Abstract
Arabinosyleytosine (1-β-D-arabinofuranosylcytosine; cytosine arabinoside; cytosar; ara-C; cytarabine) is a member of a class of nucleosides in which D-arabinose constitutes the pentose sugar moiety. Thus, these compounds are analogs of ribo- nucleosides in which the hydroxyl group at the 2’-position is inverted. However, in most respects the arabinosides do not behave biologically as ribonucleoside analogs. Certain arabinosides are naturally occurring, both arabinosylthymine and arabinosyluracil (ara-U) having been isolated from the sponge Cryptotethya crypta, (Bergman and Feeney, 1951; Bergman and Burke, 1955). Cohen (1963) has reviewed some aspects of the occurrence, isolation, and relevance to chemotherapy of the arabinosides, and suggested a possible role for these nucleosides in aging. The same author in a later review (Cohen, 1966) has outlined methods for chemical synthesis of these compounds, the metabolism of ara-C and ara-U in bacteria, and some effects of the arabinosides on mammalian cells. Much of the pharmacological information regarding ara-C that was available through 1968 may be found briefly reviewed in an article on cancer chemotherapy by Sartorelli and Creasey (1969). Clinical brochures that include some information about the chemistry, antitumor activity in experimental systems, and preliminary data obtained in man, have been prepared by Livingston and Carter (1968) and the Upjohn Company (1970). Notari et al. (1972) have defined the stability of the drug under various storage conditions and found that at neutral pH the drug retains 90% of its potency after 6 months at room temperature.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Preview
Unable to display preview. Download preview PDF.
References
Ahearn, M. J., Lewis, C. W., Campbell, L. A., Luce, J. K.: Nuclear bleb formation in human bone marrow cells during cytosine arabinoside therapy. Nature (Lond.) 215, 196–197 (1967).
Atkinson, C., Stacey, K. A.: Thymineless death induced by cytosine arabinoside. Biochim. biophys. Acta (Amst.) 166, 705–707 (1968).
Bach, M. K.: Biochemical and genetic studies of a mutant strain of mouse leukemia L1210 resistant to 1 -β-D-arabinof uranosyl cytosine (cytarabine) hydrochloride. Cancer Res. 29, 1036–1044 (1969).
Bader, J. P.: Metabolic requirements for infection by Rous sarcoma virus. I. The transient requirement for DNA synthesis. Virology 29, 444 451 (1966).
Baguley, B. C., Falkenhaug, E. M.: Plasma half-life of cytosine arabinoside (NSC-63878) in patients treated for acute myeloblastic leukemia. Cancer Chemother. Rep. 55, 291–298 (1971).
Baldini, L., Brambilla, G., Cavanna, M., Parodi, S.: Immunosuppressive activity of methotrexate and arabinosylcytosine in mice bearing L1210 leukemia. Brit. J. Pharmacol. 34, 674P–676P (1968).
Bell, E.: Informational DNA synthesis distinguished from that of nuclear DNA by inhibitors of DNA synthesis. Science 174, 603–606 (1971).
Bell, W. R., Whang, J. J., Carbone, P. P., Brecher, G., Block, J. B.: Cytogenetic and morphologic abnormalities in human bone marrow cells during cytosine arabinoside therapy. Blood 27, 771–781 (1966).
Benedict, W. P., Harris, N., Karon, M.: Kinetics of 1-β-D-arabinofuranosy Icytosine -induced chromosome breaks. Cancer Res. 30, 2477–2483 (1970).
Benedict, W. F., Karon, M.: Chromatid breakage: cytosine arabinoside-induced lesions inhibited by UV irradiation. Science 171, 680–682 (1971).
Ben-Porat, T., Brown, Mc K., Kaplan, A. S.: Effect of 1-β-D-arabinofuranosylcytosine on DNA synthesis. II. In rabbit kidney cells infected with herpes viruses. Molec. Pharmacol. 4, 139–146 (1968).
Bergmann, W., Burke, D. C.: Contributions to the study of marine products. XXXIX. The nucleosides of sponges. III. Spongothymidine and spongouridine. J. org. Chem. 20, 1501 –1507 (1955).
Bergmann, W., Feeney, R. J.: Contributions to the study of marine products. XXXII. The nucleosides of sponges. I. J. org. Chem. 16, 981–987 (1951).
Block, J. B., Bell, W., Whang, J., Carbone, P. P.: Hematologic and cytogenetic abnormalities during cytosine arabinoside (CA) therapy. Proc. Amer. Ass. Cancer Res. 6, 6 (1965).
Bors A, J., Whitmore, G. F., Valeriote, F. A., Collins, D., Bruce, W. R.: Studies on the persistence of methotrexate, cytosine arabinoside and leukovorin in the serum of mice. J. nat. Cancer Institute 42, 235–242 (1969).
Borun, T. W., Scharff, M. D., Robbins, E.: Rapidly labeled, polyribosome-associated RNA having the properties of histone messenger. Proc. nat. Acad. Sci. (Wash.) 58, 1977–1983 (1967).
Bremerskov, V., Kaden, P., Mittermayer, C.: DNA synthesis during the life cycle of L cells: morphological, histochemical and biochemical investigations with arabinosylcytosine and thioarabinosylcytosine. Europ. J. Cancer 6, 379–392 (1970).
Brewen, J. G.: The induction of chromatid lesions by cytosine arabinoside in post-DNA synthetic human leukocytes. Cytogenetics 4, 28–36 (1965).
