Abstract
The ability to target malignant cells for cytotoxicity while sparing normal host tissues has proven to be limited. These limitations have resulted in unacceptable toxicity or insufficiently effective therapy. Continuing investigation of new, potentially useful cytotoxic agents must continue. An alternative approach, also worthy of study, is the selective protection of normal tissues. This approach, used in conjunction with available therapeutic agents, may open the therapeutic window and incrementally enhance the effectiveness of cytotoxic therapy. A variety of methods have been used to protect normal tissues selectively. Regional protection can be used for certain organ systems, such as the oral mucosa. Selective protection on a systemic level is more difficult but agents that seem to protect normal but not malignant tissues selectively are being developed. Among these is amifostine, which was originally selected by the U.S. defense department for study as a radio-protectant. Pre-clinical studies have suggested that amifostine is differentially concentrated in normal tissues but not in malignant tissues. Tissue-specific differences in the activity of alkaline phosphatase, which dephosphorylates amifostine to its active metabolite WR-1065, and in pH are thought to be involved in this relative specificity. Clinical studies indicate that amifostine can reduce the myelosuppression produced by cyclophosphamide, the combination of cyclophosphamide and cisplatin, and, perhaps, carboplatin. The protective effects of amifostine on non-hematopoietic toxicities are being investigated. Future trials will investigate the integration of amifostine with cytokine-based supportive care in order to define the role of this potentially clinically useful cytoprotectant agent.
Similar content being viewed by others
References
Allegra JC (1983) Methotrexate and 5-fluorouracil following tamoxifen and premarin in advanced breast cancer. Semin Oncol 10 [Suppl 2]:23–28
Budd GT, Ganapathi R, Bauer L, et al (1993) Phase I study of WR-2721 and carboplatin. Eur J Cancer 29A:1122–1126
Bukowski RM, Murthy SA, Finke J, et al (1994) Phase I trial of cisplatin, WR-2721, and the murine monoclonal antibody R24 in patients with metastatic melanoma: clinical and biologic effects. J Immunother (in press)
Buzaid AC, Murren J, Durivage HJ (1991) High dose cisplatin plus WR-2721 in a split course in metastatic malignant melanoma. Am J Clin Oncol 14:203–207
Calabro-Jones P, Fahey RC, Smoluk GD, Ward JF (1985) Alkaline phosphatase promotes radioprotection and accumulation of WR-1065 in V79-171 cells incubated in medium containing WR-2721. Int J Radiat Biol 47:23–27
Calabro-Jones PM, Aguilera JA, Ward JF, et al (1988) Uptake of WR-2721 derivatives by cells in culture: identification of the transported form of the drug. Cancer Res 48:3634–3640
Davidson DE, Grenan MM, Sweney TR (1980) Biological characteristics of some improved radioprotectors. In: Brady L (ed) Radiation sensitizers. Masson, New York, pp 309–320
Dunlop DJ, Wright EG, Lorimore S, et al (1992) Demonstration of stem cell inhibition and myeloprotective effects of SCI/rhMIP1 alpha in vivo. Blood 9:2221–2225
Glick J, Kemp G, Rose P, et al (1992) A randomized trial of cyclophosphamide and cisplatin +/-WR-2721 in the treatment of advanced epithelial ovarian cancer. Proc ASCO 11:109
Glover D, Glick JH, Weiler C, et al (1986) WR-2721 protects against the hematologic toxicity of cyclophosphamide: a controlled phase II trial. J Clin Oncol 4:584–588
Glover D, Glick J, Weiler C, et al (1986) Phase I/II trials of WR-2721 and cisplatin. Int J Radiat Oncol Biol Phys 12:1509–1512
Glover D, Glick JH, Weiler C, Fox K, Guerry D (1987) WR-2721 and high dose cisplatin: an active combination in the treatment of metastatic melanoma. J Clin Oncol 5:574–578
