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Cyclophosphamide

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Drug Discovery

Abstract

Cyclophosphamide is a cytotoxic (cytostatic), cell-cycle-nonspecific, antiproliferative agent that is used in such diverse medical problems as neoplasia, tissue transplantation, and inflammatory diseases (Gershwin et al., 1974). It is an inert prodrug for a potent nitrogen mustard alkylating agent. After the metabolic activation of cyclophosphamide to the potent mustard by liver enzymes, a nonenzymatic generation of chemically reactive molecules occurs. These reactive molecules can form covalent bonds with biologically ubiquitous groups, such as amino, phosphate, hydroxyl, carboxyl, sulfhydryl and imidazole, and as a result, depending on dose, cyclophosphamide is capable of either interfering with the reproduction of cells or killing cells. This is especially true in the case of rapidly dividing cells (Golomb, 1963; Gershwin et al., 1974; Hill, 1975).

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References

  • Aptekar, R. Gv Atkinson, J. P., Decker, J. L., Wolff, S. M., and Chu, E. W.: Bladder toxicity with chronic oral cyclophosphamide therapy in non-malignant diseases. Arthritis Rheum. 16:461–67, 1973.

    Article  PubMed  CAS  Google Scholar 

  • Arnold, H.: UeberdieChemie neuer zytostatisch wirksamer N-Chloroaethyl-phosphorsäureesterdiamide, in Proceedings of the Fifth International Congress Chemotherapy, K. Spitzy and H. Haschek, eds., pp. 751–754, Verlag der Wiener Medizinischen-Akad.; Vienna, 1967.

    Google Scholar 

  • Arnold, H., Bourseaux, F., and Brock, N.: Neuartige Krebs-Chemotherap-eutika aus der Gruppe der zyklischen N-lost-phosphamidester. Naturwissenschaften 45:64–66, 1958a.

    Article  CAS  Google Scholar 

  • Arnold, H., Bourseaux, F., and Brock, N.: Chemotherapeutic action of a cyclic nitrogen mustard phosphamide ester (B518-ASTA) in experimental tumors of the rat. Nature 181:931, 1958b.

    Article  PubMed  CAS  Google Scholar 

  • Bennett, D. R., ed.: AMA Drug Evaluations, 5th Ed., American Medical Association, Chicago, 1983.

    Google Scholar 

  • Berd, D., Maguire, H. C., Jr., and Mastrangelo, M. J.: Induction of cell-mediated immunity to autologous melanoma cells and regression of métastases after treatment with a melanoma cell vaccine preceded by cyclophosphamide. Cancer Res. 46:2572–2577, 1986.

    PubMed  CAS  Google Scholar 

  • Bergel, F. and Stock, J. A.: Cyto-active amino-acid and peptide derivatives. Part I. Substituted phenylalanines. J. Chem. Soc. II: 2409–2417, 1954.

    Google Scholar 

  • Bergsagel, D.E., Jenkin, R. D. T., Pringle, J. F., White, D. M., Fetterly, J. C. M., Klaassen, D. J., and McDermot, R. S. R.: Lung Cancer: Clinical trial of radiotherapy alone vs. radiotherapy plus cyclophosphamide. Cancer 30: 621–627, 1972.

    Article  PubMed  CAS  Google Scholar 

  • Berkow, R., ed.: The Merck Manual, 14th Ed., Merck Sharp & Dohme Research Laboratories, Rahway, New Jersey, 1982.

    Google Scholar 

  • Bertino, J. R.: Chemical action and pharmacology of methotrexate, aza-thioprine and cyclophosphamide in man. Arthritis Rheum. 16: 79–83, 1973.

    Article  PubMed  CAS  Google Scholar 

  • Brock, N.: Pharmacologische Untersuchungen mit Neuen N-Chloroathyl-phosphoraureesterdiamiden, in Proc. Fifth Int. Congr. Chemother., vol. 2, K. H. Spitzy and H. Haschek, eds., pp. 155–161, Verlag der Wiener Medizinischen Akad., Vienna, 1967.

    Google Scholar 

  • Brock, N.: Comparative pharmacologie study in vitro and in vivo with cyclophosphamide (NSC-26271), cyclophosphamide metabolites, and plain nitrogen mustard compounds. Cancer Treat. Rep. 60:301–308, 1976.

    PubMed  CAS  Google Scholar 

  • Brock, N. and Kuhlmann, J.: Pharmacological studies with alkylsulfonyl-oxyalkyl substituted and chloroethyl substituted oxazaphosphorine-2-oxides. Arzneimittelforsch. 24:1139–1149, 1974.

