Skip to main content
SpringerLink
Log in

Antineoplastic and Immunosuppressive Drugs I: Biochemical and Clinical Pharmacological Considerations

  • Review Article
  • Published:
Drugs Aims and scope Submit manuscript

Summary

The pharmacokinetic properties of antineoplastic drugs which influence their administration and effects include absorption, plasma protein binding, passage across cell membranes, biotransformation, and excretion through the kidney, hepatobiliary system and the lung.

Some of the drugs can not be given orally while others produce more reliable blood levels if given parenterally. The serum half-life for most drugs is short. Only cyclophosphamide, and prednisone in large doses, cross the blood-brain barrier in significant concentrations. Most of the drugs are metabolised. In the case of cyclophosphamide, biotransformation by hepatic microsomal enzymes is responsible for converting the drug into an active form. A few drugs, like methotrexate, are excreted in the urine as the unchanged parent compound, thus good renal function is essential for the efficient clearance and safe use of the drug.

Although the large range of antineoplastic and immunosuppressive drugs available have widely differing specific sites of action, they all have one effect in common, in that they inhibit cellular proliferation by interferring with nuclear cleavage or by restricting the synthesis of macromolecules (nucleic acids and proteins). To be effective the unchanged drug or its active metabolite(s) must accumulate in the target tumour cell or the cell stimulated to produce antibody.

Alkylating agents (cyclophosphamide, nitrogen mustard, chlorambucil, melphalan and busulphan) alkylate the N-7 position of guanine in DNA, and antibiotics (actinomycin D and daunorubicin) inhibit DNA-dependent RNA synthesis. The enzyme colaspase (L-asparaginase) acts to limit the supply of L-asparagine to tissues unable to synthesise this amino acid, while the vinca alkaloids (vinblastine and vincristine) produce metaphase arrest probably by specific interaction with microtubular protein, a component of the spindle apparatus. The action of the glucocorticoid hormones is not clear, but it is most likely that they act via normal control mechanisms that usually mediate the effect of these hormones. The folic acid antagonist methotrexate limits the synthesis of both purine and pyrimidine nucleotides by inhibiting dihydrofolate reductase. The major site of action of 5-fluorouracil is inhibition of thymidine nucleotide formation (after activation to 5-fluorodeoxyuridylic acid). 6-Mercaptopurine inhibits the utilisation of preformed purines by tissues requiring them. It is also activated to thionucleotide analogues which interfere with the de novo synthesis of purine nucleotides from simple precursors. Cytarabine is activated to its nucleoside triphosphate derivative which then acts to inhibit DNA polymerase.

Because a major biochemical requirement of dividing cells is protein and nucleic acid synthesis, inhibition at any one of the above-mentioned sites is likely to retard proliferation.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • Adamson, R.H.: Metabolism of anticancer agents in man. Annals of the New York Academy of Sciences 179: 432 (1971).

    PubMed  CAS  Google Scholar 

  • Adamson, R.H. and Fabro, S.: Antitumour activity and other biologic properties of L-asparaginase (NSC-109229) — a review. Cancer Chemotherapy Reports 52: 617(1968).

    CAS  Google Scholar 

  • Alberts, D.S.; Bachur, N.R. and Holtzman, J.L.: The pharmacokinetics of daunomycin in man. Clinical Pharmacology and Therapeutics 12: 96 (1971).

    PubMed  CAS  Google Scholar 

  • Allison, A.C.: Tumour development following immuno-suppression. Proceedings of the Royal Society of Medicine 6 3: 1977(1970).

    Google Scholar 

  • Anderson, L.L.; Collins, C.J.; Ojima, Y. and Sullivan, R.D.: A study of the distribution of methotrexate in human tissues and tumors. Cancer Research 30: 1344(1970).

    PubMed  CAS  Google Scholar 

  • André J.A.; Schwartz, R.S.; Mitus, W.J. and Dameshek, W.: The morphologic responses of the lymphoid system to homografts. II. The effect of antimetabolites. Blood 19: 334 (1962).

    PubMed  Google Scholar 

  • Beaven, D.W.; Espiner, E.A. and Donald, R.A.: Cortico-trophin and corticosteroids: Pharmacological considerations. New Ethicals 11(8): 73 (1970); New Ethicals and Medical Progress 7(8): 77(1970).

    Google Scholar 

  • Beer, C.T. and Richards, J.F.: The metabolism of vinca alkaloids. Part II. The fate of tritiated vinblastine in rats. Lloydia 27: 352(1964).