Brewen, J. G., Christie, N. T.: Studies on the induction of chromosomal aberrations in human leukocytes by cytosine arabinoside. Exp. Cell Res. 46, 276–291 (1967).
Burchenal, J. H., Wiggins, R., Butterbaugh, J.: Activity of iN4-ydroxyl derivatives of 1-β-D-arabinofuranosylcytosine (ara-C) in Burkitt cell culture and mouse leukemia. Proc. Amer. Ass. Cancer Res. 8, 8 (1967).
Buskirk, H. H., Crim, J. A., Petering, H. G., Merritt, K., Johnson, A. G.: Effect of uracil mustard and several antitumor drugs on the primary antibody response in rats and mice. J. nat. Cancer Inst. 34, 747–758 (1965).
Buthala, D. A.: Cell culture studies on antiviral agents: 1-Action of cytosine arabinoside and some comparisons with 5-iodo-2’-deoxyuridine. Proc. Soc. Exp. Biol. (N.Y.) 115, 69 77 (1964).
Calabresi, P., Creasey,W. A., Prusoff, W. H., Welch, A. D.: Clinical and pharmacological studies with 5-iodo-2’-deoxycytidine. Cancer Res. 23, 583–592 (1963).
Camiener, G. W.: Studies of the enzymatic deamination of cytosine arabinoside. II. Properties of the deaminase of human liver. Biochem. Pharmacol. 16, 1681–1689 (1967a).
Camiener, G. W.: Studies of the enzymatic deamination of cytosine arabinoside. III. Substrate requirements and inhibitors of the deaminase of human liver. Biochem. Pharmacol. 16, 1691–1702 (1967 b).
Camiener, G. W., Smith, C. G.: Studies of the enzymatic deamination of cytosine arabinoside. I. Enzyme distribution and species specificity. Biochem. Pharmacol. 14, 1405–1416 (1965).
Camiener, G. W., Smith, C. G.: Studies of the enzymatic deamination of aracytidine. V. Inhibition in vitro and in vivo by tetrahydrouridine and other reduced pyrimidine nucleosides. Biochem. Pharmacol. 17, 1981–1991 (1968).
Cardeilhac, P. T., Cohen, S. S.: Some metabolic properties of nucleotides of 1-β-D-arabino-furanosylcytosine. Cancer Res. 24, 1595–1603 (1964).
Chaube, S., Kreis, W., Uchida, K., Murphy, M. L.: The teratogenic effect of 1-β-D-arabino- furanosylcytosine in the rat. Protection by deoxycytidine. Biochem. Pharmacol. 17, 1213 –1226 (1968).
Chu, M. Y.: Incorporation of arabinosylcytosine into 2–7 S ribonucleic acid and cell death. Biochem. Pharmacol. 20, 2057–2063 (1971).
Chu, M. Y., Fischer, G. A.: A proposed mechanism of action of 1 -β-D-arabin of uranosylcytosine as an inhibitor of the growth of leukemic cells. Biochem. Pharmacol. 11, 423–430 (1962).
Chu, M.Y., Fischer, G. A.: Comparative studies of leukemic cells sensitive and resistant to cytosine arabinoside. Biochem. Pharmacol. 14, 333–341 (1965).
Chu, M. Y., Fischer, G. A.: Effects of cytosine arabinoside on the cell viability and uptake of deoxypyrimidine nucleosides in L5178 Y cells. Biochem. Pharmacol. 17, 741–751 (1968a).
Chu, M. Y., Fischer, G. A.: The incorporation of 3H-cytosine arabinoside and its effect on murine leukemic cells (L5178Y). Biochem. Pharmacol. 17, 753–767 (1968b).
Cleaver, J. E.: Repair replication and degradation of bromouracil-substituted DNA in mammalian cells after irradiation with ultraviolet light. Biophys. J. 8, 775–791 (1968).
Cline, M. J.: Prediction of in vivo cytotoxicity of chemotherapeutic agents by their effect on malignant leukocytes in vitro. Blood 30, 176–188 (1967).
Cline, M. J., Rosenbaum, E.: Prediction of in vivo cytotoxicity of chemotherapeutic agents by their in vitro effect on leukocytes from patients with acute leukemia. Cancer Res. 28, 2516–2521 (1968).
Cohen, S. S.: Sponges, cancer chemotherapy and cellular aging. Perspect. biol. Med. 6, 215–227 (1963).
Cohen, S. S.: Introduction to the biochemistry of D-arabinosyl nucleotides. Progr. nucleic Acid Res. 5, 1–88 (1966).
Colby, C., Edlin, G.: Nucleotide pool levels in growing, inhibited, and transformed chick fibroblast cells. Biochemistry 9, 917–920 (1970).
Creasey, W. A.: Studies on the metabolism of 5-iodo-2’-deoxycytidine in vitro. J. biol. Chem. 238, 1772–1776 (1963).
Creasey, W. A., Deconti, R. C., Kaplan, S. R.: Biochemical studies with 1 -β-D-arabinofurano-sylcytosine in human leukemic leukocytes and normal bone marrow cells. Cancer Res. 28, 1074–1081 (1968).
Creasey, W. A., Flanigan, S., Mccollum, R. W., Calabresi, P.: Intraventricular administration of antimetabolites in patients with neoplasms and infections of the CNS. Proc. Amer. Ass. Cancer Res. 9, 16 (1968).
