Abstract
In 1988, Dr. Brian Leyland-Jones questioned “Whither the Modulation of Platinum” in an editorial in the Journal of the National Cancer Institute (Leyland-Jones, 1988). The quest for specific chemoprotectants clearly predates the advent of platinum-based chemotherapy and yet, progress has been slow with only a few chemoprotectants available in the clinic. These include mesna for the oxazophosphorines (Shaw, 1987), amifostine for cisplatin (in certain European countries), and more recently, the cardioprotectant iron chelator, cardioxane (ADR-529 or ICRF-187) [Speyer et al., 1988 and 1992]. For the platinum-based antitumor agents, a large number of thiol-based or sulfur-containing nucleophiles have been tested. These include the endogenous tripeptide glutathione, disulfiram and its metabolite, diethyldithiocarbamate, the inorganic salt, sodium thiosulfate, and the phosphorylated aminothiol, amifostine (Ethyol or WR-2721) (Glover et al., 1987) (Figure 1). Of these, several appear to have promise for clinical utility against platinum-induced nephrotoxicity and possibly the peculiar cumulative-dose limiting neuropathy. For this condition, a unique melanocortin-derived neuropeptide, ORG-2766, appears to have potential utility.
This is a preview of subscription content, log in via an institution.
Buying options
Tax calculation will be finalised at checkout
Purchases are for personal use only
Learn about institutional subscriptionsPreview
Unable to display preview. Download preview PDF.
References
Aamdal S., Fedstad O., and Pihl A., 1988, Sodium thiosulfate fails to increase the therapeutic index of intravenously administered cis-diammine-dichloroplatinum (II) in mice bearing murine and human tumors, Cancer Chemother Pharmacol 21:129.
Andrews P.A., and Howell S.B., 1990, Cellular pharmacology of cisplatin: perspectives on mechanisms of acquired resistance, Cancer Cells, 2(2):35.
Andrews P.A., Murphy M.P., and Howel S.B., 1985, Differential potentiation of alkylating and platinating agent cytotoxicity in human ovarian carcinoma cells by glutathione depletion, Cancer Res. 30:643.
Asta-Werke Degussa Pharma Grouppe, 1984, Uromitexan (mesna) uroprotector, basic information, Bielefeld, FRG.
Baskin S.I., Horowitz A.M., and Nealley E.W., 1992, The antidotal action of sodium nitrite and sodium thiosulfate against cyanide poisoning, J Clin Pharmacol 32:368.
Berry J.M., Jacobs C., Sikic B., et al, 1990, Modification of cisplatin toxicity with diethyldithiocarbamate, J Clin Oncol 8:1585.
Bodenner D.I., Dedon P.C., Keng P.C., et al., 1986, Effect of diethyldithiocarbamate (DDTC) on cis-diamminedichloroplatinum (II)-induced cytotoxicity, DNA cross-linking and gamma-glutamyl transpeptidase inhibition, Cancer Res. 46:2745.
Bohm S., Spatti G., De Re F., et al., 1991, A feasibility study of cisplatin administration with low-volume hydration and glutathione protection in the treatment of ovarian carcinoma, Anticancer Res. 11:1613.
Bonadonna G., and Karnofsky D.A., 1965, Protection studies with sodium thiosulfate against methyl bis (β-chloroethyl)amine hydrochloride (HN2) and its ethylenimonium derivative, Clin Pharmacol Ther. 6(1):50.
Borch R.F., and Pleasants M.E., 1979, Inhibition of cis-platinum nephrotoxicity by diethyldithiocarbamate rescue in a rat model, Proc Natl Acad Sci USA. 76(12):6611.
Borch R.F., Katz J.C., Lieder P.H., and Pleasants M.E., 1980, Effect of diethyldithiocarbamate rescue on tumor response to cis-platinum in a rat model, Proc Natl Acad Sci USA. 77(9):5441.