    CAS  Google Scholar 

  • Belisario, J.C.: Topical cytotoxic therapy of solar keratoses with 5-fluorouracil. Medical Journal of Australia 2: 1136 (1969).

    PubMed  CAS  Google Scholar 

  • Bensch, K.G. and Malawista, S.E.: Microtubular crystals in mammalian cells. Journal of Cell Biology 40: 95 (1969).

    PubMed  CAS  Google Scholar 

  • Berenbaum, M.C.: The effect of cytotoxic agents on the production of antibody to TAB vaccine in the mouse. Biochemical Pharmacology 11: 29 (1962).

    PubMed  CAS  Google Scholar 

  • Berenbaum, M.C.: Immunosuppressive agents. Proceedings of the Royal Society of Medicine 60: 125 (1967a).

    PubMed  CAS  Google Scholar 

  • Berenbaum, M.C.: Immunosuppressive agents and allogenic transplantation. Journal of Clinical Pathology 20: 471 (1967b).

    Google Scholar 

  • Berenbaum, M.C.: Immunosuppression by L-asparaginase. Nature (Lond.) 225: 550 (1970).

    CAS  Google Scholar 

  • Berenbaum, M.C.; Ginsberg, H. and Gilbert, D.M.: Effects of L-asparaginase on lymphocyte-target cell reactions in vitro. Nature (Lond.) 227: 1147 (1970).

    CAS  Google Scholar 

  • Bertino, J.R.: The mechanism of action of the folate antagonists in man. Cancer Research 23: 1286 (1963).

    PubMed  CAS  Google Scholar 

  • Bertino, J.R.; Booth, B.A. and Sartorelli, A.C.: Metabolic alterations accompanying amethopterin resistance in Ehrlich ascites carcinoma. Proceedings of the American Association for Cancer Research 3: 303 (1962).

    Google Scholar 

  • Bertino, J.R.; Hillicoat, B.L. and Johns, D.G.: Folate antagonists: some biochemical and pharmacological considerations. Federation Proceedings 26: 893 (1967).

    PubMed  CAS  Google Scholar 

  • Billingham, R.E.; Krohn, P.L. and Medawar, P.B.: Effects of cortisone on survival of skin homografts in rabbits. British Medical Journal 1: 1157(1951).

    PubMed  CAS  Google Scholar 

  • Booth, B.A.; Creasy, W.A. and Sartorelli, A.C.: Alterations in cellular metabolism associated with cell death induced by uracil mustard and 6-thioguanine. Proceedings of the National Academy of Science (US) 52:1396(1964).

    CAS  Google Scholar 

  • Brewer, H.B.; Comstock, J.P. and Aronow, L.: Effects of nitrogen mustard on protein and nucleic acid synthesis in mouse fibroblasts growing in vitro. Biochemical Pharmacology 8: 281 (1961).

    PubMed  CAS  Google Scholar 

  • Brock, N. and Hohorst, H.J.: Ueber die aktivierung von cyclophosphamid in vivo and in vitro. Arzneimittel-Forschung 13: 1021(1963).

    PubMed  CAS  Google Scholar 

  • Burgio, G.R.; Astaldi, A.; Kie, I.; Mitu, D. and Astaldi, G: L-Asparaginase and inhibition of the lymphocyte immune reaction. Farmaco 25: 85 (1970).

    CAS  Google Scholar 

  • Burnet, F.M.: in The clonal selection theory of acquired immunity (Cambridge University Press, Cambridge 1959).

    Google Scholar 

  • Calabresi, P. and Parks, R.E.: Alkylating agents, antimetabolites, hormones and other anitproliferative agents; in Goodman and Gilman The Pharmacological Basis of Therapeutics. 4th Ed., p. 1348 (MacMillan, Toronto 1970).

    Google Scholar 

  • Calendi, E; DiMarco, A.; Reggiani, M.; Scarpinato, B. and Valentini, L.: On physico-chemical interactions between daunomycin and nucleic acids. Biochimica et Biophysica Acta 103: 25(1965).

    PubMed  CAS  Google Scholar 

  • Caspersson, T.; Farber, S.; Foley, G.E. and Killander, D: Cytochemical observations on the nucleolusribosome system. Effects of actinomycin D and nitrogen mustard. Experimental Cell Research 32: 529 (1963).