Creasey, W. A., Papac, R. J., Markiw, M. E., Calabresi, P., Welch, A. D.: Biochemical and pharmacological studies with 1-β-D-arabinofuranosylcytosine in man. Biochem. Pharmacol. 15, 1417–1428 (1966).
Cummings, D. J.: Comments on “thymineless death induced by cytosine arabinoside”. Bio-chim. biophys. Acta (Amst.) 179, 237–238 (1969).
Dabżynkiewicz, E., Kuśwerek, J. T., Shugar,D.: o’-Methyl derivatives of arabinosylcytosine. Biochem. biophys. Res. Commun. 46, 1734–1741 (1972).
Dixon, R. L., Adamson, R. H.: Antitumor activity and pharmacologic disposition of cytosine arabinoside (NSC 63878). Cancer Chemother. Rep. 48, 11–16 (1965).
Doering, A., Keller, J., Cohen, S. S.: Some effects of D-arabinosylnucleosides on polymer synthesis in mouse fibroblasts. Cancer Res. 26, 2444–2450 (1966).
Dollinger, M. R., Burchenal, J. H., Kreis, W., Pox, J. J.: Analogs of 1-β-D-arabinofuranosyl- cytosine. Studies on mechanisms of action in Burkitt’s cell culture and mouse leukemia, and in vitro deamination studies. Biochem. Pharmacol. 16, 689–706 (1967).
Dollinger, M., Kreis, W., Stoll, D., Fox, J., Burchenal, J. H.: Deamination of cytosine arabinoside and its analogs. Proc. Amer. Ass. Cancer Res. 8, 14 (1967).
Drahovsky, D., Kreis, W.: Studies on drug resistance-II. Kinase patterns in P815 neoplasms sensitive and resistant to 1 -β-D-arabinofuranosylcytosine. Biochem. Pharmacol. 19, 940 –944 (1970).
Durham, J. F., Ives, D. H.: Feedback control of calf thymus deoxycytidine kinase. Fed. Proc. 26, 808 (1967).
Durham, J. P., Ives, D. H.: Deoxycytidine kinase. 1. Distribution in normal and neoplastic tissues and inter-relationships of deoxycytidine and 1-β-D-arabinof uranosylcy tosine phosphorylation. Molec. Pharmacol. 5, 358–375 (1969).
Evans, J. S., Bostwick, L., Mengel, G. D.: Synergism of the antineoplastic activity of cytosine arabinoside by porfiromycin. Biochem. Pharmacol. 13, 983–988 (1964).
Evans, J. S., Mengel, G. D.: The reversal of cytosine arabinoside activity in vivo by deoxycytidine. Biochem. Pharmacol. 13, 989–994 (1964).
Evans, J. S., Musser, E. A., Bostwick, L., Mengel, G. D.: The effect of 1-β-D-arabinofuranosyl- cytosine hydrochloride on murine neoplasms. Cancer Res. 24, 1285–1293 (1964).
Evans, J. S., Musser, E. A., Mengel, G. D., Forsblad, K. R., Hunter, J. H.: Antitumor activity of 1 -β-D-arabinofuranosylcytosine hydrochloride. Proc. Soc. exp. Biol. (N.Y.) 106, 350–353 (1961).
Fahmy, O. G., Fahmy, M. J., De Vrye, C. E.: The mutagenic properties of the nucleosides of pyrimidine analogues in Drosophilia melanogaster. Biochem. Pharmacol. 15, 299–316 (1966).
Falco, E. A., Fox, J. J.: Nucleosides XLVIII. Synthesis of 1 -(5-deoxy-D-arabinosy 1) cytosine and related compounds. J. med. Chem. 11, 148–151 (1968).
Feldman, L. A., Rapp, F.: Inhibition of adenovirus replication by 1-β-D-arabinofuranosyl-cytosine. Proc. Soc. exp. Biol. (N.Y.) 122, 243–247 (1966).
Finkelstein, J. Z., Scher, J., Karon,M.: Pharmacologic studies of tritiated cytosine arabinoside (NSC-63878) in children. Cancer Chemother. Rep. 54, 35–39 (1970).
Fischer, D. S., Cassidy, E. P., Welch, A. D.: Immunosuppression by pyrimidine nucleoside analogs. Biochem. Pharmacol. 15, 1013–1022 (1966).
Flickinger,R.A.: Delay of normal development of sea urchin embryos by cytosine arabinoside. Experientia (Basel) 23, 136 (1967).
Fox, J. J., Yung, N., Bendich, A.: Pyrimidine nucleosides. II. The synthesis of 1-β-D-arabino-furanosylthymine (spongothymidine). J. Amer. chem. Soc. 79, 2775–2778 (1957).
Furlong, N. B., Gresham, C.: Inhibition of DNA synthesis but not of poly-DAT synthesis by the arabinose analogue of cytidine in vitro. Nature (Lond.) 233, 212–214 (1971).
Furth, J. J., Cohen, S. S.: Inhibition of mammalian DNA polymerase by the 5’-triphosphate of 1-β-D-arab inof uranosy ladenine. Cancer Res. 27, 1528–1533 (1967).
Furth, J. J., Cohen, S. S.: Effect of the 5’-triphosphates of 1-β-D-arabinof uranosylcytosine and 1-β-D-arabinofuranosyladenine on the enzymatic synthesis of nucleic acid in mammalian tissues. Proc. Amer. Ass. Cancer Res. 9, 23 (1968 a).