    PubMed  CAS  Google Scholar 

  • Brock, N. and Potel, J.: Pharmakologische Untersuchungen mit Alkyl-sulfonyl-oxyalkyl-bzw. Chloräthyl-substituierten Oxazaphosphorin-2-oxiden. Arzneimittelforsch. 24:1149–1160, 1974.

    CAS  Google Scholar 

  • Calabresi, P. and Parks, R. E., Jr.: Antiproliferative agents and drugs used for immunosuppression, in The Pharmacological Basis of Therapeutics, 7th Ed., A. G. Gilman, L. S. Goodman, T. W. Rail, and F. Murad, eds., pp. 1247–1306, Macmillan, New York, 1985.

    Google Scholar 

  • Capell, H. A., Daymond, T. J., Carson Dick, W.: Cytotoxic drugs, in Rheumatic Disease, pp. 179–186, Springer-Verlag, Berlin, 1983.

    Chapter  Google Scholar 

  • Coggins, P. R., Ravdin, R. G., and Eisman, S. H.: Clinical pharmacology and preliminary evaluation of Cytoxan (cyclophosphamide). Cancer Chemo-ther. Rep. June: 9–11, 1959.

    Google Scholar 

  • Colvin, M.: A review of pharmacology and clinical use of cyclophosphamide, in Clinical Pharmacology of Anti-Neoplastic Drugs, H. M. Pinedo, ed., pp. 245–261, Elsevier, Amsterdam, 1978.

    Google Scholar 

  • Cooperating Clinics Committee of the American Rheumatism Association: A controlled trial of cyclophosphamide in rheumatoid arthritis. N. Engl. J. Med. 283:883–389, 1970.

    Article  Google Scholar 

  • Curry, H. L. F.: Immune suppression and immune enhancement, in Rheumatoid Arthritis: Cellular Pathology and Pharmacology, J. L. Gordon and B. L. Hazleman, eds., pp. 157–163, Elsevier, Amsterdam, 1977.

    Google Scholar 

  • Diaz, C.J.: Treatment of dysreaction diseases with nitrogen mustards. Ann. Rheum. Dis. 10:144–151, 1951.

    Article  Google Scholar 

  • Diaz, C. J., Garcia, E. L., Merchante, A., and Perianes, J.: Treatment of rheumatoid arthritis with nitrogen mustard. Preliminary report. JAMA 147: 1418,1419, 1951.

    Article  Google Scholar 

  • Everett, J. L., Roberts, J. J., and Ross, W. C. J.: Aryl-2-halogenoalkylamines. Part XII. Some carboxylic derivatives of N N-di-2-chloroethylaniline. J. Chem. Soc, III: 2386–2392, 1953.

    Google Scholar 

  • Foad, B. S. I. and Hess, E. V.: Urinary bladder complications with cyclophosphamide therapy. Arch. Intern. Med. 136:616–619, 1976.

    Article  PubMed  CAS  Google Scholar 

  • Fosdick, W. M., Parsons, J. L., and Hill, D. F.: Long-term cyclophosphamide therapy in rheumatoid arthritis: Arthritis Rheum. 9:855,856, 1966.

    Google Scholar 

  • Fosdick, W. M., Parsons, J. L., and Hill, D. F.: Long-term cyclophosphamide therapy in rheumatoid arthritis. Arthritis Rheum. 11:151–161, 1968.

    Article  PubMed  CAS  Google Scholar 

  • Fosdick, W. M., Parsons, J. L., and Hill, D. F.: Long-term cyclophosphamide (CP) therapy in rheumatoid arthritis: A progress report, six years’ experience. Arthritis Rheum. 12:663, 1969.

    Article  Google Scholar 

  • Gershwin, M.E., Goetzl, E.J., and Steinberg, A.D.: Cyclophosphamide: Use in practice. Ann. Intern. Med. 80:531–540, 1974.

    PubMed  CAS  Google Scholar 

  • Gilman, A.: The initial clinical trial of nitrogen mustard. Am. J. Surg. 105: 574–578, 1963.

    Article  PubMed  CAS  Google Scholar 

  • Gilman, A. and Philips, F. S.: The biological actions and therapeutic applications of the ß-chloroethyl amines and sulphides. Science 103:409–415, 1946.

    Article  CAS  Google Scholar 

  • Golomb, F. M.: Agents used in cancer chemotherapy. Am.J. Surg. 105:579–590, 1963.