    PubMed  CAS  Google Scholar 

  • Chalmers, A.H.; Atkinson, M.R.; Burgoyne, L.A. and Murray, A.W.: Evidence for the utilization of performed purines by rat lymphoid tissues: Implication to immunosuppression by 6-thiopurine analogues. Australian Journal of Experimental Biology and Medical Science (accepted for publication,1971.

  • Chalmers, A.H.; Knight, P.R. and Atkinson, M.R.: 6-Thiopurines as substrates and inhibitors of purine oxidases: A pathway for conversion of azathioprine into 6-thiouric acid without release of 6-mercaptopurine. Australian Journal of Experimental Biology and Medical Science 47: 263 (1969).

    PubMed  CAS  Google Scholar 

  • Choudhuri, N.K.; Montag, B.J. and Heidelberger, C.: Studies on fluorinated pyrimidines. II. The metabolism of 5-fluoro-orotic-2-C 14 acid in vivo. Cancer Research 18:318 (1958).

    Google Scholar 

  • Chu, M.Y. and Fischer, G.A.: Comparative studies of leukemic cells sensitive and resistant to cytosine arabinoside. Biochemical Pharmacology 14: 333 (1965).

    PubMed  CAS  Google Scholar 

  • Clarkson, B.; Krakoff, I.; Burcharal, J.; Karnofsky, D; Golbey, R.; Dowling, M.; Oettgen, H. and Lipton, A.: Clinical results of treatment with E. coli L-asparaginase in adults with leukaemia, lymphoma and solid tumours. Cancer 25: 279 (1970).

    PubMed  CAS  Google Scholar 

  • Cohen, S.S.: Introduction to biochemistry of D-arabinosyl nucleosides. Progress in Nucleic Acid Research and Molecular Biology 5: 1 (1966).

    PubMed  Google Scholar 

  • Connors, T.A. and Jones, M.: Antagonism of the anti-tumour effects of asparaginase by methotrexate. Biochemical Pharmacology 19: 2927 (1970).

    PubMed  CAS  Google Scholar 

  • Cooney, D.A. and Handschumacher, R.E.: L-Asparaginase and L-asparagine metabolism. Annual Review of Pharmacology 10:421 (1970).

    PubMed  CAS  Google Scholar 

  • Creasey, W.A.; Papac, R.J.; Markiw, M.E.; Calabresi, P. and Welch, A.D.: Biochemical and pharmacological studies with l-β-D-arabinofuranosylcytosine in man. Biochemical Pharmacology 15: 1417 (1966).

    PubMed  CAS  Google Scholar 

  • Cutts, J.H.: The effect of vincaleukoblastine on dividing cells in vivo. Cancer Research 21: 168 (1961).

    PubMed  CAS  Google Scholar 

  • Dagg, C.P.: Sensitive stages for the production of developmental abnormalities in mice with 5-fluorouracil. American Journal of Anatomy 106: 89 (1960).

    PubMed  CAS  Google Scholar 

  • DeVita, V.T. and Rall, D.P.: Pharmacologic aspects of the chemotherapy of solid tumors. Pharmacology for Physicians 2: 1(1968).

    Google Scholar 

  • DiMarco, A.; Gaetani, M.; Orezzi, P.; Scarpinato, B.A.; Silvestrini, R.; Soldati, M.; Dasdia, T. and Valentini, L: Daunomycin a new antibiotic of the rhodomylin group. Nature(Lond.) 201: 706(1964).

    Google Scholar 

  • Dorigiotti, L.: Studio al microscopio electronico dej modificanzoni indotte dall a daunomicini seulle cellule HeLa. Tumori 50: 117 (1964).

    Google Scholar 

  • Dougherty, T.F: Hormones and the RES. Journal of the Reticuloendothelial Society 4: 229 (1967).

    PubMed  CAS  Google Scholar 

  • Durham, J.P and Ives, D.H.: Deoxycytidine kinase. Molecular Pharmacology 5: 3 58 (1969).

    Google Scholar 

  • Eckhardt, A.; Sellei, C. and Hartai, F.: A mannitmyleran (1,6-dimethylsulfonoxy-D-mannitol) latasa idult myeloid leukemias betegekre. Orvosi Hetilap (Budapest) 102: 1987(1961).

    CAS  Google Scholar 

  • Mon, G.B.: Biochemistry and pharmacology of purine analogs. Federation Proceedings 26: 898(1967).