Burchenal J.H., Kalaher K., Dew K., et al., 1978, Studies of cross-resistance, synergistic combinations and blocking of activity of platinum derivatives, Biochimie. 60:961.
Cascinu S., Cordelia L., Del Ferro E., et al., 1995, Neuroprotective effect of reduced glutathione on cisplatin-based chemotherapy in advanced gastric cancer: a randomized double-blind placebo-controlled trial, J Clin Oncol. 13(1):26.
Cavaletti G., Tredici G., Pizzini G., et al., 1992, Morphologic, morphometric and toxicologie evaluations of the effect of cisplatin alone or in combination with glutathione on the rat nervous system, Clin Neuropathol. 11:169.
Cersosimo R.J., 1989, Cisplatin neurotoxicity, Cancer Treat Rep. 16:195.
Cohen J.D., and Robins H.I., 1990, Cytotoxicity of diethyldithiocarbamate in human versus rodent cell lines, Invest New Drugs. 8:137.
Colombo N., Bird S., Miceli D., et al., 1995, Weekly cisplatin ± glutathione in relapsed ovarian carcinoma, Int J Gynecol Cancer. 5:81.
Cozzaglio L., Doci R., Colla G., et al., 1990, A feasibility study of high-dose cisplatin and 5-fluorouracil with glutathione protection in the treatment of advanced colorectal cancer, Tumori. 76:590.
De Re F., Bohm S., Oriana S., et al., 1993, High-dose cisplatin and cyclophosphamide with glutathione in the treatment of advanced ovarian cancer, Ann Oncol. 4:55.
De Wied D., and Jolies J., 1982, Neuropeptides derived from pro-opiocortin: behavioral, physiological and neurochemical effects, Physiol Rev. 62:976.
de Koning P., Neijt J.P., Jennekens F.G.I., and Gispen W.H., 1987, Org.2766 protects from cisplatin-induced neurotoxicity in rats, Exper Neurol. 97:746.
de Sauvage F.J., Hass P.E., Spencer S.D., et al., Stimulation of megakaryocytopoiesis and thrombopoiesis by the c-Mpl ligand, Nature. 369:533.
Dedon P.C., and Borch R.F., 1987, Characterization of the reactions of platinum antitumor agents with biologic and nonbiologic sulfur-containing nucleophiles, Biochem Pharmacol. 36:1955.
DeGregorio M.W., Gandara D.R., Holleran W.M., et al, 1989, High-dose cisplatin with diethyldithiocarbamate (DDTC) rescue therapy: preliminary pharmacologie observations, Cancer Chemother Pharmacol. 23:276.
Di Re F., Bohm S., Oriana S., et al., 1990, Efficacy and safety of high-dose cisplatin and cyclophosphamide with glutathione protection in the treatment of bulky advanced epithelial ovarian cancer. Cancer Chemother Pharmacol. 25:355.
Dible S.E., Siddik Z.H., Boxall F.E., et al., 1987, The effect of diethyldithiocarbamate on the haematological toxicity and antitumor activity of carboplatin, Eur J Cancer Clin Oncol. 23:813.
Doroshow J.H., Locker G., Ifrim I., et al, 1981, Prevention of doxorubicin cardiac toxicity in the mouse by N-acetylcysteine, J Clin Invest. 64:1053.
Doroshow J.H., Locker G.Y., and Myers C.E., 1980, The enzymatic defenses of the mouse heart against oxygen metabolites, J Clin Invest. 65:128.
Dorr R.T., and Lagel L., 1989, Interaction between cisplatin and mesna in mice. J Cancer Res Clin Oncol. 115:604.
Dorr R.T., Soble M., and Alberts D.S., 1988, Efficacy of sodium thiosulfate as alocal antidote to mechlorethamine skin toxicity in the mouse, Cancer Chemother Pharmacol 22:299.
Elderson A., van der Hoop G.P., Haanstra W., et al., 1989, Vibration perception and thermoperception as quantitative measurements in the monitoring of cisplatin-induced neurotoxicity, J Neurol Sci. 93:167.
