-nitrone protects against myelotoxicity and cardiotoxicity of adriamycin while preserving the cytotoxic activity. Anticancer Res. 13:1993;1607-1612.
152. Yen H.-C., Oberly T.D., Vichitbandha S., Ho Y.-S., St. Clair D.K. The protective role of manganese superoxide dismutase against adriamycin-induced acute cardiac toxicity in transgenic mice. J Clin Invest. 98:1996;1253-1260.
153. Wexler L.H., Andrich M.P., Venzon D., Berg S.L., Weaver-McClure L., Chen C.C., Dilsizian V., Avila N., Jarosinski P., Ballis F.M., Poplack D.G., Horowitz M.E. Randomized trials of the cardioprotective agent ICRF-187 in pediatric sarcoma patients treated with doxorubicin. J Clin Oncol. 14:1996;362-372.
154. Schiavetti A., Castello M.A., Versacci P., Varrasso G., Padula A., Ventriglia F., Werner B., Colloridi V. Use of ICRF-187 for prevention of anthracycline cardiotoxicity in children Preliminary results . Pediatr Hematol Oncol. 14:1997;213-222.
155. Herman E.H., Ferrans V.J., Myers C.E., Van Vleet J.F. Comparison of the effectiveness of IRCF-187 and N-acetylcysteine in preventing chronic doxorubicin cardiotoxicity in beagles. Cancer Res. 45:1985;276-281.
156. Wadler S., Green M.D., Basch R., Muggia F.M. Lethal and sublethal effects of the combination of doxorubicin and the bisdioxopiperazine, (+)-1,2-bis (3-5-dioxopiperazinyl-1-yl) propane (ICRF-187), on murine sarcoma S180 in vitro. Biochem Pharmacol. 36:1987;1495-1501.
157. Lee V., Randhawa A.K., Singal P.K. Adriamycin-induced myocardial dysfunction in vitro is mediated by free radicals. Am J Physiol. 261:1991;H989-H995.
158. Mimnaugh E.G., Gram T.E., Trush M.A. Stimulation of mouse heart and liver microsomal lipid peroxidation by anthracycline anticancer drugs. Characterization and effects of reactive oxygen scavengers. J Pharmacol Exp Ther. 226:1983;806-816.
159. Mimnaugh E.G., Kennedy K.A., Trush M.A., Gram T.E. Adriamycin-enhanced membrane lipid peroxidation in isolated rat nuclei. Cancer Res. 45:1985;3296-3304.
160. Mimnaugh E.G., Trush M.A., Gram T.E. Stimulation by adriamycin of rat heart and liver microsomal NADPH-dependent lipid peroxidation. Biochem Pharmacol. 30:1981;2797-2804.
161. Thayer W.S. Serum peroxides in rats treated chronically with adriamycin. Biochem Pharmacol. 33:1984;2259-2263.
162. Julicher R.H.M., Sterrenberg L., Bast A., Riksen R.O.W.M., Koomen J.M., Noordhoek J. The role of lipid peroxidation in acute doxorubicin-induced cardiotoxicity as studied in isolated rat heart. J Pharm Pharmacol. 38:1986;277-282.
163. Demant E.F.J., Wasserman K. Doxorubicin induced alterations in lipid metabolism of cultured myocardial cells. Biochem Pharmacol. 34:1985;1741-1746.
164. Jackson J.A., Reeves J.P., Muntz K.H., Kruk D., Prough R.A., Willerson J.T., Buja L.M. Evaluation of free radical effects and catecholamine alterations in adriamycin cardiotoxicity. Am J Pathol. 117:1984;140-153.
165. Olson R.D., Mushlin P.S. Doxorubicin cardiotoxicity Analysis of prevailing hypotheses . FASEB J. 4:1990;3076-3086.
166. Unverferth D.V., Leier C.V., Balcerzak S.P., Hamlin R.L. Usefulness of free radical scavenger in preventing doxorubicin-induced heart failure in dogs. Am J Cardiol. 56:1985;157-161.