    Article  PubMed  CAS  Google Scholar 

  • Goodman, L. S., Wintrobe, M. M., Dameshek, W., Goodman, M. J., Gilman, A., and McLennan, M. T.: Nitrogen mustard therapy: Useofmethyl-bis (beta-chloroethyl)amine hydrochloride for Hodgkin’s disease, lympho-sarcoma, leukemia and certain allied and miscellaneous disorders. JAMA 132:126–132, 1946.

    Article  CAS  Google Scholar 

  • Gross, R. and Lambers, K.: Vorläufige klinische Beobachtungen mit einem neuen N-Lost-Phosphamidester in der Tumortherapie. Naturwissenschaft 45:66, 1958a.

    Article  CAS  Google Scholar 

  • Gross, R. and Lambers, K.: Erste Erfahrungen in der Behandlung maligner Tumoren mit einem neuen N-Lost-Phosphamidester. Dtsch. Med. Wochenschr. 83:458–162, 1958b.

    Article  PubMed  CAS  Google Scholar 

  • Hektoen, L. and Corper, H. J.: The effect of mustard gas (dichlorethyl sul-phid) on antibody formation. J. Infect. Dis. 28:279–285, 1921.

    Article  Google Scholar 

  • Hench, P. S., Kendall, E. C., Slocumb, C. H., and Polley, H. F.: The effect of a hormone of the adrenal cortex (17-hydroxy-ll-dehydrocorticosterone: Compound E) and of pituitary adrenocorticotropic hormone on rheumatoid arthritis. Proc. Staff Mtg. Mayo Clinic 24:181–197, 1949.

    CAS  Google Scholar 

  • Hill, D. L.: A Review of Cyclophosphamide, Charles C. Thomas, Springfield, IL, 1975.

    Google Scholar 

  • Horslev-Petersen, K., Beyer, J.A., and Helin, P.: Intermittent cyclophosphamide in refractory rheumatoid arthritis. Br. Med. J. 287:711,712,1983.

    Article  CAS  Google Scholar 

  • Kaplan, S. R. and Calabresi, P.: Drug therapy. Immunosuppressive agents. N. Engl. J. Med. 289:952–955, 1973.

    Article  PubMed  CAS  Google Scholar 

  • Klein, J.: Responses dominated by T-lymphocytes, in Immunology: The Science of Self-Nonself Discrimination, pp. 445–574, Wiley, New York, 1982.

    Google Scholar 

  • Klein, F. A. and Smith, M. J. V.: Urinary complications of cyclophosphamide therapy: Etiology, prevention, and management. South. Med. J. 76:1413–1416, 1983.

    Article  PubMed  CAS  Google Scholar 

  • Korst, D. R., Clifford, G. O., Fowler, W. M., Louis, J., Will, J., and Wilson, H. E.: Multiple myeloma. II. Analysis of cyclophosphamide therapy in 165 patients. JAMA 189:758–762, 1964.

    Article  PubMed  CAS  Google Scholar 

  • Krumbhaar, E. B.: Role of the blood and the bone marrow in certain forms of gas poisoning. I. Peripheral blood changes and their significance. J. Am. Med. Assoc. 72:39–41, 1919.

    Article  Google Scholar 

  • Krumbhaar, E. B. and Krumbhaar, H. D.: The blood and bone marrow in yellow cross gas (mustard gas) poisoning. J. Med. Res. 40:497–507, 1919.

    PubMed  CAS  Google Scholar 

  • Lampe, K. F., ed.: Drug Evaluations, 6th Ed., American Medical Association, Chicago, 1986.

    Google Scholar 

  • Lidsky, M. D., Sharp, J. T., and Billings, S.: Double blind study of cyclophosphamide in rheumatoid arthritis. Arthritis Rheum. 16:148–153, 1973.

    Article  PubMed  CAS  Google Scholar 

  • Lyttle, D. A. and Petering, H. G.: 5-Bis-(2-chloroethyl)-aminouracil, a new antitumor agent. J. Am. Chem. Soc. 80:6459,6460,1958.

    Article  CAS  Google Scholar 

  • McCarty, D.J., and Carrera, G.F.: Intractable rheumatoid arthritis: Treatment with combined cyclophosphamide, azathioprine, and hydroxychloro-quine. JAMA 248:1718–1723, 1982.