Evans R.G., Wheatley C., Engel C., et al, 1984, Modification of the bone marrow toxicity of cis-diamminedichloroplatinum(II) in mice by diethyldithiocarbamate, Cancer Res. 44:3686.
Filipski J., Kohn K.W., Prather R., and Bonner W.M., 1979, Thiourea reverses cross-links and restroes biological activity in DNA treated with dichlorodiaminoplatinum(II), Science. 204:181.
Fontanelli R., Spatti G., Raspagliesi F., et al., 1992, A preoperative single course of high-dose cisplatin and bleomycin with glutathione protection in bulky stage IB/n carcinoma of the cervix, Ann Oncol. 3:117.
Francis P., Markman M., Hakes T., et al., 1989, Diethyldithiocarbamate chemoprotection of carboplatin-induced hematological toxicity, J Cancer Res Clin Oncol. 119:360.
Freeman M.L., and Meredith M.J., 1989, The relationship between intracellular glutathione concentration and cisplatin cytotoxicity, Proc Amer Assoc Cancer Res. 30:460.
Friedman H.S., Colvin O.M., Aisaka K., et al., 1990, Glutathione protects cardiac and skeletal muscle from cyclophosphamide-induced toxicity, Cancer Res. 50:2455.
Gale G.R., Atkins L.M., and Walker, Jr., E.M., 1982, Further evaluation of diethyldithiocarbamate as an antagonist of cisplatin toxicity, Ann Clin Lab Sci. 12(5):345.
Gandara D.R., Nahhas W.A., Adelson M.D., et al., 1995, Randomized placebo-controlled multicenter evaluation of diethyldithiocarbamate for chemoprotection against cisplatin-induced toxicities, J Clin Oncol. 13(2):490.
Glover D., Glick J.H., Weiler C., et al., 1987, WR-2721 and high-dose cisplatin: an active combination in the treatment of metastatic melanoma, J Clin Oncol. 5:574.
Goel R., Cleary S.M., Horton C., et al., 1989, Effect of sodium thiosulfate on the pharmacokinetics and toxicity of cisplatin, J Natl Cancer Inst. 81:1552.
Goldberg J.M., and Lindblom U., 1979, Standardised method of determining vibratory perception thresholds for diagnosis and screening in neurological investigation, J Neurol Neurosurg Psychiatry. 42:793.
Gonias S.L., Oakley A.C., Walther P.J., and Pizzo S.V., 1984, Effects of diethyldithiocarbamate and nine other nucleophiles on the intersubunit protein cross-linking and inactivation of purified human α2-macroglobulin by cis-diamminedichloroplatinum(II), Cancer Res. 44:5764.
Gregg R.W., Molepo J.M., Monpetit V.J.A., et al., 1992, Cisplatin neurotoxicity: the relationship between dosage, time, and platinum concentration in neurologic tissues, and morphologic evidence of toxicity, J Clin Oncol. 10(5):795.
Griffith O.W., and Meister A., 1979, Potent and specific inhibition of glutathione synthesis by buthionine sulfoximine (S-n-butyl homocysteine sulfoximine), J Biol Chem. 254:7558.
Hacker M.P., Ershler W.B., Newman R.A., and Gamelli R.L., 1982, Effect of disulfiram (tetraethylthiuram disulfide) and diethyldithiocarbamate on the bladder toxicity and antitumor activity of cyclophosphamide in mice, Cancer Res, 42:4490.
Halonen P., 1986, Quantitative vibration perception thresholds in healthy subjects of working age, Eur J Appl Physiol. 54:647.
Hamers F.P.T., Gispen W.H., and Neijt J.P., 1991, Neurotoxic side-effects of cisplatin, Eur J Cancer. 27:372.
Hamers F.P.T., Brakkee J.H., Cavalletti E., et al., 1993a, Reduced glutathione protects against cisplatin-induced neurotoxicity in rats, Cancer Res. 53:544.
