Abstract
As a result of clinical research over the last ten years, the simultaneous use of multiple pharmacologic agents in the therapy of malignant disease has become the accepted form of treatment for acute leukemia (Holland, 1968), advanced Hodgkin’s disease (Devita et al., 1970), lymphosarcoma (Bagley et al., 1972), and other tumors (Cooper, 1969; James et al., 1965). These therapeutic advances were largely the outgrowth of earlier experiences with single agents, which despite obvious antitumor activity, elicited incomplete responses or complete remissions of only brief duration. The limitations of single drug therapy were two-fold: (1) the toxicity of the drug limited the amount and duration of drug exposure tolerated by the host, and thus restricted cell kill, and (2) adaptive mechanisms allowed survival and proliferation of a fraction of resistant neoplastic cells despite a metabolic block lethal to the bulk of the tumor. Noting the effectiveness of combined chemotherapy in infectious diseases such as malaria (Blount, 1967), tuberculosis (Barry, 1964), and enterococcal bacterial endocarditis (Lerner and Weinstein, 1966), oncologists reasoned that the use of several active agents in combination might produce greater cell kill, while delaying the appearance of resistance to the individual drugs. The success of such combinations has established a permanent and expanding role for chemotherapy in the treatment of human malignancy.
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References
Adamson, R.H.: Metabolism of anticancer agents in man. Ann. N.Y. Acad. Sci. 179, 432 – 441 (1971).
Bagley, C.M., Jr., Devita, V.T., Berard, C.W., Canellos, G.P.: Advanced lymphosarcoma: intensive cyclical combination chemotherapy with cyclophosphamide, vincristine, and prednisone. Ann. intern. Med. 76, 227–234 (1972).
Barry, V.C.: Chemotherapy of tuberculosis. London: Butterworths 1964.
Bell, N.H., Andrioli, V.T., Sabesin, S.M., Utz, J.P.: On the nephrotoxicity of amphotericin B in man. Amer. J. Med. 33, 64–69 (1962).
Bennett, L.L., Jr., Simpson, L., Golden, J., Barker, T.L.: The primary site of inhibition by 6-mercaptopurine on the purine biosynthetic pathway in some tumors in vivo. Cancer Res. 23, 1574–1580 (1963).
Berman, L.B., Katz, S.: Kanamycin nephrotoxicity. Ann. N.Y. Acad. Sci. 76, 149–156 (1958).
Berneis, K., Kofler, M., Bollag, W., Kaiser, A., Langemann, A.: The degradation of deoxyribonucleic acid by new tumor inhibiting compounds: the intermediate formation of hydrogen peroxide. Experientia (Basel) 19, 132–133 (1963).
Bertino, J.R.: The mechanism of action of the folate antagonists in man. Cancer Res. 23, 1286–1306 (1963).
Blount, R.E.: Management of chloroquine-resistant falciparum malaria. Arch. intern. Med. 119, 557–560 (1967).
Broome, J. D.: Studies on the mechanism of tumor inhibition by L-asparaginase. Effects of the enzyme on asparagine levels in the blood, normal tissues, and 6C3HED lymphomas of mice: differences in asparagine formation and utilization in asparaginase-sensitive and -resistant lymphoma cells. J. exp. Med. 127, 1055–1072 (1968).
Bruce, W.R., Meeker, B.E., Valeriote, F.A.: Comparison of the sensitivity of normal hematopoietic and transplanted lymphoma colony-forming cells to chemotherapeutic agents administered in vivo. J. nat. Cancer Inst. 37, 233–245 (1966).
Burchenal, J.H., Dollinger, M.R.: Cytosine arabinoside (NSC-63878) in combination with 6-mercaptopurine (NSC-755), methotrexate (NSC-740) or 5-fluorouracil (NSC-19893) in L 1210 mouse leukemia. Cancer Chemother. Rep. 51, 435–438 (1967).
Burgert, E.O., Jr., Glidewell, O.: Dactinomycin in Wilm’s tumor. J. Amer. med. Ass. 199, 464–468 (1967).
Burkitt, D.: African lymphoma. Observations on response to vincristine sulphate therapy. Cancer (Philad.) 19, 1131–1137 (1966).
Canellos, G.P., Devita, V.T., Whang-Peng, J., Carbone, P.P.: Hematologic and cytogenetic remission of blastic transformation in chronic granulocytic leukemia. Blood 38, 671–679 (1971).
Capizzi, R.L., Nichols, R., Mullins, J.: Long-term survival of leukemic mice by therapeutic synergism between asparaginase (A’ASE) and methotrexate (MTX). Fed. Proc. 31, 553 Abs (1972).