    Google Scholar 

  • Eurenius, K.; Dalton, T.V.; Lokey, H.J. and McIntyre, O.R.: The mechanism of glucocorticoid action on the phytohaemagglutin-stimulated lymphocyte. Biochimica et Biophysica Acta 177: 572 (1969).

    PubMed  CAS  Google Scholar 

  • Fischer, G.A.: Increased levels of folic acid reductase as a mechanism of resistance to amethopterin in leukaemic cells. Biochemical Pharmacology 7: 75 (1961).

    PubMed  CAS  Google Scholar 

  • Fox, M.: Suppression of tissue immunity by cyclophosphamide. Transplantation 2:475 (1964).

    PubMed  CAS  Google Scholar 

  • Frei, E. and Loo, T.L.: Pharmacologic basis for the chemotherapy of leukemia. Pharmacology for Physicians 1: 1 (1967).

    Google Scholar 

  • Furth, J.J. and Cohen, S.S.: Inhibition of mammalian DNA polymerase by the 5′-triphosphate of l-β-D-arabino-furanosyl cytosine and the 5′-triphosphate of 9-β-D-arabinofuranosyl adenine. Cancer Research 25:2061(1968).

    Google Scholar 

  • Gerhatz, H.: Klinische ergebrisse liner Chemotherapie mit Endoxan. Unio Internationalis Contra Cancrum Acta 20: 366(1964).

    Google Scholar 

  • Graham, F.L. and Whitmore, G.F.: The effect of 1-β-D-arabinofuranosyl cytosine on growth, viability and DNA synthesis of mouse L-cells. Cancer Research 30:2627 (1970).

    PubMed  CAS  Google Scholar 

  • Grindey, G.B.; Saslaw, L.D. and Waravdekar, V.S.: Effects of uracil derivatives on phosphorylation of arabinosyl cytosine. Molecular Pharmacology 4: 96(1968).

    PubMed  CAS  Google Scholar 

  • Grunicke, H.; Zummerman, F. and Holzer, H: The effects of the alkylating cytostatic agent, 2,3,5-trisethyl-eneimino-benzoquinone-1,4 (Trenimon) on the priming ability of DNA from mouse ascites-tumour cells in the RNA-polymerase system. Biochemical and Biophysical Research Communcations 18: 319 (1965).

    CAS  Google Scholar 

  • Harbers, E; Choudhuri, N.K. and Heidelberger, C.: Studies on fluorinated pyrimidines. VII. Further biochemical and metabolical investigations. Journal of Biological Chemistry 234: 1255(1959).

    PubMed  CAS  Google Scholar 

  • Hartman, G.; Goller, H.; Koschel, K; Kernten, K. and Kersent, H.: Hemming der DNA-abRangigen RNA und DNA synthese durch antibiotica. Biochimica Zeitschrift 341: 126(1964).

    Google Scholar 

  • Heidelberger, C.: in Harris Biological Approaches to Cancer Chemotherapy (Academic Press, New York 1961).

    Google Scholar 

  • Heidelberger, C. and Ansfield. F.J.: Experimental and clinical use of fluorinated pyrimidines in cancer chemotherapy. Cancer Research 23: 1226 (1963).

    PubMed  CAS  Google Scholar 

  • Henderson, E.S.; Adamson, R.H. and Oliverio, V.T.: The metabolic fate of tritiated methotrexate. II. Absorption and excretion in man. Cancer Research 25: 1018(1965).

    PubMed  CAS  Google Scholar 

  • Heunnekens, F.M.: The role of dihydrofolic reductase in the metabolism of one-carbon units. Biochemistry 2: 151(1963).

    Google Scholar 

  • Heunnekens, F.M.: in Bittar The Biological Basis of Medicine (Academic Press, New York 1969).

    Google Scholar 

  • Hertz, R.: Combined Clinical Staff Conference of the National Institutes of Health. Annals of Internal Medicine 59: 931 (1963).

    PubMed  Google Scholar 

  • Hill, J.M.; Roberts, J.; Loeb, E; Khan, A.; MacLellan. A. and Hill, R.B.: L-Asparaginase therapy for leukemia and other malignant neoplasms. Journal of the American Medical Association 202: 882(1967).

    PubMed  CAS  Google Scholar 

  • Hirschberg, E.: Cancer chemotherapy screening data. XXI. Patterns of response of animal tumours to anti-cancer agents. Cancer Research (Suppl.) 23: 521 (1963).