Howell SB, Pfeifle CE, Wung WE, Olshen RA (1983) Intraperitoneal cis-diamminedichloroplatinum with systemic thiosulfate protection. Cancer Res 43:1426–1431
Issels RD, Nagele A (1989) Promotion of cystine uptake, increase of glutathione biosynthesis, and modulation of glutathione status by S-2-(3-aminopropylamino)ethyl phosphorothioic acid (WR-2721) in Chinese hamster cells. Cancer Res 49:2082–2086
Kligerman MM, Turrissi AT III, Urtasun RC, et al (1988) Final report on phase I trial of WR-2721 before protracted fractionated radiation therapy. Int J Radiat Oncol Biol Phys 14:1119–1122
Mahood DJ, Dose AM, Loprinzi CL, et al (1991) Inhibition of fluorouracil-induced stomatitis by oral cryotherapy. J Clin Oncol 9:449–452
Millar JL, McElwain TJ, Clutterbuck RD, Wist EA (1982) The modification of melphalan toxicity in tumor bearing mice by S-2-(3-aminopropylamino)ethylphosphorothioic acid (WR-2721). Am J Clin Oncol 5:321–328
Mollman JE (1991) Protection against cisplatin neurotoxicity in cultured dorsal root ganglion cells by WR-2721. 7th International Conference on Chemical Modifiers of Cancer Treatment, pp 328–329
Mollman JE, Glover DJ, Hogan M, Furman RE (1988) Cisplatin neuropathy: risk factors, prognosis, and protection by WR-2721. Cancer 61:2192–2195
Patchen ML, MacVittie TJ, Souza LM (1992) Postirradiation treatment with granulocyte colony-stimulating factor and preirradiation WR-2721 synergize to enhance hemopoietic reconstitution and increase survival. Int J Radiat Oncol Biol Phys 22:773–779
Shpall EJ, Johnston C, Jones RE, et al (1991) Amifostine (WR-2721) shortens the engraftment period of 4-HC purged bone marrow in breast cancer patients receiving high-dose chemotherapy with autologous bone marrow support. Proc Am Soc Hematol 78:192a
Tanaka Y (1984) Clinical experiences with a chemical radioprotector in tumor radiotherapy: WR-2721. In: Sugahara T (ed) Modification of radio-sensitivity in cancer treatment. Academic Press, Tokyo New York, pp 61–81
Treskes M, Nitjman LG, Fichtinger-Schepman A, et al (1992) Effects of the modulating agent WR-2721 and its main metabolites on the formation and stability of cisplatin/DNA adducts in vitro. Biochem Pharmacol 43:1013–1019
Turrisi AT, Glover DJ, Hurwitz S, et al (1986) Final report of the phase I trial of single-dose WR-2721. Cancer Treat Rep 70:1389–1393
Wasserman TH, Phillips TL, Ross G, et al (1981) Differential protection against cytotoxic chemotherapeutic effects on bone marrow CFU's by WR-2721. Cancer Clin Trials 4:3–6
Wooley PV, Ayoob MJ, Smith FP, Dritschilo A (1983) Clinical trial of the effect of WR-2721 on the toxicity of cyclophosphamide. J Clin Oncol 1:198–203
Yuhas JM (1979) Differential protection of normal and malignant tissues against the cytotoxic effects of mechlorethamine. Cancer Treat Rep 63:971–976
Yuhas JM (1980) Active versus passive absorption kinetics as the basis for selective protection of normal tissues by S-2-(3-aminopropylamino)-ethylphosporothioic acid. Cancer Res 40:1519–1524
Yuhas JM, Culo F (1980) Selective inhibition of the nephrotoxicity of cis-dichlorodiammineplatinum (II) by WR-2721 without altering its antitumor properties. Cancer Treat Rep 64:57–64
Yuhas JM, Spellman JM, Jordan SW, et al (1986) Treatment of tumours with the combination of WR-2721 and cis-dichlorodiammineplatinum (II) or cyclophosphamide. Br J Cancer 42:1509–1512
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Budd, G.T., Lorenzi, V., Ganapathi, R. et al. Amifostine: potential for clinically useful cytoprotection. Support Care Cancer 2, 380–384 (1994). https://doi.org/10.1007/BF00344052
Issue Date:
DOI: https://doi.org/10.1007/BF00344052