Furth, J. J., Cohen, S. S.: Inhibition of mammalian DNA polymerase by the 5’-triphosphate of 1-JFT-D-arabinofuranosylcytosine and the 5’-triphosphate of 1-β-D-arabinofuranosyl- adenine. Cancer Res. 28, 2061–2067 (1968b).
Gish, D. T., Neil, G. L., Wechter, W. J.: Nucleic acids. 12. Synthesis of the L–enantiomer of 1 –β-D-arabinof uranosy Icy tosine and of 02, 02’-anhydro-1-β-D-arabinofuranosylcytosine. J. med. Chem. 14, 882–883 (1971).
Giziewicz, J., Kuśmierek, J.T., Shugar, D.: 5’-O-Methyl derivatives of 1-β-D-arabinofuran- osylcytosine and 1-β-D-arabinofuranosyluracil. J. med. Chem. 15, 839–840 (1972).
Goldenberg, D. M.: Oral activity of 1-β-D-arabinofuranosyl cytosine in a transplantable hamster melanoma. Chemotherapy 16, 294–299 (1971).
Graham, F. L., Whitmore, G. F.: Studies in mouse L-cells on the incorporation of 1-β-D- arabinofuranosylcytosine into DNA and on inhibition of DNA polymerase by 1-β-D- arabinofuranosylcytosine-5’-triphosphate. Cancer Res. 30, 2636–2644 (1970a).
Graham, F.L., Whitmore,G.F.: The effect of 1-β-D-arabinofuranosylcytosine on growth, viability and DNA synthesis of mouse L-cells. Cancer Res. 30, 2627–2635 (1970b).
Gray, G. D., Nichol. R., Miokelson, M. M., Camiener, G. W., Gish, D. T., Kelly, R. C., Wech-Ter, W. J., Moxley, T. E., Neil, G. L.: Immunosuppressive, antiviral and antitumor activities of cytarabine derivatives. Biochem. Pharmacol. 21, 465–475 (1972).
Greenstein, J. P., Carter, C. E., Chalkley, H. W.: Enzymatic degradation of ribose-nucleic and desoxyribosenucleic acids with an addendum on the effect of nucleates on the heat stability of proteins. Cold Spr. Harb. Symp. Quant. Biol., 12, 64 (1947).
Grindey, G. B., Saslaw, L. D., Waravdekar, V. S.: Relationship of uracil derivatives to the metabolism of arabinosylcytosine (ara-C). Proc. Amer. Ass. Cancer Res. 8, 24 (1967).
Grindey, G. B., Saslaw, L. D., Waravdekar, V. S.: Effects of uracil derivatives on phosphorylation of arabinosylcytosine. Molec. Pharmacol. 4, 96–103 (1968).
Griswold, D. P., Jr., Simpson-Herren, L., Schabel, F. M., Jr.: Altered sensitivity of a hamster plasmacytoma to cytosine arabinoside (NSC-63878). Cancer Chemother. Rep. 54, 337 –346 (1970).
Hall, T. C., Levine, R.: Deamination of cytosine arabinoside by normal and malignant tissues. Proc. Amer. Ass. Cancer Res. 8, 24 (1967).
Hanka, L. J., Kuentzel, S. L., Neil, G. L.: Improved microbiological assay for cytosine arabinoside (NSC-63878). Cancer Chemother. Rep. 54, 393–397 (1970).
Hanze, A. R.: Nucleic acids. IV. The catalytic reduction of pyrimidine nucleosides (human liver deaminase inhibitors). J. Amer. chem. Soc. 89, 6720–6725 (1967).
Haus, E., Halberg, F., Scheving, L. E., Pauly, J. E., Cardoso, S., Kuhl, J. F. W., Sothern, R.B., Shiotsuka, R. N., Hwang, D. S.: Increased tolerance of leukemic mice to arabinosylcytosine with schedule adjusted to circadian system. Science 177, 80–82 (1972).
Heneen, W. K., Nichols, W. W.: Cell morphology of a human diploid cell strain (WI-38) after treatment with arabinosylcytosine. Cancer Res. 27, 242–250 (1967).
Heppner, G. H., Calabresi,P.: Suppression by cytosine arabinoside of serum-blocking factors of cell-mediated immunity to syngeneic transplants of mouse mammary tumors. J. nat. Cancer Inst. 48, 1161–1167 (1972).
Hirschman, S. Z., Fischinger, P. J., O’connor, T. E.: The inhibition by cytosine arabinoside of the replication of murine leukemia and sarcoma viruses in mouse embryo cultures. J. Cancer 4, 671–677 (1969).
Ho, D. H. W., Frei, E., ILL: Clinical pharmacology of 1 D-arabinofuranosyIcytosine. Clin. Pharmacol. Therap. 12, 944–954 (1971).
Ho, D. H. W., Freireioh, E. J.: Clinical pharmacology of arabinosylcytosine. In: Sartorelli, A. C., Johns, D. J. (Eds.): Handbook of experimental pharmacology, Vol. 38. Antineoplastic and immunosuppressive agents. Berlin-Heidelberg-New York: Springer 1975.
Hoshi, A., Kanzawa, F., Kuretani, K., Saneyoshi, M., Arai,Y.: 2,2’-o-Cyclocytidine, antitumor cytidine analog resistant to cytidine deaminase. Gann 02, 145–146 (1971).
Hunt, D. E., Pittillo, R. F.: Determination of certain antitumor agents in mouse blood by microbiologic assay. Cancer Res. 28, 1095–1109 (1968).