Capizzi, R.L., Summers, W.P., Bertino, J.R.: Antagonism of the antineoplastic effect of methotrexate (MTX) by L-asparaginase (ASN’ASE) or L-asparagine (ASN) deprivation. Proc. Amer. Ass. Cancer Res. 11, 14 (1970).
Carbone, P.P., Spurr, C.: Management of patients with malignant lymphoma: a comparative study with cyclophosphamide and vinca alkaloids. Cancer Res. 28, 811–822 (1968).
Carey, R.W.: Comparative study of cytosine arabinoside (CA) therapy alone and combined with thioguanine (TG), mercaptopurine (MP), or daunomycin (DN) in acute myelocytic leukemia (AML). Proc. Amer. Ass. Cancer Res. 11, 15 (1970).
Chavelier, L., Glidewell, O.: Schedule of 6-mercaptopurine and effect of inducer drugs in prolongation of remission maintenance in acute leukemia. Proc. Amer. Ass. Cancer Res. 8, 10 (1967).
Chu, M.-Y., Fischer, G.A.: The incorporation of 3H-cytosine arabinoside and its effect on murine leukemic cells (L 5178 Y). Biochem. Pharmacol. 17, 753–767 (1968).
Clarke, D. A.: In discussion of Mantel, N.: An experimental design in combination chemotherapy. Ann. N.Y. Acad. Sci. 76, 909–931 (1958).
Clarkson, B., Ohkita, T., Ota, K., Fried, J.: Studies of cellular proliferation in human leukemia. I. Estimation of growth rates of leukemic and normal hematopoietic cells in two adults with acute leukemia given single injections of tritiated thymidine. J. clin. Invest. 46, 506–529 (1967).
Cohen, S.S., Flaks, J. G., Barner, H.D., Loeb, M.R., Lichtenstein, J.: The mode of action of 5-fluorouracil and its derivatives. Proc. nat. Acad. Sci. (Wash.) 44, 1004–1012 (1958).
Connors, T. A., Jones, M.: Antagonism of the anti-tumor effects of asparaginase by methotrexate. Biochem. Pharmacol. 19, 2927–2929 (1970).
Cooper, R. G.: Combination chemotherapy in hormone resistant breast cancer. Proc. Amer. Ass. Cancer Res. 10, 15 (1969).
Creasey, W.A.: Tumor-inhibitory effects of combinations of the vinca alkaloids with actino-mycin D. Biochem. Pharmacol. 15, 367–375 (1966).
Creasey, W.A.: Modifications in biochemical pathways produced by the vinca alkaloids. Cancer Chemother. Rep. 52, 501–507 (1968).
Defendi, V., Manson, L.A.: Analysis of the life-cycle in mammalian cells. Nature (Lond.) 198, 359–361 (1963).
Devita, V.T., Jr., Canellos, G.P.: Treatment of the lymphomas. Sem. Hemat. 9, 193–209 (1972).
Devita, V.T., Jr., Serpick, A.A., Carbone, P.P.: Combination chemotherapy in the treatment of advanced Hodgkin’s disease. Ann. intern. Med. 73, 881–895 (1970).
Di Marco, A., Silvestrini, R., de 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, 545–550 (1965).
Donelli, M.G., Garattini, S.: Drug metabolism after repeated treatments with cytotoxic agents. Europ. J. Cancer 7, 361–364 (1971).
Dougherty, T.F.: Effect of hormones on lymphatic tissue. Physiol. Rev. 32, 379–401 (1952).
Elion, G.B., Callahan, S., Nathan, H., Bieber, S., Rundles, R.W., Hitchings, G.H.: Potentiation by inhibition of drug degradation: 6-substituted purines and xanthine oxidase. Biochem. Pharmacol. 12, 85–93 (1963).
Elion, G.B., Singer, S., Hitchings, G.H.: Antagonists of nucleic acid derivatives. VIII. Synergism in combinations of biochemically related antimetabolites. J. biol. Chem. 208, 477–488 (1954).
Evans, A.E., Heyn, R.M., Newton, W.A., Jr., Leikin, S.L.: Vincristine sulfate and cyclophosphamide for children with metastatic neuroblastoma. J. Amer. med. Ass. 207, 1325 – 1327 (1969).
Evans, J.S., Musser, E.A., Bostwick, L., Mengel, G.D.: The effect of 1-β-D-arabino-furanosylcytosine hydrochloride on murine neoplasms. Cancer Res. 24, 1285–1293 (1964).