    Article  PubMed  CAS  Google Scholar 

  • Mouridsen, H. T., Faber, O., and Skovsted, L.: The metabolism of cyclophosphamide. Dose dependency and the effect of long-term treatment with cyclophosphamide. Cancer 37:665–670, 1976.

    Article  PubMed  CAS  Google Scholar 

  • Papac, R., Petrakis, N. L., Amini, F., and Wood, D. A.: Comparative clinical evaluation of two alkylating agents. Mannitol mustard and cyclophosphamide (Cytoxan). JAMA 172:1387–1391, 1960.

    Article  CAS  Google Scholar 

  • Pappenheimer, A. M. and Vance, M.: The effects of intravenous injections of dichloroethyl sulphide in rabbits, with special reference to its leuco-toxic action. J. Exp. Med. 31:71–93, 1920.

    Article  PubMed  CAS  Google Scholar 

  • Pedersen-Bjergaard, J., Ersboll, J., Hansen, V. L., Serensen, B. L., Christoffersen, K., Hou-Jensen, K., Nissen, N. I., Rnudsen, J. B., and Hansen, M. M.: Carcinoma of the urinary bladder after treatment with cyclophosphamide for non-Hodgkin’s lymphoma. N. Engl. J. Med. 318:1028–1032, 1988.

    Article  PubMed  CAS  Google Scholar 

  • Perry, S., Thomas, L. B., Johnson, R. E., Carbone, P. P., and Haynes, H. A.: Hodgkin’s disease. Combined clinical staff conference at the National Institutes of Health. Ann. Intern. Med. 67:424–442, 1967.

    PubMed  CAS  Google Scholar 

  • Phillips, G. L., Herzig, R. H., Lazarus, H. M., Fay, J. W., Wolff, S. N., Mill, W. B., Lin, H-S., Thomas, P. R. M., Glasgow, G. P., Shina, D. C., and Herzig, G. P.: Treatment of resistant malignant lymphoma with cyclophosphamide, total body irradiation, and transplantation of cryopreserved auto-logous marrow. N. Engl. J. Med. 310:1557–1561, 1984.

    Article  CAS  Google Scholar 

  • Presant, C. A., Kolhouse, J. F., and Klahr, C: Adriamycin, l,3-bis(2-chloro-ethyD-1-nitrosourea (BCNU-NSC 409462), and cyclophosphamide in refractory adenocarcinoma of the breast and other tumors. Cancer 37:620–628, 1976.

    Article  PubMed  CAS  Google Scholar 

  • Rothermich, N. O., Whisler, R. L., Brower, A. C., and Kantor, S. M.: Im-munosuppressive agents and other forms of treatment, in Rheumatoid Arthritis, pp. 226–238, Grune and Stratton, Orlando, FL, 1985.

    Google Scholar 

  • Samuels, M. L. and Howe, C. D.: Cyclophosphamide in the management of Swing’s sarcoma. Cancer 20:961–966, 1967.

    Article  PubMed  CAS  Google Scholar 

  • Santos, G. W., Tutschka, P. J., Brookmeyer, R., Saral, R., Beschorner, W. E., Bias, W. B., Braine, H. G., Burns, W. H., Elfenbein, G. J., Kaizer, H., Mellits, D., Sensenbrenner, L. L., Stuart, R. K., and Yeager, A. M.: Marrow transplantation for acute nonlymphocytic leukemia after treatment with bu-sulfan and cyclophosphamide. N. Engl. J. Med. 309:1347–1353, 1983.

    Article  PubMed  CAS  Google Scholar 

  • Wall, R. L. and Conrad, F. G.: Cyclophosphamide therapy. Its use in leukemia, lymphoma and solid tumors. Arch. Intern. Med. 108: 456–482, 1961.

    Article  PubMed  CAS  Google Scholar 

  • Williams, H. J., Reading, J. C., Ward, J. R., and O’Brien, W. M.: Comparison of high and low dose cyclophosphamide therapy in rheumatoid arthritis. Arthritis Rheum. 23:521–527, 1980.

    Article  PubMed  CAS  Google Scholar 

  • Zon, G.: Cyclophosphamide analogues, in Progress in Medicinal Chemistry, vol. 19, G. P. Ellis and G. B. West, eds., pp. 205–246, Elsevier, Amsterdam, 1982.

    Google Scholar 

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Maxwell, R.A., Eckhardt, S.B. (1990). Cyclophosphamide. In: Drug Discovery. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-4612-0469-5_20

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  • DOI: https://doi.org/10.1007/978-1-4612-0469-5_20

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