Hunter, J. H.: Transforming 1-β-D-xylofuranosyluracil nucleosides into 1-β-D-arabinofurano- syluracil nucleosides. U.S. Patent 3, 183, 226, May 11, 1965, in Chem. Abstr. 03, 16446g (1965).
Inagaki, A., Naeamura, T., Wakisaka, G.: Studies on the mechanism of action of 1- β -D- arabinofuranosy Icy tosine as an inhibitor of DNA synthesis in human leukemic leukocytes. Cancer Res. 29, 2169–2176 (1969).
Kanai, T., Kojima, T., Maruyama, O., Ichino, M.: Pyrimidine nucleosides. III. Reaction of cytidine or N-4-acetylcytidine with partially hydrolyzed phosphorous oxychloride. Chem. pharm. Bull. (Tokyo) 18, 2569–2570 (1970).
Kaplan, A. S., Brown, McK., Ben-Porat, T.: Effect of 1-β-D-arabinofuranosylcytosine on DNA synthesis I. In normal rabbit kidney cell cultures. Molec. Pharmacol. 4, 131–138 (1968).
Karnofsky, D. A., Lacon, C. R.: The effects of 1-β-D-arabinofuranosylcytosine on the developing chick embryo. Biochem. Pharmacol. 15, 1435–1442 (1966).
Karon, M., Henry, P., Weissman, S., Meyer, C.: The effect of 1-β-d-arabinofuranosyl cytosine on macromolecular synthesis in KB spinner cultures. Cancer Res. 26, 166–171 (1966).
Karon, M., Shirakawa,S.: The locus of action of 1-β-d-arabinofuranosylcytosine in the cell cycle. Cancer Res. 29, 687–696 (1969).
Kessel, D.: Transport and phosphorylation of cytosine arabinoside by normal and leukemic cells. Proc. Amer. Ass. Cancer Res. 8, 36 (1967).
Kessel,D.: Some observations on the phosphorylation of cytosine arabinoside. Molec. Pharmacol. 4, 402–410 (1968a).
Kessel,D.: Properties of deoxycytidine kinase partially purified from L1210 cells. J. biol. Chem. 243, 4739–4744 (1968b).
Kessel, D., Hall, T. C.: Transport and phosphorylation as factors in the antitumor action of cytosine arabinoside. Science 156, 1240–1241 (1967).
Kessel, D., Hall, T. C., Rosenthal, P.: Uptake and phosphorylation of cytosine arabinoside by normal and leukemic blood cells in vitro. Cancer Res. 29, 459–463 (1969).
Kessel, D., Hall, T. C., Wodinsky, I.: Transport and phosphorylation as factors in the antitumor action of cytosine arabinoside. Science 156, 1240–1241 (1967).
Kessel, D., Shttrin, S. B.: Transport of two non-metabolized nucleosides, deoxycytidine and cytosine arabinoside, in a sub-line of the L1210 murine leukemia. Biochim. biophys. Acta (Amst.) 163, 179–187 (1968).
Kihlman, B. A., Nichols, W. W., Levan, A.: The effect of deoxyadenosine and cytosine arabinoside on the chromosomes of human leukocytes in vitro. Hereditas 50, 139–143 (1963).
Kim, J. H., Eidinoff, M. L.: Action of 1-β-d-arabinofuranosylcytosine on the nucleic acid metabolism and viability of HeLa cells. Cancer Res. 25, 698–702 (1965).
Kim, J. H., Eidinoff, M. L., Fox, J. J.: Action of 1-β-D-arabinofuranosyl-5-fluorocytosine on the nucleic acid metabolism and viability of HeLa cells. Cancer Res. 26, 1661–1664 (1966).
Kimball, A. P., Bowman, B., Bush, P. S., Herriot, J., LePage, G. A.: Inhibitory effects of the arabinosides of 6-mercaptopurine and cytosine on purine and pyrimidine metabolism. Cancer Res. 26, 1337–1343 (1966).
Kimball. A. P., Wilson, M. J.: Inhibition of DNA polymerase by 1-β-D-arabinosylcytosine and reversal of inhibition by deoxycytidine-5’ -triphosphate. Proc. Soc. exptl. Biol. (N.Y.) 127, 429–432 (1968).
Kit, S., DeTorres, R. A., Dubbs, D. R.: Arabinofuranosylcytosine-induced stimulation of thymidine kinase and deoxycytidylic deaminase activities of mammalian cultures. Cancer Res. 26, 1859–1866 (1966).
Kline, I., Venditti, J. M., Tyrer, D. D.; Goldin, A.: Chemotherapy of leukemia L1210 in mice with 1-β-D-arabinofuranosylcytosine hydrochloride I. Influence of treatment schedules. Cancer Res. 26, 853–859 (1966).
Kozai, Y.. Sugino, Y.: Enzymatic phosphorylation of 1-β-D-arabinofuranosylcytosine. Cancer Res. 31, 1376–1382 (1971).
Kreis, W., Drahovsky, D., Borberg, H.: Characterization of protein and DNA in P815 cells sensitive and resistant to 1-β-d-arabinofuranosylcytosine. Cancer Res. 32, 696–701 (1972).
Larsson, A., Reichard, P.: Enzymatic synthesis of deoxyribonucleotides X. Reduction of purine ribonucleotides; allosteric behavior and substrate specificity of the enzyme system from Escherichia coli B. J. biol. Chem. 241, 2540–2549 (1966).
