Radiotherapy and chemotherapy are the basic approaches in cancer treatment, but these procedures are often associated with a number of undesirable side effects worsening the quality of life of the patient. In recent years a number of protective compounds capable of reducing or eliminating these side effects have been extensively investigated (for example: dexrazoxan, mesna, glutathion or N-acetylcystein). One of these compounds is amifostine (WR-2721), a broad-spectrum cytoprotective drug, selectively protecting normal tissues from the toxic effects of therapy, while the malignant tissues are subject to the anti-tumour effects of the treatment. In addition, several studies have revealed certain antimutagenic activities of amifostine making this agent potentially useful in the prevention of therapy-induced secondary malignancies. This article summarizes the information available on the antimutagenic and cytoprotective effects of amifostine and its effects also on the activity of the p53 tumour suppressor.
amifostine; tumour suppressor p53; cytoprotective and antimutagenic compounds; WR-2721; WR-1065
Acosta JC, Richard C, Delgado MD, Horita M, Rizzo MG, Fernandez-Luna JL, Leon J: Amifostine impairs p53-mediated apoptosis of human myeloid leukemia cells. Mol Cancer Ther 2:893-900, 2003.
Andreassen CN, Grau C, Lindegaard J C: Chemical radioprotection: a critical review of amifostine as a cytoprotector in radiotherapy. Semin Radiat Oncol 13:62-72, 2003.
Appella E, Anderson CW: Post-translational modifications and activation of p53 by genotoxic stresses. Eur J Biochem 268:2764-2772, 2001.
Calabro-Jones PM, Aguilera JA, Ward JF, Smoluk GD, Fahey RC: Uptake of WR-2721 derivatives by cells in culture: identification of the transported form of the drug. Cancer Res 48:3634-3640, 1988.
Camhi SL, Lee P, Choi AM: The oxidative stress response. New Horiz 3:170-182, 1995.
Capizzi RL: The preclinical basis for broadspectrum selective cytoprotection of normal tissues from cytotoxic therapies by amifostine. Semin Oncol 26:3-21, 1999.
Culy CR, Spencer CM: Amifostine: an update on its clinical status as a cytoprotectant in patients with cancer receiving chemotherapy or radiotherapy and its potential therapeutic application in myelodysplastic syndrome. Drugs 61:641-684, 2001.
DeNeve WJ, Everett CK, Suminski JE, Valeriote FA: Influence of WR2721 on DNA crosslinking by nitrogen mustard in normal mouse bone marrow and leukemia cells in vivo. Cancer Res 48:6002-6005, 1988.
Flaman JM, Robert V, Lenglet S, Moreau V, Iggo R, Frebourg T: Identification of human p53 mutations with differential effects on the bax and p21 promoters using functional assays in yeast. Oncogene 16:1369-1372, 1998.
Grdina DJ, Murley JS, Kataoka Y, Epperly W: Relationships between cytoprotection and mutation prevention by WR-1065. Mil Med 167:51-53, 2002a.
Grdina DJ, Murley JS, Kataoka Y: Radioprotectants: current status and new directions. Oncology 63:2-10, 2002b.
Hainaut P, Milner J: Redox modulation of p53 conformation and sequence-specific DNA binding in vitro. Cancer Res 53:4469-4473, 1993.
Hensley ML, Schuchter LM, Lindley C, Meropol NJ, Cohen GI, Broder G, Gradishar WJ, Green DM, Langdon RJ Jr., Mitchell RB, Negrin R, Szatrowski TP et al.: American Society of Clinical Oncology clinical practice guidelines for the use of chemotherapy and radiotherapy protectants. J Clin Oncol 17:3333-3355, 1999.
http://www.drugs.com, downloaded 28th February 2007.
Kataoka Y, Murley JS, Patel R, Grdina DJ: Cytoprotection by WR-1065, the active form of amifostine, is independent of p53 status in human malignant glioma cell lines. Int J Radiat Biol 76:633-639, 2000.
Koukourakis MI: Amifostine: is there evidence of tumour protection? Semin Oncol 30:18-30, 2003.
Kramer DL, Vujcic S, Diegelman P, Alderfer J, Miller JT, Black JD, Bergeron RJ, Porter CW: Polyamine analogue induction of the p53- p21WAF1/CIP1-Rb pathway and G1 arrest in human melanoma cells. Cancer Res 59:1278-1286, 1999.
Lee E, Gerhold M, Palmer MW, Christen RD: p53 protein regulates the effects of amifostine on apoptosis, cell cycle progression, and cytoprotection. Br J Cancer 88:754-759, 2003.