    CAS  Google Scholar 

  • Hitchings, G.H. and Rhoads, C.P.: The chemistry and biochemistry of purine analogs. Annals of the New York Academy of Sciences 60: 183 (1954).

    Google Scholar 

  • Hodes, M.E.; Rohn, E.J.; Bond, W.H. and Yardley, J.: Vincaleukoblastine. III. Clinical trial with oral preparations. Cancer Chemotherapy Reports 14: 129 (1961).

    CAS  Google Scholar 

  • Holmquist, N.D.: Effect of normal sera of several related rodents on GC3HE D lymphomam vivo. Proceedings of the Society for Experimental Biology and Medicine 113:444(1963).

    PubMed  CAS  Google Scholar 

  • Holtermann, O.A. and Nordin, A.A.: The effect of cytosine arabinoside upon the primary immune response in vitro. Proceedings of the Society for Experimental Biology and Medicine 132: 1003 (1969).

    PubMed  CAS  Google Scholar 

  • Holton, C.P.; Lonsdale, D.; Nora, H.H.; Thurman, W.G. and Vietti, T.J.: Clinical study of daunomycin (NSC-82151) in children with acute leukaemia. Cancer 22: 1014(1968).

    PubMed  CAS  Google Scholar 

  • Horowitz, B.; Madras, B.K.; Meister, A.; Old, L.J.; Boyse, E.A. and Stocken, E.: Asparagine synthetase activity of mouse leukemias. Science 160: 533 (1968).

    PubMed  CAS  Google Scholar 

  • Huggins, C.: Endocrine-induced regression of cancers. Science 156: 1050(1967).

    PubMed  CAS  Google Scholar 

  • Hurwitz, J.; Furth, J.J.; Malamy, M. and Alexander, M.: The role of deoxyribonucleic acid in ribonucleic acid synthesis. III. The inhibition of the enzymatic synthesis of ribonucleic acid and deoxyribonucleic acid by actinomycin D and proflavin. Proceedings of the National Academy of Science (US) 48: 1222 (1962).

    CAS  Google Scholar 

  • Ishidata, M. and Metcalf, D.: The patterns of lymphopoiesis in mouse thymus after cortisone administration on adrenalectomy. Australian Journal of Experimental Biology and Medical Science 41: 637 (1963).

    Google Scholar 

  • Israels, L.G.; Galton, D.A.G.; Tiel, M. and Wiltshaw, E: Clinical evaluation of CB1348 in malignant lymphoma and related diseases. Annals of the New York Academy of Sciences 68: 915 (1958).

    PubMed  CAS  Google Scholar 

  • Johnson, I.S.: Historical background of vinca alkaloid research and areas of future interest. Cancer Chemotherapy Reports 52: 455(1968).

    CAS  Google Scholar 

  • Kahan, E.; Kahan, F.M. and Hurwitz, J.: The role of deoxyribonucleic acid in ribonucleic acid synthesis. VI. Specificity of action of actinomycin D. Journal of Biological Chemistry 238: 2491 (1963).

    PubMed  CAS  Google Scholar 

  • Kay, J.E. and Cooper, H.L.: Differential inhibition of 28S and 18S ribosomal RNA synthesis by actinomycin. Biochemical and Biophysical Research Communications 55: 526(1969).

    Google Scholar 

  • Kessel, D.; Myers, M. and Wodensky, I.: Accumulation of two alkylating agents, nitrogen mustard and busulphan, by murine leukaemic cells in vitro. Biochemical Pharmacology 18: 1229 (1969).

    PubMed  CAS  Google Scholar 

  • Kindred, J.E.: Histological changes occurring in hemopoietic organs of albino rats after single infections of 2-chloroethyl vesicants: quantitative study. Archives of Pathology (Chicago) 43: 253 (1947).

    CAS  Google Scholar 

  • Krishan, A. and Hsu, D.: Observations on the association of helical polyribosomes and filaments with vincristine-induced crystals in Earle’s L-cell fibroblasts. Journal of Cell Biology 43: 553 (1969).

    PubMed  CAS  Google Scholar 

  • Lajtha, L.G. and Vane, J.R.: Dependence of bone marrow cells on the liver for purine supply. Nature (Lond.) 752:191(1958).