Lenaz, L., Sternberg, S. S., Philips, F. S.: Cytotoxic effects of 1-β-d-arabinofuranosy 1-5- fluorocytosine and of 1-β-d-arabinofuranosyIcytosine in proliferating tissues in mice. Cancer Res. 29, 1790–1798 (1969).
Livingston, R. B., Carter, S. K.: Cytosine arabinoside (NSC-63878)-clinical brochure. Cancer Chemother. Rep. 1, 179–205 (1968).
Loh, P. C., Soergel, M.: Macromolecular synthesis in cells infected with reovirus type 2 and the effect of ara-C. Nature (Lond.) 214, 622–623 (1967).
Mitchell, M. S., Wade, M. E., DeConti, R. C., Bertino, J. R., Calabresi, P.: Immunosuppressive effects of cytosine arabinoside and methotrexate in man. Ann. intern. Med. 70, 535 –547 (1969).
Momparler, R. L.: Kinetic and template studies with 1-β-d-arabinofuranosylcytosine 5’-tri- phosphate and mammalian deoxyribonucleic acid polymerase. Molec. Pharmacol. 8, 362–370 (1972).
Momparler, R. L., Chu, M. Y., Fischer, G. A.: Studies on a new mechanism of resistance of L5178Y murine leukemia cells to cytosine arabinoside. Biochim. biophys. Acta (Amst.) 161, 481–493 (1968).
Momparler, R. L., Fischer, G. A.: Mammalian deoxynucleoside kinases I. Deoxycytidine kinase: purification, properties, and kinetic studies with cytosine arabinoside. J. biol. Chem. 243, 4298–4304 (1968).
Momparler, R. L., Labitan, A., Rossi, M.: Enzymatic estimation and metabolism of 1-β-d- arabinofuranosylcytosine in man. Cancer Res. 32, 408–412 (1972).
Montgomery, J. A., Thomas, H. J.: Acyl derivatives of 1-β-D-arabinofuranosyl cytosine. J. med. Chem. 15, 116–118 (1972).
Moore, E. C., Cohen, S. S.: Effects of arabinonucleotides on ribonucleotide reduction by an enzyme system from rat tumor. J. biol. Chem. 242, 2116–2118 (1967).
Müller, W. E. G., Yamazak, Z. I., Sögtrop, H. H., Zahn, R. K.: Action of 1-β-D-arabinofuran-osylcytosine on mammalian tumor cells-2. Inhibition of mammalian and oncogenic viral polymerases. Europ. J. Cancer 8, 421–428 (1972).
Mulligan, L.T., Jr., Mellett, L. B.: Comparative metabolism of cytosine arabinoside and inhibition of deamination by tetrahydrouridine. Pharmacologist 10, 167 (1968).
Neil, G. L., Weley, P. F., Manak, R. C., Moxley, T. E.: Antitumor effect of 1-β-D-arabino-furanosylcytosine 5’-adamantoate (NSC-117614) in leukemic mice. Cancer Res. 30, 1047– 1054 (1970).
Nordenskjöld, B. A., Skoog, L., Brown, N. C., Reichard,P.: Deoxyribonucleotide pools and deoxyribonucleic acid synthesis in cultured mouse embryo cells. J. biol. Chem. 245, 5360 –5368 (1970).
Notari, R. E.: A mechanism for the hydrolytic deamination of cytosine arabinoside in aqueous buffer. J. pharm. Sci. 56, 804–809 (1967).
Notari, R. E., Chin, M. L., Wittebort,R.: Arabinosylcytosine stability in aqueous solutions: pH profile and shelflife predictions. J. pharm. Sci. 61, 1189–1196 (1972).
Nutter, R.L., Rapp, F.: The effect of cytosine arabinoside on virus production in various cells infected with herpes simplex virus types 1 and 2. Cancer Res. 33, 166–170 (1973).
Panzica,R.P., Robins, R.K., Townsend,L.B.: Synthesis and anticancer activity of cytosine arabinoside 3-N-oxide (ara-C 3-N-oxide). J. med. Chem. 14, 259 (1971).
Papac,R.J., Calabresi,P., Hollingsworth,J.W., Welch,A.D.: Effects of 1-0-D-arabino- furanosylcytosine hydrochloride on regenerating bone marrow. Cancer Res. 25, 1459–1462 (1965).
Papac, R. J., Creasey, W. A., Calabresi, P., Welch, A. D.: Clinical and pharmacological studies with 1-β-D-arabinofuranosylcytosine (cytosine arabinoside). Proc. Amer. Ass. Cancer Res. 6, 50 (1965).
Pearson, P. M., Kit, S., Dubbs, D. R.: Induction of dihydrofolate reductase by SV40 and polyoma virus. Cancer Res. 26, 1653–1660 (1966).
Peterkofsky, B., Tomkins, G. sM.: Effect of inhibitors of nucleic acid synthesis on steroid-mediated induction of tyrosine aminotransferase in hepatoma cell cultures. J. molec. Biol. 80, 49–61 (1967).
Pitillo, R. F., Hunt, D. E.: Cytosine arabinoside sensitivity in actinobolin-resistant Streptococcus fecalis: the basis of a utilitarian microbiological assay. Proc. Soc. exp. Biol. (N.Y.) 124, 636–640 (1967).
Pizer, L. I., Cohen, S. S.: Metabolism of pyrimidine arabinonucleotides and cyclonucleosides in Escherichia coli. J. biol. Chem. 235, 2387–2392 (1960).
Rama Reddy, G. V., Goulian, M., Hendler, S. S.: Inhibition of E. coli DNA polymerase II by ara CTP. Nature (Lond.) 234, 286–288 (1971).