Liu SC, Murley JS, Woloschak, Grdina DJ: Repression of c-myc gene expression by the thiol and disulfide forms of the cytoprotector amifostine. Carcinogenesis 18:2457-2459, 1997.
Mann K, Hainaut P: Aminothiol WR1065 induces differential gene expression in the presence of wild-type p53. Oncogene 24:3964-3975, 2005.
Maurici D, Monti P, Campomenosi P, North S, Frebourg T, Fronza G, Hainaut P: Amifostine (WR2721) restores transcriptional activity of specific p53 mutant proteins in a yeast functional assay. Oncogene 20:3533-3540, 2001.
MedImmune Oncology, Inc.: Ethyol Monograph. Package Insert, Gaithersburg, MD 2005.
Meier T, Issels RD: Degradation of 2-(3- aminopropylamino)-ethanethiol (WR-1065) by Cu-dependent amine oxidases and influence on glutathione status of Chinese hamster ovary cells. Biochem Pharmacol 50:489-496, 1995.
Milner J: Flexibility: The key to p53 function? Trends Biochem Sci 20:49-51, 1995.
Minet E, Michel G, Mottet D, Piret JP, Barbieux A, Raes M, Michiels C: c-JUN gene induction and AP-1 activity is regulated by a JNK-dependent pathway in hypoxic HepG2 cells. Exp Cell Res 265:114-124, 2001.
Mitchell JL, Rupert J, Leyser A, Judd GG: Mammalian cell polyamine homeostasis is altered by the radioprotector WR1065. Biochem J 335:329-334, 1998.
Murley JS, Constantinou A, Kamath NS, Grdina DJ: WR-1065, an active metabolite of the cytoprotector amifostine, affects phosphorylation of topoisomerase II alpha leading to changes in enzyme activity and cell cycle progression in CHO AA8 cells. Cell Prolif 30:283-294, 1997.
Murley JS, Grdina DJ: The effects of cycloheximide and WR-1065 on radiationinduced repair processes: A mechanism for chemoprevention. Carcinogenesis 16:2699-2705, 1995.
Murley JS, Kataoka Y, Hallahan DE, Roberts JC, Grdina DJ: Activation of NFkappaB and MnSOD gene expression by free radical scavengers in human microvascular endothelial cells. Free Radic Biol Med 30:1426-1439, 2001.
North S, El-Ghissassi F, Pluquet O, Verhaegh G, Hainaut P: The cytoprotective aminothiol WR1065 activates p21waf-1 and down regulates cell cycle progression through a p53- dependent pathway. Oncogene 19:1206-1214, 2000.
North S, Pluquet O, Maurici D, El-Ghissassi F, Hainaut P: Restoration of wild-type conformation and activity of a temperaturesensitive mutant of p53 (p53(V272M)) by the cytoprotective aminothiol WR1065 in the esophageal cancer cell line TE-1. Mol Carcinog 33:181-188, 2002.
Paasinen-Sohns A, Kielosto M, Kaariainen E, Eloranta T, Laine A, Janne OA, Birrer MJ, Holtta E: c-Jun activation-dependent tumourigenic transformation induced paradoxically by overexpression or block of S-adenosylmethionine decarboxylase. J Cell Biol 151:801-810, 2000.
Pataer A, Fanale MA, Roth JA, Swisher SG, Hunt KK: Induction of apoptosis in human lung cancer cells following treatment with amifostine and an adenoviral vector containing wild-type p53. Cancer Gene Ther 13:806-814, 2006.
Pluquet O, North S, Bhoumik A, Dimas K, Ronai Z, Hainaut P: The cytoprotective aminothiol WR1065 activates p53 through a nongenotoxic signaling pathway involving c-Jun N-terminal kinase. J Biol Chem 278:11879-11887, 2003a.
Pluquet O, North S, Richard MJ, Hainaut P: Activation of p53 by the cytoprotective aminothiol WR1065: DNA-damageindependent pathway and redox-dependent modulation of p53 DNA-binding activity. Biochem Pharmacol 65:1129-1137, 2003b.
Pollard KJ, Samuels ML, Crowley KA, Hansen JC, Peterson CL: Functional interaction between GCN5 and polyamines: A new role for core histone acetylation. EMBO J 18:5622-5633, 1999.
Prives C, Hall PA: The p53 pathway. J Pathol 187:112-126, 1999.
Provinciali M, Ciavattini A, Di Stefano G, Argentati K, Garzetti GG: In vivo amifostine (WR-2721) prevents chemotherapy-induced apoptosis of peripheral blood lymphocytes from cancer patients. Life Sci 64:1525-1532, 1999.