Hamers F.P.T., Pette C., Bravenboer B., et al., 1993b, Cisplatin-induced neuropathy in mature rats: effects of the melanocortin-derived peptide ORG 2766, Cancer Chemother Pharmacol 32:162.
Hamilton T.C., Winker M.A., Louis K.G., et al., 1985, Augmentation of adriamycin, melphalan and cisplatin cytotoxicity in drug-resistant and-sensitive human ovarian carcinoma cell lines by buthionine sulfoximine mediated glutathione depletion, Biochem Pharmacol. 34:2583.
Hovestadt A., Van der Burg M.E.L., Verbiest H.B.C., et al., 1992, The course of neuropathy after cessation of cisplatin treatment, combined with ORG 2766 or placebo, J Neurol. 239:143.
Howell S.B., and Taetle R., 1980, Effect of sodium thiosulfate on cis-dichlorodiammineplatinum(II) toxicity and antitumor activity in L1210 leukemia, Cancer Treat Rep. 64(4–5):611.
Howell S.B., Pfeifle C.E., Wung W.E., and Olshen R.A., 1982, Intraperitoneal chemotherapy with cisplatin, Proc Am Soc Clin Oncol. 1:27.
Howell S.B., Pfeifle C.E., Wung W.E., and Olshen R.A., 1983, Intraperitoneal cis-diamminedichloroplatinum with systemic thiosulfate protection, Cancer Res. 43:1426.
Leone R., Fracasso M.E., Soresi E., et al., 1992, Influence of glutathione administration on the disposition of free and total platinum in patients after administration of cisplatin, Cancer Chemother Pharmacol 29:385.
Lerza R., Bogliolo G., Muzzulini C., and Pannacciulli I., 1986, Failure of N-acetylcysteine to protect against cis-dichlorodiammineplatinum(II)-induced hematopoietic toxicity in mice, Life Sci Rev. 38(19):1795.
Leyland-Jones B., 1988, Whither the modulation of platinum?, J Natl Cancer Inst. 80(18):1432.
Leyland-Jones B., Deesen P., Reidenberg M.M., et al., 1980, Amelioration of cisplatin renal and gastrointestinal toxicity by N-acytylcysteine in rats, Clin Res. 28:622A.
Leyland-Jones B., Morrow C., Tate S., et al., 1983, cis-Diamminedichloro platinum (II) nephrotoxicity and its relationship to renal γ-glutamyl transpeptidase and glutathione, Cancer Res. 43:6072.
Litterest C.L., Bertolero F., and Uozumi J., 1986, The role of glutathione and metallothionein in the toxicity and subcellular binding of cisplatin: In: MCBrain D.C.H., and Slater T.F. (eds) Biochemical mechanism of platinum antitumor drugs, IRL Press, Oxford p 227.
Litterst C.L., Tong S., Hirokata Y., and Siddik Z.H., 1982, Alteration in hepatic and renal levels of glutathione and activities of glutathione S-transferases from rats treated with cis-dichlorodiammine platinum-II, Cancer Chemother Pharmacol 8:67.
Maines M.D., 1986, Differential effect of cis-platinum on regulation of liver and kidney haem and haemoprotein metabolism, Biochem J. 237:713.
Mayer R.D., and Maines M.D., 1990, Promotion of fnms-platinum in vivo effects on renal heme and hemoprotein metabolism by D,L-buthionine-S,R-sulfoximine, Biochem Pharmacol 39(10):1565.
Mayer R.D., Lee K., and Cockett A.T.K., 1987, Inhibition of cisplatin induced nephrotoxicity in rats by buthionine sulfoximine, a glutathione synthesis inhibitor, Cancer Chemother Pharmacol 20:207.
Meister A., Tate S. S., and Griffith O. W., 1981, γ-Glutamyl trans-peptidase, Methods Enzymol. 77:237.