Reichard, P., Cannalakis, Z. N., Cannalakis, E. S.: Studies on a possible regulatory mechanism for the biosynthesis of deoxyribonucleic acid. J. biol. Chem. 236, 2514–2519 (1961).
Renis, H. E., Johnson, H.G.: Inhibition of plaque formation of vaccinia virus by cytosine arabinoside hydrochloride. Bacterid. Proc. 140 (1962).
Ritter, E. J., Scott, W. J., Wilson, J. G.: Teratogenesis and inhibition of DNA synthesis induced in rat embryos by cytosine arabinoside. Teratology 4, 7–14 (1971).
Roberts, D. W., Hall,T. C., Rosenthal, D.: Sequential changes in biochemical parameters following cytosine arabinoside administration. Proc. Amer. Ass. Cancer Res. 9, 60 (1968).
Roberts, D.W., Loehr, E. V.: Methotrexate and cytosine arabinoside modulation of thymidyl- ate synthetase activity in CCRF-CEM cells. Cancer Res. 31, 457–462 (1971).
Roberts, W. K., Dekker, C. A.: A convenient synthesis of arabinosylcytosine (cytosine arabinoside). J. org. Chem. 32, 816–817 (1967).
Russell, D. H.: Effects of me thotrexate and cytosine arabinoside on polyamine metabolism in a mouse L1210 leukemia. Cancer Res. 32, 2459–2462 (1972).
Sartorelli, A. C., Creasey, W. A.: Cancer Chemotherapy. Ann. Rev. Pharmacol. 9, 51–72 (1969).
Sartorelli, A. C., Creasey,W. A.: Combination chemotherapy. In: Holland,J. F., Frei,E. III (Eds.): Cancer medicine, pp. 707–717. Philadelphia: Lea and Febiger 1973.
Schabel, F. M., Jr.: In vivo leukemia cell kill kinetics and “curability” in experimental systems. In: The proliferation and spread of neoplastic cells, pp. 379–408. Baltimore: Williams and Wilkins 1968.
Schmidt, G.: Über den fermentativen Abbau der Guanylsäure in der Kaninchenleber. Hoppe-Seyler Z. physiol. Chem. 208, 185–224 (1932).
Schochetman, G., Perry, R. P.: Early appearance of histone messenger RNA in polyribosomes of cultured L cells. J. molec. Biol. 63, 591–596 (1972).
Schrecker, A. W.: Metabolism of 1-β-D-arabinofuranosyIcytosine in leukemia L1210: nucleoside and nucleotide kinases in cell-free extracts. Cancer Res. 30, 632–641 (1970).
Schrecker, A. W., Goldin, A.: Antitumor effect and mode of action of 1-β-D-arabinofuranosyl-cytosine 5’-phosphate in leukemia L1210. Cancer Res. 28, 802–803 (1968).
Schrecker, A. W., Urshel, M. J.: Nucleoside kinases in leukemia L1210 and a subline resistant to arabinosylcytosine. Proc. Amer. Ass. Cancer Res. 8, 58 (1967).
Schrecker, A. W., Urshel,M.J.: Metabolism of 1-β-D-arabinofuranosylcytosine in leukemia L1210: studies with intact cells. Cancer Res. 28, 793–801 (1968).
Silagi, S.: Metabolism of 1-β-D-arabinof uranosylcy tosine in L cells. Cancer Res. 25, 1446–1453 (1965).
Skipper, H. E., Schabel, F. M., Jr., Mellett, L. B., Montgomery, J. A., Wilkoff, L. J., Lloyd, H. H., Brockman, R.W.: Implications of biochemical, cytokinetic, pharmacologic, and toxicologic relationships in the design of optimal therapeutic studies. Cancer Chemother. Rep. 54, 431–449 (1970).
Skipper, H. E., Schabel, F. M., Jr., Wilcox, W. S.: Experimental evaluation of potential anticancer agents. XXI. Scheduling of arabinosylcytosine to take advantage of its S-phase specificity against leukemia cells. Cancer Chemother. Rep. 51, 125–165 (1967).
Skoog, L., Nordenskjold, B.: Effects of hydroxyurea and 1-β-D-arabinof uranosylcytosine on deoxyribonucleotide pools in mouse embryo cells. Europ. J. Biochem. 19, 81–89 (1971).
Slechta, L.: Effect of arabonucleosides on growth and metabolism of E. coli. Fed. Proc. 20, 357 (1961).
Smith, C. G., Buskirk, H. H., Lummis, W. L.: Effect of arabinofuranosyluracil on the cytotoxicity of arabinofuranosylcytosine in PPLO-contaminated cell cultures. Proc. Amer. Ass. Cancer Res. 6, 60 (1965).
Smith, D. B., Chu, E. H. Y.: A genetic approach to the study of cytotoxicity and resistance of cultured Chinese hamster cells in the presence of cytosine arabinoside. Cancer Res. 32, 1651–1657 (1972).
Smrt, J.: Nucleic acid components and their analogues. C. Arabinof uranosyluracil and arabino-furanosylcytosine phosphates. Coll. Czech. Chem. Commun. 32, 3958–3965 (1967).
Steuart, C. D., Burke, P. J.: Cytidine deaminase and the development of resistance to arabinosylcytosine. Nature (Lond.) 233, 109–110 (1971).
Steuart, C. D., Burke, P. J., Owens, A. H., Jr.: Correlation of ara-C metabolism and clinical response in adult acute leukemia. Proc. Amer. Ass. Cancer Res. 12, 89 (1971).