    Google Scholar 

  • Lange, R.D.; Gallagher, N.I.; McCarthy, J.M. and Wright, S: Myelotoxic action of the aminonucleoside of puromycin, a potential cancer chemotherapeutic agent. Proceedings of the 7th International Congress for the International Society for Haematology (Rome) 2: 192 (1960).

    Google Scholar 

  • Liegler, D.G.; Henderson, ES.; Hahn, M.A. and Oliverio, V.T.: The effect of organic acids on renal clearance of methotrexate in man. Clinical Pharmacology and Therapeutics 10: 849(1970).

    Google Scholar 

  • Lightfoot, R.W.Jr. and Garfein, G.R.: The effect of steroids on the clearance and fate of bacteria. Journal of the Reticuloendothelial Society 5: 340(1968).

    PubMed  Google Scholar 

  • Many, A. and Schwartz, R.S.: Drug induced immunologixc tolerance: Site of action of cyclophosphamide. Proceedings of the Society for Experimental Biology and Medicine 133: 754 (1970).

    PubMed  CAS  Google Scholar 

  • Miller, H.K.; Salser, J.S. and Balis, M.E: Amino acid levels following L-asparagine amidohydrolase(EC.3.5.1.1) therapy. Cancer Research 29: 183 (1969).

    PubMed  CAS  Google Scholar 

  • Miller, J.J. and Cole, L.J.: Resistance of long-lived lymphocytes and plasma cells in rat lymph nodes to treatment with prednisone, cyclophosphamide, 6-mercaptopurine and actinomycin D. Journal of Experimental Medicine 126: 109 (1967).

    PubMed  CAS  Google Scholar 

  • Mowbray, J.F.: The complications of anti-lymphocyte therapy. Proceedings of the Royal Society of Medicine 63: 1067(1970).

    PubMed  CAS  Google Scholar 

  • Mukherjee, K.L.; Curreri, A.R.; Javid, M. and Heidelberger, C.: Studies on fluorinated pyrimidines. XVII. Tissue distribution of 5-fluorouracil-2-C14 and 5-fluoro-2′-deoxyuridine in cancer patients. Cancer Research 25:67(1963).

    Google Scholar 

  • Murray, A.W.; Elliott, D.C. and Atkinson, M.R.: Nucleotide biosynthesis from preformed purines in mammalian cells: regulatory mechanisms and biological significance. Progress in Nucleic Acid Research and Molecular Biology 10: 87 (1970).

    PubMed  CAS  Google Scholar 

  • Neil, G.L.; Moxley, T.E. and Manak, R.C.: Enhancement by tetrahydrouridine of 1-β-D-arabinofuranosyl cytosine (Cyt-Arabine) oral activity in L-1210 leukemic mice. Cancer Research 30: 2166(1970).

    PubMed  CAS  Google Scholar 

  • Olmsted, J.B.; Carlson, K.; Klebe, R.; Ruddle, R. and Rosenbaum, J.: Isolation of microtubule protein from cultured mouse neuroblastoma cells. Proceedings of the National Academy of Sciences (US) 65: 129(1970).

    CAS  Google Scholar 

  • Palmer, C.G; Livengood, D.; Warren, A.K.; Simpson, P.J. and Johnson, I.S.: The action of vincaleukoblastine on mitosis in vitro. Experimental Cell Research 20: 198(1960).

    PubMed  CAS  Google Scholar 

  • Papac, R.J.; Galabresi, P.; Hollingsworth, J.W. and Welch, A.D.: Effects of 1-β-D-arabinofuranosyl cytosine hydrochloride on regenerating bone marrow. Cancer Research 25: 1459(1965).

    PubMed  CAS  Google Scholar 

  • Peterson, R.E.; Pierce, CE.; Wyngaarden, J.B.; Buniur and Brodie, B.B.: The physiological disposition and metabolic fate of cortisone in man. Journal of Clinical Investigation 36: 1301 (1957).

    PubMed  CAS  Google Scholar 

  • Philips, F.S.; Schwartz, H.S.; Sternberg, S.S. and Tan, T.C: The toxicity of actinimycin D. Annals of the New York Academy of Science 89: 348 (1960).

    CAS  Google Scholar 

  • Piliero, S.J.: Immune suppressants. Bio-Science 20: 710 (1970).

    CAS  Google Scholar 

  • Pritchard, J.B.; Chavez-Peon, F. and Berlin, R.D.: Purines: Supply by liver to tissues. American Journal of Physiology 219: 1263(1970).