Müller L.J., van der Hoop R.G., Moorer-van Delft CM, et al., 1990, Morphological and electrophysiological study of the effects of cisplatin and ORG · 2766 on rat spinal ganglion neurons, Cancer Res. 50:2437.
Neijt J., Van der burg M., Vecht C., et al., 1994, A double-blind randomised study with ORG-2766, an ACTH (4-9) analog, to prevent cisplatin neuropathy, Proc Am Soc Clin Oncol 13:261.
O’Dwyer P.J., Hamilton T.C., Young R.C., et al, 1992, Depletion of glutathione in normal and malignant human cells in vivo by buthionine sulfoximine: Clinical and biochemical results, J Natl Cancer Inst 34:264.
Ongerboer de Visser B.W., and Tiessens G., 1985, Polyneuropathy induced by cisplatin, Prog Exp Tumor Res. 29:190.
Owens G., and Hatiboglu I., 1961, Clinical evaluation of sodium thiosulfate, a systemic neutralizer of nitrogen mustard, Ann Surg. 154:895.
Paredes J., Hong W.I., Felder T.B., et al., 1988, Prospective randomized trial of high dose cisplatin and fluorouracil infusion with or without sodium diethyldithiocarbamate in recurrent and/or metastatic squamous cell carcinoma of the head and neck, J Clin Oncol 6:955.
Pfeifle C.E., Howell S.B., Felthouse R.D., et al, 1985, High-dose cisplatin with sodium thiosulfate protection, J Clin Oncol 3(2):237.
Pirovano C., Balzarini A., Bohm S., et al., 1992, Peripheral neurotoxicity following high-dose cisplatin with glutathione: clinical and neurophysiological assessment, Tumori. 78:253.
Powell A.K., 1954, Effect of dithiocarbamates on sarcoma cells and fibrocytes in vitro, Br J Cancer. 8:529.
Qazi R., Chang A.Y.C., Borch R.F., et al., 1988, Phase I clinical and pharmacokinetic study of diethyldithiocarbamate as a chemoprotector from toxic effects of cisplatin, J Natl Cancer Inst. 80:1486.
Renoux G., and Renoux M., 1984, Diethyldithiocarbamate (DTC). A biological augmenting agent specific for T cells, In: R.L. Fenichel and M.A. Chirigos (eds) Immune Modulation Agents and Their Mechanisms, Marcel Dekker, Inc., New York, 1984, p. 7.
Rumack B.H., Peterson R.C., Koch G.G., and Amara I.A., 1981, Acetaminophen overdose: 662 cases with evaluation of oral acetylcysteine treatment, Arch Intern Med. 141:380.
Scheef W., Klein H.O., Brock N., et al., 1979, Controlled clinical studies with an antidote against the urotoxicity of oxazaphosphorines: preliminary results, Cancer Treat Rep. 63:501.
Schmalbach T.K., and Borch R.F., 1990, Mechanism of diethyldithiocarbamate modulation of murine bone marrow toxicity, Cancer Res. 50:6218.
Schnellmann R.G., and Mandell L.J., 1986, Multiple effects of presumed glutathione depletors on rabbit proximal tubule, Kidney Int. 29:858.
Shaw I.C., and Graham M.I., 1987, Mesna — a short review, Cancer Treat Rev. 14:67.
Shea M., Koziol J.A., and Howell S.B., 1984, Kinetics of sodium thiosulfate, a cisplatin neutralizer, Clin Pharmacol Ther. 35(3):419.
Slater T.F., Ahmed J., and Ibrahim S.A., 1977, Studies on the nephrotoxicity of cis-dichlorodiammine-platinum2+ and related substances, J Clin Hematol Oncol. 7:534.
Soble M.J., and Dorr R.T., 1987, Lack of enhanced myelotoxicity with buthionine sulfoximine and sulfhydryl-dependent anticancer agents in mice, Res Commun Chem Pathol Pharmacol. 55(2):161.