167. Doroshow J.H., Locker G.Y., Ifrim I., Myers C.E. Prevention of doxorubicin cardiac toxicity in the mouse by N-acetylcysteine. J Clin Invest. 68:1981;1053-1064.
168. Tsuruo T., Iida H., Tsukagoshi S., Sakurai Y. Increased accumulation of vincristine and adriamycin in drug-resistant P388 tumor cells following incubation with calcium antagonists and calmodulin inhibitors. Cancer Res. 42:1982;4730-4733.
169. Coley H.M., Twentyman P.R., Workman P. Improved cellular accumulation is characteristic of anthracyclines which retain high activity in multidrug resistant cell lines, alone or in combination with verapamil or cyclosporin A. Biochem Pharmacol. 38:1989;4467-4475.
170. Ross W.R., Glaubiger D.L., Kohn K.W. Protein-associated DNA breaks in cells treated with adriamycin or ellipticine. Biochim Biophys Acta. 519:1978;23-30.
171. Ross W.R., Glaubiger D.L., Kohn K.W. Qualitative and quantitative aspects of intercalator-induced DNA strand breaks. Biochim Biophys Acta. 562:1979;41-50.
172. Ross W.E., Bradley M.O. DNA double-strand breaks in mammalian cells after exposure to intercalating agents. Biochim Biophys Acta. 654:1981;129-134.
173. Ross W.E., Smith M.C. Repair of DNA lesions caused by adriamycin and ellipticine. Biochem Pharmacol. 31:1982;1931-1935.
174. Goldenberg G.J., Wang H., Blair G.W. Resistance to adriamycin Relationship of cytotoxicity to drug uptake and DNA single- and double-strand breakage in cloned cell lines of adriamycin-sensitive and -resistant P388 leukemia . Cancer Res. 46:1986;2978-2983.
175. Capranico G., De Isabella P., Penco S., Tinelli S., Zunino F. Role of DNA breakage in cytotoxicity of doxorubicin, 9-deoxydaunorubicin and 4-demethyl-6-deoxydoxorubicin in murine leukemia P388 cells. Cancer Res. 49:1989;2022-2027.
176. Belvedere G., Suarto A., Geroni C., Guiliani F.C., D'Incalci M. Comparison of intracellular drug retention, DNA damage and cytotoxicity of derivatives of doxorubicin and daunorubicin in a human colon adenocarcinoma cell line (Lovo). Biochem Pharmacol. 38:1989;3713-3721.
177. Spadari S., Pedrali N.G., Focher F., Montecucco A., Bordoni T., Geroni C., Giuliani F.C., Ventrella G., Arcamone F., Ciarrocchi G. DNA polymerase and DNA topoisomerase as targets for the development of anticancer drugs. Anticancer Res. 6:1986;935-940.
178. Gewirtz D.A., Orr M.S., Fornari F.A., Randolph J.K., Yalowich J.C., Ritke M.K., Povirk L.F., Bunch R.T. Dissociation between bulk damage to DNA and the antiproliferative activity of teniposide (VM-26) in the MCF-7 breast tumor cell line Evidence for induction of gene-specific damage and alterations in gene expression . Cancer Res. 53:1993;3547-3554.
179. Zwelling L.A., Bales E., Altschuler E., Mayes J. Circumvention of resistance by doxorubicin, but not by idarubicin in a human leukemia cell line containing an intercalator-resistant form of topoisomerase II Evidence for a non-topoisomerase II mediated mechanism of doxorubicin toxicity . Biochem Pharmacol. 45:1993;516-520.
180. Binaschi M., Capranico G., Dal Bo L., Zunino F. Relationship between lethal effects and topoisomerase II mediated double-strand DNA breaks produced by anthracyclines with different sequence specificity. Mol Pharmacol. 51:1997;1053-1059.