    PubMed  CAS  Google Scholar 

  • Ross, W.C.J.: in Biological alkylating agents, p. 5 (Butter-worth, London 1962).

    Google Scholar 

  • Santos, G.W.: The pharmacology of immunosuppressive drugs. Pharmacology for Physicians 2: 1 (1968).

    PubMed  CAS  Google Scholar 

  • Schabet, F.M. Jr.; Laster, W.R. Jr. and Trader, M.W.: Specific DNA inhibitors vs. leukemia L-1210. Development of resistance to Ara-C and ribonucleotide reductase inhibitors. Proceedings of the American Association for Cancer Research 62: 67 (1971).

    Google Scholar 

  • Schabel, FM.Jr.; Skipper, H.E.; Trader, M.W. and Wilcox, W.S.: Experimental evaluation of potential anticancer agents. XIX. Sensitivity of nondividing leukaemic cell populations to certain classes of drugs in vivo. Cancer Chemotherapy Reports 48: 17 (1965).

    CAS  Google Scholar 

  • Schwartz, M.K.; Lash, ED.; Oettgen, H.F. and Tomao, F.A.: L-Asparaginase activity in plasma and other biological fluids. Cancer 25: 244 (1970).

    PubMed  CAS  Google Scholar 

  • Schwartz, R.S.: Immunosuppression by L-asparaginase. Nature (Lond.) 224: 275 (1969).

    CAS  Google Scholar 

  • Schwartz, R.S. and André, J.: Clearance of proteins from blood of normal and 6-MP-treated rabbits. Proceedings of the Society for Experimental Biology and Medicine 104:228(1960).

    PubMed  CAS  Google Scholar 

  • Schwartz, R.S. and Eisner, A.: Effect of 6-MP on immune responses. Clinical Research 7: 39(1959).

    Google Scholar 

  • Sharbough, R.J. and Grogan, J.B.: Suppression of reticulo-endothelial function in the rat with cyclophosphamide. Journal of Bacteriology 100: 117(1969).

    Google Scholar 

  • Silberman, H.R. and Wyngaarden, J.B.: 6-Mercaptopurine as substrate and inhibitor of xanthine oxidase. Biochimica et Biophysica Acta 47: 178 (1961).

    CAS  Google Scholar 

  • Skipper, H.E.; Schabel, FM.Jr.; Mellett, L.B.; Montgomery, J.A.; Wilkoff, L.J.; Lloyd, H.H. and Brockman, R.W.: Implications of biochemical, cytokinetic, pharmacologic, and toxicologic relationships in the design of optimal therapeutic schedules. Cancer Chemotherapy Reports Part I 54: 431 (1970).

    CAS  Google Scholar 

  • Spurr, C.H.; Smith, T.R. and Jacobson, L.W.: Chemotherapy in human lymphomas, leukaemias and allied disorders of the hemopoietic system. Radiology 50: 387(1948).

    PubMed  CAS  Google Scholar 

  • Steuart, C.D.; Burke, P.J. and Owens, A.H.: Correlation of Ara-C metabolism and clinical response in adult acute leukaemia. Proceedings of the American Society for Cancer Research 62: 89 (1971).

    Google Scholar 

  • Suguira, K.: Investigation of diverse systems for cancer chemotherapy screening; studies in spectrum of mouse and rat tumours. Cancer Research (Suppl.) 3: 18(1955).

    Google Scholar 

  • Suguira, K.: Effects of compounds on the Friend mouse virus leukaemia. Gann 50: 251 (1959).

    Google Scholar 

  • Tallal, L.; Tan, C.; Oettgen, H; Wollner, N.; McCarthy, M.; Helson, L.; Burchenal, J.; Karnofsky, D. and Murphy, M.L.: Ecoli L’asparaginase in the treatment of leukaemia and solid tumours in 131 children. Cancer 25: 306(1970).

    PubMed  CAS  Google Scholar 

  • Taylor, W.: Steroid metabolism in the cat. Biliary and urinary excretion of metabolites of (4-14C) cortisone. Biochemical Journal 113: 259(1969).

    PubMed  CAS  Google Scholar 

  • Theologides, A.; Barbro, J.W. and Kennedy, B.J.: Daunomycin inhibition of DNA and RNA synthesis. Cancer 21: 16(1968).

    PubMed  CAS  Google Scholar 

  • Turk, J.L. in Fairley and Simister Cyclophosphamide, p. 151 (Wright, Bristol 1964).