Falco, F.G., Smith, H.M., Arcieri, G.M.: Nephrotoxicity of aminoglycosides and gent-amycin. J. infect. Dis. 119, 406–409 (1969).
Frei III, E., Freireich, E. J.: Progress and perspectives in the chemotherapy of acute leukemia. Advanc. Chemother. 2, 269–298 (1965).
Freireich, E. J., Bodey, G.P., Hart, S., Rodriguez, V., Whitecar, J.P., Frei III, E.: Remission induction in adults with acute myelogenous leukemia. Rec. Res. Cancer Res. 30, 85–91 (1970).
Frenkel, E.P., Skinner, W.N., Smiley, J. D.: Studies on a metabolic defect induced by hydroxyurea (NSC-32065). Cancer Chemother. Rep. 40, 19–22 (1964).
Gee, T.S., Tu, K.-P., Clarkson, B.D.: Treatment of adult acute leukemia with arabinosyl-cytosine and thioguanine. Cancer (Philad.) 23, 1019–1032 (1969).
Goldin, A., Mantel, N.: The employment of combinations of drugs in the chemotherapy of neoplasia: a review. Cancer Res. 17, 635–654 (1957).
Graul, E.H., Schaumlöffel, E., Hundeshagen, H., Wilmanns, H., Simon, G.: Metabolism, of radioactive cyclophosphamide. Animal tests and clinical studies. Cancer (Philad.) 20 896–899 (1967).
Guyer, R. J., Winfield, D.A., Shahani, R.T., Blackburn, E.K.: Combination chemotherapy in acute myeloblasts leukemia. Brit. med. J. 1971I, 231–232.
Hanasono, G.K., Fischer, L.J.: Plasma levels and urinary excretion of [14C] cyclophosphamide and its radioactive metabolites in rats pretreated with prednisolone. Biochem. Pharmacol. 21, 272–276 (1972).
Hardisty, R.M., Mc Elwain, T.J., Darby, C.W.: Vincristine and prednisone for the induction of remissions in acute childhood leukemia. Brit. med. J. 1969II, 662–665.
Hayakawa, T., Kanai, N., Yamada, R., Kuroda, R., Higashi, H., Mogami, H., Jinnai, D.: Effect of steroid hormone on activation of endoxan (cyclophosphamide). Biochem. Pharmacol. 18, 129–135 (1969).
Hayes, D.M., Costa, J., Moon, J.H., Hoogstraten, B., Harley, J.B.: Combination therapy with thioguanine (NSC-752) and azaserine (NSC-742) for multiple myeloma. Cancer Chemother. Rep. 51, 235–238 (1967).
Heidelberger, C.: Biochemical mechanisms of action of fluorinated pyrimidines. Exp. Cell Res. Suppl. 9, 462–471 (1963).
Henderson, E.S., Samaha, R.J.: Evidence that drugs in multiple combinations have materially advanced the treatment of human malignancies. Cancer Res. 29, 2272–2280 (1969).
Henderson, J.P., Junga, I.G.: Potentiation of carcinostasis by combinations of thioguanine and 6-mercaptopurine. Biochem. Pharmacol. 5, 167–168 (1960).
Hertz, R., Lewis, J., Jr., Lepsett, M.B.: Five years’ experience with the chemotherapy of metastatic choriocarcinoma and related trophoblastic tumors in women. Amer. J. Obstet. Gynec. 82, 631–640 (1961).
Hill, D.L., Laster, W.R., Jr., Struck, R.F.: Enzymatic metabolism of cyclophosphamide and nicotine and production of a toxic cyclophosphamide metabolite. Cancer Res. 32, 658–665 (1972).
Hitchings, G.H., Burchall, J.J.: Inhibition of folate biosynthesis and function as a basis for chemotherapy. Advan. Enzymol. 27, 417–468 (1965).
Holland, J.F.: Progress in the treatment of acute leukemia. In: Dameshek, W., Dutcher, R.M. (Eds.): Perspectives in leukemia, pp. 217–240. New York-London: Grune and Stratton 1968.
Hoogstraten, B., Owens, A.H., Lenhard, R.E., Glidewell, O.J., Leone, L.A., Olson, K.B., Harley, J.B., Townsend, S.R., Miller, S.P., Spurr, C.L.: Combination chemotherapy in lymphosarcoma and reticulum cell sarcoma. Blood 33, 370–378 (1969).
Hyman, G.A., Ellsworth, R.M., Feind, C.R., Tretter, P.: Combination therapy in retinoblastoma. A 15-year summary of methods and results. Arch. Ophthal. 80, 744–746 (1968).