Talley, R.W., O’bryan, R. M., Tucker, W. G., Loo, R. V.: Clinical pharmacology and human antitumor activity of cytosine arabinoside. Cancer 20, 809–816 (1967).
Talley, R., Vaitkevtcius, V.: Megaloblastosis produced by a cytosine antagonist, 1-β-D- arabinofuranosylcytosine, Blood 21, 352–362 (1963).
Temin, H. M.: Studies on carcinogenesis by avian sarcoma viruses. V. Requirement for new DNA synthesis and for cell division. J. Cell Physiol. 69, 53–64 (1967).
Tobey, R. A.: Effects of cytosine arabinoside, daunomycin, mithramycin, azacytidine, adriamycin, and camptothecin on mammalian cell cycle traverse. Cancer Res. 32, 2720–2725 (1972).
Tolman, R. L., Robins, R. K.: Synthesis of l-β-L-arabinof uranosylcy tosine, the enantiomer of cytosine arabinoside. J. med. Chem. 14, 1112 (1971).
Tono, H., Cohen, S. S.: The activity of nucleoside phosphorylase on 1-β-D-arabinosyluracil within Escherichia colu J. biol. Chem. 237, 1271–1282 (1962).
Tuominen, F. W., Kenney, F. T.: Inhibition of RNA-directed DNA polymerase from Rauscher leukemia virus by the 5’-triphosphate of cytosine arabinoside. Biochem. biophys. Res. Commun. 48, 1469–1475 (1972).
Tyrer, D. D., Kline, I., Venditti, J. M., Goldin, A.: Separate and sequential chemotherapy of mouse leukemia L1210 with 1-β-D-arabinof uranosylcy tosine hydrochloride and 1, 3-bis- (2-chloroethyl)nitrosourea. Cancer Res. 27, 873–879 (1967).
Uchida,K., Kreis,W., Hutchison, D. J.: Distribution of 1-β-D-arabinof uranosy Icy tosine (ara-C) and enzyme profiles of mice carrying ara-C-sensitive and -resistant P815 neoplasms. Proc. Amer. Ass. Cancer Res. 9, 72 (1968).
Underwood, G. E.: Activity of 1- β-D-arabinofuranosylcytosine hydrochloride against herpes simplex keratitis. Proc. Soc. exp. Biol. (N. Y.) III, 660–664 (1962).
Upjohn Company: Cytarabine (Cytosar). Clin. Pharmacol. Therap. 11, 155–160 (1970).
Verbin, R. S., Diluiso, G., Liang, H., Farber, E.: Synchronization of cell division in vivo through the combined use of cytosine arabinoside and colcemid. Cancer Res. 32, 1489–1495 (1972).
Walwick, E. R., Roberts, W. K., Dekker, C. A.: Cyclization during the phosphorylation of uridine and cytidine by polyphosphoric acid; a new route to the 02, 2’-cyclonucleosides. Proc. chem. Soc. 84 (1959).
Warner, D. T., Neil, G. L., Taylor, A. J., Weohter, W. J.: Nucleic acids. 13. 3’-0- and 2’-0- esters of 1 -β-D-arabinofuranosylcytosine as antileukemic and immunosuppressive agents. J. med. Chem. 15, 790–792 (1972).
Wempen, I., Miller, N., Falco, E. A., Fox, J. J.: Nucleosides XLVII. Synthesis of some N4- substituted derivatives of 1-β-D-arabinofuranosyl-cytosine and -5-fluorocytosine. J. med. Chem. 11, 144–148 (1968).
Wilkoff, L. J., Wilcox, W. S., Burdeshaw, J. A., Dixon, G. J., Dulmadge, E. A.: Effect of antimetabolites on kinetic behavior of proliferating cultured L1210 leukemia cells. J. nat. Cancer Inst. 89, 965–975 (1967).
Wodinsky, I., Kensler, C. J.: Activity of cytosine arabinoside (NSC-63878) in a spectrum of rodent tumors. Cancer Chemother. Rep. 47, 65–68 (1965).
Young, C.W., Hodas, S.: Acute effects of cytotoxic compounds on incorporation of precursors into DNA, UNA, and protein of HeLa cell monolayers. Biochem. Pharmacol. 14, 205–214 (1965).
Young, R. S. K., Fischer, G. A.: The action of arabinosylcytosine on synchronously growing populations of mammalian cells. Biochem. biophys. Res. Commun. 32, 23–29 (1968).
Zahn, R. K., Muller, W. E. G., Forster, W., Maidhof, A., Beyer, R.: Action of 1-β-D-arabino- furanosylcytosine on mammalian tumor cells-1. Incorporation into DNA. Europ. J. Cancer 8, 391–396 (1972).
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 1975 Springer-Verlag Berlin · Heidelberg
About this chapter
Cite this chapter
Creasey, W.A. (1975). Arabinosylcytosine. In: Sartorelli, A.C., Johns, D.G. (eds) Antineoplastic and Immunosuppressive Agents. Handbuch der experimentellen Pharmakologie / Handbook of Experimental Pharmacology, vol 38 / 2. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-65806-8_13
Download citation
DOI: https://doi.org/10.1007/978-3-642-65806-8_13
Publisher Name: Springer, Berlin, Heidelberg
Print ISBN: 978-3-642-65808-2
Online ISBN: 978-3-642-65806-8
eBook Packages: Springer Book Archive