    Google Scholar 

  • Vodopick, H; Hamilton, H.E.; Jackson, H.L.; Peng, C.T. and Streets, R.F.: Metabolic fate of tritiated busulphan in man. Journal of Laboratory and Clinical Medicine 73: 266(1969).

    PubMed  CAS  Google Scholar 

  • Wagner, E.K. and Roizman, B.: Effect of vinca alkaloids on RNA synthesis in human cells in vitro. Science 762: 569 (1968).

    Google Scholar 

  • Waidenstrom,, J.: Melphalan therapy in myelomatosis. British Medical Journal 1:859(1964).

    Google Scholar 

  • Waqar, M.A.; Burgoyne, L.A. and Atkinson, M.R.: DNA synthesis in mammalian nuclei. Biochemical Journal 121:803 (1971).

    PubMed  CAS  Google Scholar 

  • Werkheiser, W.C.: Selective permeability and the response of tissues and tumours to the 4-amino-folic acid antagonists. Proceedings of the American Association for Cancer Research 3: 371 (1962).

    Google Scholar 

  • Werkheiser, W.C.; Law, L.W.; Roosa, R.A. and Nichol, CA.: Further evidence that selective uptake modifies cellular response to 4-amino-folic acid antagonists. Proceedings of the American Association for Cancer Research 4:71(1963).

    Google Scholar 

  • Wheeler, G.P.: Some biochemical effects of alkylating agents. Federation Proceedings 26: 885(1967).

    PubMed  CAS  Google Scholar 

  • Wheeler, G.P. and Alexander, J.A.: Effects of nitrogen mustard and cyclophosphamide upon the synthesis of DNA in vivo and in cell free preparations. Cancer Research 29: 98(1969).

    PubMed  CAS  Google Scholar 

  • Whiteside, J.A.; Philips, F.S.; Dargeon, H.W. and Burchenal, J.H.: Intrathecal amethopterin in neurological manifestations of leukaemia. Archives of Internal Medicine 101: 279(1958).

    PubMed  CAS  Google Scholar 

  • Wilkinson, J.F. and Turner, R.L.: Chemotherapy of chronic myeloid leukaemia with special reference to Myleran. Progress in Haematology 2: 225 (1959).

    Google Scholar 

  • Wilson, L; Bryan, J.; Ruby, A. and Mazia, D.: Precipitation of proteins by vinblastine and calcium ions. Proceedings of the National Academy of Sciences (US) 66: 807 (1970).

    CAS  Google Scholar 

  • Wisniewski, H.; Shelanski, M.L. and Terry, R.D.: Effects of mitotic spindle inhibitors on neurotubules and neurofilaments in anterior horn cells. Journal of Cell Biology 38: 224 (1968).

    PubMed  CAS  Google Scholar 

  • Zaharko, D.S.; Bruckner, H. and Oliverio, V.T.: Antibiotics alter methotrexate metabolism and excretion. Science 166: 887(1969).

    PubMed  CAS  Google Scholar 

  • Zetterberg, A.: Nuclear and cytoplasmic growth during interphase in mammalian cells, in Prescott, Goldstein and McConkey Advances in Cell Biology, Vol. 1, p. 211 (North-Holland, Amsterdam 1970).

    Google Scholar 

  • Zittle, C.A.: Hydrolysis of acid amides and amino acid amides, The Enzymes 1: 929.

Download references

Author information

Authors and Affiliations

  1. Department of Surgery, University of Adelaide, South Australia, 5001, Australia

    A. H. Chalmers,  L. A. Burgoyne &  A. W. Murray

  2. School of Biological Sciences, Flinders University, Bedford Park, South Australia, 5042, Australia

    A. H. Chalmers,  L. A. Burgoyne &  A. W. Murray

Authors
  1. A. H. Chalmers
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. L. A. Burgoyne
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. A. W. Murray
    View author publications

    You can also search for this author in PubMed Google Scholar

Additional information

First of 3 parts (II: Therapeutic Uses; III: Adverse Effects and Therapeutic Problems).

See subject index in this issue for further indexing terms.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Chalmers, A.H., Burgoyne, L.A. & Murray, A.W. Antineoplastic and Immunosuppressive Drugs I: Biochemical and Clinical Pharmacological Considerations. Drugs 3, 227–253 (1972). https://doi.org/10.2165/00003495-197203030-00004

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.2165/00003495-197203030-00004

Key Words

Search

Navigation