Ramakrishnan N, Catravas GN: N-(2- mercaptoethyl)-1,3-propanediamine (WR- 1065) protects thymocytes from programmed cell death. J Immunol 148:1817-1821, 1992.
Romano MF, Lamberti A, Bisogni R, Garbi C, Pagnano AM, Auletta P, Tassone P, Turco MC, Venuta S: Amifostine inhibits hematopoietic progenitor cell apoptosis by activating NFkappaB/ Rel transcription factors. Blood 94:4060-4066, 1999.
Santini V, Giles FJ: The potential of amifostine: from cytoprotectant to therapeutic agent. Haematologica 84:1035-1042, 1999.
Savoye C, Swenberg C, Hugot S, Sy D, Sabattier R, Charlier M, Spotheim-Maurizot M: Thiol WR- 1065 and disulphide WR-33278, two metabolites of the drug ethyol (WR-2721), protect DNA against fast neutron-induced strand breakage. Int J Radiat Biol 71:193-202, 1997.
Shaw L M, Bonner HS, Schuchter L, Schiller J, Lieberman R: Pharmacokinetics of amifostine: effects of dose and method of administration. Semin Oncol 26:34-36, 1999.
Shen H, Chen ZJ, Zilfou JT, Hopper E, Murphy M, Tew KD: Binding of the aminothiol WR-1065 to transcription factors influences cellular response to anticancer drugs. J Pharmacol Exp Ther 297:1067-1073, 2001.
Sherr CJ, Weber JD: The ARF/p53 pathway. Curr Opin Genet Dev 10:94-99, 2000.
Toledo F, Wahl GM: Regulating the p53 pathway: in vitro hypotheses, in vivo veritas. Nat Rev Cancer 6:909-923, 2006.
van der Vijgh WJ, Korst AE: Amifostine (Ethyol): Pharmacokinetic and pharmacodynamic effects in vivo. Eur J Cancer 32:S26-S30, 1996.
Vousden KH, Lu X: Live or let die: the cell's response to p53. Nat Rev Cancer 2:594-604, 2002.
Vousden KH: Activation of the p53 tumour suppressor protein. Biochim Biophys Acta 1602:47-59, 2002.
Wadler S, Haynes H, Beitler JJ, Goldberg G, Holland JF, Hochster H, Bruckner H, Mandeli J, Smith H, Runowicz C: Management of hypocalcemic effects of WR2721 administered on a daily times five schedule with cisplatin and radiation therapy. J Clin Oncol 11:1517-1522, 1993.
Woloschak G E, Paunesku T, Chang-Liu CM, Grdina DJ: Expression of thymidine kinase messenger RNA and a related transcript is modulated by radioprotector WR1065. Cancer Res 55:4788-4792, 1995.
Yuhas JM, Storer JB: Differential chemoprotection of normal and malignant tissues. J Natl Cancer Inst 42:331-335, 1969.
Zhang X, Lai PP, Taylor YC: Differential radioprotection of cultured human diploid fibroblasts and fibrosarcoma cells by WR1065. Int. J Radiat Oncol Biol Phys 24:713-719, 1992.
Mukherjee N, Carroll BL, Spees JL, Delay ER. Pre-Treatment with Amifostine Protects against Cyclophosphamide-Induced Disruption of Taste in Mice. Plos One. 8, Art No: e61607, 2013.
Novakovic M, Stankovic M, Vuckovic I, Todorovic N, Trifunovic S, Tesevic V, Vajs V, Milosavljevic S. Diarylheptanoids from Alnus glutinosa Bark and Their Chemoprotective Effect on Human Lymphocytes DNA. Planta Med. 79: 499-505, 2013.
Slovackova J, Smarda J, Smardova J. Roscovitine-induced apoptosis of H1299 cells depends on functional status of p53. Neoplasma. 59: 606-612, 2012.
Vuckovic I, Vajs V, Stankovic M, Tesevic V, Milosavljevic S: A New Prenylated Flavanonol from Seseli annuum Roots Showing Protective Effect on Human Lymphocytes DNA. Chem Biodiversity. 7: 698-704, 2010.
Aydemir N, Sevim N, Celikler S, Vatan O, Bilaloglu R: Antimutagenicity of amifostine against the anticancer drug fotemustine in the Drosophila somatic mutation and recombination (SMART) test. Mutat Res-Genet Toxicol Environ Mutagen. 679: 1-5, 2009.
Arican GO, Arican E: Cytoprotective activity of amifostine on HeLa cell cultures treated with daunorubicin and evaluation of gene expression by RT-PCR. Pharm Biol. 47: 527-532, 2009.