181. Pommier Y. DNA topoisomerase II inhibitors. Teicher B.A. Cancer Therapeutics Experimental and Clinical Agents . 1997;153-174 Humana Press, Totowa, NJ.
182. Gewirtz D.A. Does bulk damage to DNA explain the cytostatic and cytotoxic effects of topoisomerase II inhibitors? Biochemical Pharmacol. 42:1991;2253-2258.
183. Watson N.C., Di Y.M., Orr M.S., Fornari F.A., Randolph J.K., Magnet K.J., Jain P.T., Gewirtz D.A. Influence of ionizing radiation on proliferation, c-myc expression and the induction of apoptotic cell death in two breast tumor cell lines differing in p53 status. Int J Radiat Biol. 72:1997;547-559.
184. Whitacre C.M., Berger N.A. Factors affecting topotecan induced programmed cell death Adhesion protects cells from apoptosis and impairs cleavage of poly(ADP-ribose) polymerase . Cancer Res. 57:1997;2157-2163.
185. Oberhammer F., Wilson J.W., Dive C., Morris I.D., Hickman J.A., Wakeling A.E., Walker P.R., Sikorska M. Apoptotic death in epithelial cells: Cleavage of DNA to 300 and/or 50 kb fragments prior to or in the absence of internucleosomal fragmentation. EMBO J. 12:1993;3679-3684.
186. Han J.-W., Dionne C.A., Kedersha N.L., Goldmacher V.S. p53 status affects the rate of the onset but not the overall extent of doxorubicin-induced cell death in Rat-1 fibroblasts constitutively expressing c-Myc. Cancer Res. 57:1997;176-182.
187. Lock R.B., Stribinskiene L. Dual modes of death induced by etoposide in human epithelial tumor cells allow Bcl-2 to inhibit apoptosis without affecting clonogenic survival. Cancer Res. 56:1996;4006-4012.
188. 2 arrest in Chinese hamster ovary cells treated with anticancer drugs. J Natl Cancer Inst. 57:1976;1139-1143.
189. 2 block induced by DNA crosslinking agents and its possible consequences. Biochem Pharmacol. 37:1988;2303-2309.
190. 1 activity induced by doxorubicin in synchronized P388 cells. Mol Pharmacol. 49:1996;832-841.
191. 1 arrest checkpoint in response to DNA damage. Mol Cell Biol. 18:1998;378-387.
192. + leukemia cells. Leukemia. 1:1987;188-197.
193. Dinnen R.D., Robinow C.F., Ebisuzaki K. An anticancer drug-sensitive murine erythroleukemia clone Implications for the mechanism of action of antineoplastic drugs . Cancer Res. 53:1993;1877-1882.
194. Colombo R., Necco A., Vailati G., Milzani A. Dose-dependence of doxorubicin effect on actin assembly in vitro. Exp Mol Pathol. 49:1988;297-304.
195. Molinari A., Calcabrini A., Crateri P., Arancia G. Interaction of anthracyclinic antibiotics with cytoskeletal components of cultured carcinoma cells (CG5). Exp Mol Pathol. 53:1990;11-33.
196. Ito H., Miller S.C., Billingham M.E., Akimoto H., Torti S.V., Wade R., Gahlmann R., Lyons G., Kedes L., Torti F.M. Doxorubicin selectively inhibits muscle gene expression in cardiac muscle cells in vivo and in vitro. Proc Natl Acad Sci USA. 87:1990;4275-4279.
197. Cummings J., Anderson L., Willmott N., Smyth J.F. The molecular pharmacology of doxorubicin in vivo. Eur J Cancer. 27:1991;532-535.
198. Doroshow J.H. Anthracyclines and anthracenediones. Chabner B.A., Longo D.L. Cancer Chemotherapy and Biotherapy Principles and Practice . 2nd Edn. 1996;409-434 Lippincott-Raven, Philadelphia, PA.