Spath A., and Tempel K., 1987, Diethyldithiocarbamate inhibits scheduled and unscheduled DNA synthesis of rat thymocytes in vitro and in vivo — dose-effect relationships and mechanisms of action, Chem-Biol Interact. 64:151.
Speer R.J., Ridgway H., Hall L.M., et al., 1975, Coordination complexes of platinum as antitumor agents, Cancer Chemother Rep. 59:629.
Speyer J.L., Green M.D., Kramer, E., et al., 1988, Protective effect of the bispiperazinedione ICRF-187 against doxorubicin-induced cardiac toxicity in women with advanced breast cancer, N Engl J Med., 319:745.
Speyer J.L., Green M.D., Zeleniuch-Jacquotte A., et al., 1992, ICRF-187 permits longer treatment with doxorubicin in women with breast cancer, J Clin Oncol 10(1):117.
Stewart D.J., Verma S., and Maroun J.A., 1987, Phase I study of the combination of disulfiram with cisplatin, Am J Clin Oncol 10(6):517.
Strand F.L., and Smith CM., 1986, LPH, ACTH, MSH and motor systems. In: De Wied D, Gispen WH, Wimersma Greidanus TjB (eds) Neuropeptides and Behavior, Pergamon Press, Oxford Vol. 1, p. 245.
Sunderman F.W., 1971, The treatment of acute nickel-carbonyl poisoning with sodium diethyldithiocarbamate, Ann Clin Res. 3:182.
Ten Bokkel Huinink W.W., Wanders J., and Dubbelman R., 1987, High dose carboplatin in refractory ovarian cancer: a phase II trial assessing the protective role against myelosuppression by diethyldithiocarbamate, Madrid: Eur Cancer Soc. 214.
Trugman J., Hogenkamp H.P.C., Roelofs R., and Hrushesky W.J.M., 1985, Cisplatin neurotoxicity: failure to demonstrate vitamin B12 inactivation, Cancer Treat Rep. 69(4):453.
Uozumi J., and Litterst C.L., 1986, The effect of sodium thiosulfate on subcellular localization of platinum in rat kidney after treatment with cisplatin, Cancer Let. 32:279.
Uozumi J., Ishizawa M., Iwamoto Y., and Baba T., 1984, Sodium thiosulfate inhibits cis-diamminedichloroplatinum (II) activity, Cancer Chemother Pharmacol 13:82.
van der Hoop R.G., de Koning P., Boven E., et al., 1988, Efficacy of the neuropeptide ORG.2766 in the prevention and treatment of cisplatin-induced neurotoxicity in rats, Eur J Cancer Clin Oncol 24(4):637.
van der Hoop R.G., Vecht C.J., van der Burg M.E.L., et al., 1990, Prevention of cisplatin neurotoxicity with an ACTH(4-9) analogue in patients with ovarian cancer, N Engl J Med. 322:89.
Zunino F., Pratesi G., Micheloni A., et al., 1989, Protective effect of reduced glutathione against cisplatin-induced renal and systemic toxicity and its influence on the therapeutic activity of the antitumor drug, Chem Biol Interact. 70:89.
Zunino F., Tofanetti O., Besati A., et al., 1983, Protective effect of reduced glutathione against cis-dichlorodiammine Pt(II)induced nephrotoxicity and lethal toxicity, Tumori. 69:106.
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 1996 Springer Science+Business Media New York
About this chapter
Cite this chapter
Dorr, R.T. (1996). A Review of the Modulation of Cisplatin Toxicities by Chemoprotectants. In: Pinedo, H.M., Schornagel, J.H. (eds) Platinum and Other Metal Coordination Compounds in Cancer Chemotherapy 2. Springer, Boston, MA. https://doi.org/10.1007/978-1-4899-0218-4_12
Download citation
DOI: https://doi.org/10.1007/978-1-4899-0218-4_12
Publisher Name: Springer, Boston, MA
Print ISBN: 978-1-4899-0220-7
Online ISBN: 978-1-4899-0218-4
eBook Packages: Springer Book Archive