James, D.H., Jr., Hustu, O., Wrenn, E.L., Jr., Pinkel, D.: Combination chemotherapy of childhood neuroblastoma. J. Amer. med. Ass. 194, 123–126 (1965).
Karnofsky, D. (Ed.): Comparative clinical and biological effects of alkylating agents. Ann. N.Y. Acad. Sci. 68, 657–1266 (1958).
Kimball, A.P., Wdlson, M.J.: Inhibition of DNA polymerase by β-D-arabinosylcytosine and reversal of inhibition by deoxycytidine-5′-triphosphate. Proc. Soc. exp. Biol. (N.Y.) 127, 429–432 (1968).
Kline, I., Venditti, J.M., Mead, J.A.R., Tyrer, D.D., Goldin, A.: The antileukemic effectiveness of 5-fluorouracil and methotrexate in the combination chemotherapy of advanced leukemia. Cancer Res. 26, 848–852 (1966).
Kreis, W., Yen, W.: An antineoplastic C14-labeled methylhydrazine derivative in P 815 mouse leukemia. A metabolic study. Experientia (Basel) 21, 284–286 (1965).
Lacher, M. J., Durant, J. R.: Combined vinblastine and chlorambucil therapy of Hodgkin’s disease. Ann. intern. Med. 62, 468–476 (1965).
LePage, G.A.: Incorporation of 6-thioguanine into nucleic acids. Cancer Res. 20, 403–408 (1960).
LePaoe, G.A., White, S.C.: Scheduling of arabinosylcytosine (ara-C) and 6-thioguanine (6-TG) therapy. Proc. Amer. Ass. Cancer Res. 13, 11 (1972).
Lerner, P.L, Weinstein, L.: Infective endocarditis in the antibiotic era (to be concluded). New Engl. J. Med. 274, 323–331 (1966).
Levitt, M., Marsh, J. C., Deconti, R.C., Mitchell, M.S., Skeel, R.T., Farber, L.R., Bertino, J.R.: Combination sequential chemotherapy in advanced reticulum cell sarcoma. Cancer (Philad.) 29, 630–636 (1972).
Li, M.C., Hsu, K.-P.: Combined drug therapy for ovarian carcinoma. Clin. Obstet. Gynec. 13, 928–944 (1970).
Lr, M.C., Whitmore, W.F., Jr., Golbey, R., Grabstald, H.: Effects of combined drug therapy in metastatic cancer of the testis. J. Amer. med. Ass. 174, 1291–1299 (1960).
Liegler, D.G., Henderson, E.S., Hahn, M.A., Oliverio, V.T.: The effect of organic acids on renal clearance of methotrexate in man. Clin. Pharmacol. Ther. 10, 849–857 (1969).
Loewe, S.: The problem of synergism and antagonism of combined drugs. Arzneimittel -Forsch. 3, 285–290 (1953).
Lowenbraun, S., Devita, V.T., Serpick, A.A.: Combination chemotherapy with nitrogen mustard, vincristine, procarbazine, and prednisone in lymphosarcoma and reticulum cell sarcoma. Cancer (Philad.) 25, 1018–1025 (1970).
Mackenzie, A. R.: Chemotherapy of metastatic testis cancer. Cancer (Philad.) 19, 1369–1376 (1966).
Mantel, N.: An experimental design in combination chemotherapy. Ann. N.Y. Acad. Sci. 76, 909–931 (1958).
Mendelson, D., Block, J.B., Serpick, A.A.: Effect of large intermittent intravenous doses of cyclophosphamide in lymphoma. Cancer (Philad.) 25, 715–720 (1970).
Montgomery, J.: In: Burger, A. (Ed.): Medicinal chemistry, 3rd ed., pp. 703–707. New York: Wiley-Interscience 1970.
Perry, R.P.: The cellular sites of synthesis of ribosomal and 4 S RNA. Proc. nat. Acad. Sci. (Wash.) 48, 2179–2186 (1962).
Pinkel, D., Hernandez, K., Borella, L., Holton, C., Aur, R., Samoy, G., Pratt, C.: Drug dosage and remission duration in childhood lymphocytic leukemia. Cancer (Philad.) 27, 247–256 (1971).
Potter, V.R.: Sequential blocking of metabolic pathways in vivo. Proc. Soc. exp. Biol. (N.Y.) 76, 41–46 (1951).
Pratt, C.B., Fleming, I.D., Huster, H.O.: Multimodal therapy of childhood rhabdomyosarcoma. Proc. Amer. Ass. Cancer Res. 12, 26 (1971).
Rauen, H.M., Kramer, K.-P.: Der Gesamtalkylantien-Blutspiegel von Ratten nach Verabreichung von Cyclophosphamid und Acyclophosphamid. Arzneimittel-Forsch. 14, 1066 – 1067 (1964).
Roberts, J. J., Brent, T. P., Crathorn, A.R.: The mechanism of alkylating agents on the mammalian cells. Inactivation of the DNA template and its repair. In: Campbell, P.N. (Ed.): A symposium on the interactions of drugs and subcellular components in animal cells. Boston: Little, Brown 1968.
Sartorelli, A. C.: Approaches to the combination chemotherapy of transplantable neoplasms. Prog. exp. Tumor Res. (Basel) 6, 228–288 (1965).
Sartorelli, A.C.: Some approaches to the therapeutic exploitation of metabolic sites of vulnerability of neoplastic cells. Cancer Res. 29, 2292–2299 (1969).
Sartorelli, A.C., Lepage, G.A.: Inhibition of ascites cell growth by combinations of 6-thioguanine and azaserine. Cancer Res. 18, 938–942 (1958).
Skipper, H.E., Perry, S.: Kinetics of normal and leukemic leukocyte populations and relevance to chemotherapy. Cancer Res. 30, 1883–1897 (1970).
Sladek, N.E.: Therapeutic efficacy of cyclophosphamide as a function of its metabolism. Cancer Res. 32, 535–542 (1972).
Tardiff, R.G., Dubois, K.P.: Inhibition of hepatic microsomal enzymes by alkylating agents. Arch. int. Pharmacodyn. 177, 445–456 (1969).
Tarnowski, G.S., Mountain, I.M., Stock, C.C.: Combination therapy of animal tumors with L-asparaginase and antagonists of glutamine or glutamic acid. Cancer Res. 30, 1118–1122 (1970).
Vadlamudi, S., Padarathsingh, M., Waravdekar, V.S., Goldin, A.: Leukemia P 1798 as a possible experimental model for remission induction and remission maintenance for acute leukemia. Proc. Amer. Ass. Cancer Res. 12, 16 (1971).
van Eden, E.B., Falkson, H.C., Falkson, G.: 1, 3-bis-(2-chloroethyl)-l-nitrosourea (BCNU; NSC-409962) given concomitantly with cytosine arabinoside (NSC-63878) in the treatment of cancer. Cancer Chemother. Rep. 54, 347–359 (1970).
Venditti, J.M., Humphreys, S.R., Mantel, N., Goldin, A.: Combined treatment of advanced leukemia (L 1210) in mice with amethopterin and 6-mercaptopurine. J. nat. Cancer Inst. 17, 631–638 (1956).
Vogler, W.R.: Clinical trials of 1-β-D-arabinofuranosyl cytosine and l, 3-bis-(2-chloroethyl)-1-nitrosourea combination in metastatic cancer and acute leukemia. Cancer (Philad.) 27, 1081–1088 (1971).
Wilbur, J.R., Sutow, W.W., Sullivan, M.P., Costio, J.R., Taylor, H.G.: Successful treatment of rhabdomyosarcoma with combination chemotherapy and radiotherapy. Presented at the American Society of Clinical Oncology, Chicago, April 7, 1971.
Wodinski, I., Kensler, C.J.: Activity of selected compounds in subline of leukemia L 1210 resistant to cytosine arabinoside (NSC-63878). Cancer Chemother. Rep. 43, 1–3 (1964).
Wodinsky, I., Kensler, C. J.: Activity of cytosine arabinoside (NSC-63878) in a spectrum of rodent tumors. Cancer Chemother. Rep. 47, 65–68 (1965).
Wolinsk, Y.E., Hines, J.D.: Neurotoxic and nephrotoxic effects of Colistin in patients with renal disease. New Engl. J. Med. 266, 759–762 (1962).
Zager, R.P., Frisby, S.A., Oliverio, V.T.: Cellular transport and antitumor activity of methotrexate (MTX) in combination with clinically useful drugs. Proc. Amer. Ass. Cancer Res. 13, 33 (1972).
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Chabner, B.A., Oliverio, V.T. (1975). Drug Interactions in Cancer Chemotherapy. In: Gillette, J.R., Mitchell, J.R. (eds) Concepts in Biochemical Pharmacology. Handbuch der experimentellen Pharmakologie / Handbook of Experimental Pharmacology, vol 28 / 3. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-46314-3_13
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