Pharmacologic and Clinical Studies of N4-Behenoyl-1-Beta-D-Arabinofuranosylcytosine

  • Kazumasa Yamada
  • Kohei Kawashima
  • Yukio Kato
  • Yasuo Morishima
  • Mitsune Tanimoto
  • Ryuzo Ohno
Part of the Recent Results in Cancer Research book series (RECENTCANCER, volume 70)


Two metabolites of N4-behenoyl-1-β-D-arabinofuranosylcytosine (BH-AC) were found in the plasma and urine, and a hydrolytic product, arabinosylcytosine (ara-C) and its deaminated product, arabinosyluraci (ara-U), were found in a preclinical study using monkeys. Of a given dose, 96% was found as ara-U and 3% as ara-C in urine in 24 h. The plasma disappearance curve of BH-AC is biphasic; the half-life of the initial phase is 40 min and that of the second phase is 120 min. At 8 h the BH-AC level is 21.9 μg/ml and falls exponentially to 3.6 μg/ml by 12 h. Ara-C was detected at the levels of 0.4–0.6 μg/ml for 4 h. Comparative data of pharmacokinetic parameters among BH-AC, ara-C, and O2,2′-cyclocytidine showed that BH-AC had the longest plasma half-life, the smallest elimination-rate constant and the smallest excretion-rate constant. The plasma-clearance study of BH-AC in 13 patients showed essentially a pattern similar to that in monkeys; the plasma t1/2 of 60 min in the first phase and of 180 min in the second. The BH-AC level at 2 h is 15.4 μg/ml, and 1.8 μg/ml at 8 h.

Initial phase I study of BH-AC was evaluated in 14 patients with leukemia and other malignancies. The starting dose was 1.5 mg/kg given as a single IV infusion for 3. The doses were then escalated up to 5.0 mg/kg. No side effects were noted with a single dose schedule. Daily consecutive infusions of 2.0 mg/kg–6.0 mg/kg for 4–21 days resulted in two patients having nausea, two anorexia, and one developing skin eruptions. Significant hematologic effects were noted with the daily infusion. One patient with acute myeloblasts leukemia achieved complete remission with 5.0 mg/kg BH-AC given daily for 21 days.

Its pharmacologic features, minimal toxicity, and the capability of inducing complete remission in acute leukemia indicate that BH-AC undoubtedly deserves further prospective clinical trials.


Acute Lymphoblastic Leukemia Acute Leukemia Cytosine Arabinoside Acute Myeloblastic Leukemia Urinary Excretion Data 
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  1. 1.
    Aoshima, M., Tsukagoshi, S., Sakurai, Y., Ohishi, J., Ishida, T., Kobayashi, H.: Antitumor activities of newly synthesized N4-acyl-1-β-D-arabinofuranosylcytosine. Cancer Res., 36, 2726–2732 (1976)PubMedGoogle Scholar
  2. 2.
    Aoshima, M., Tsukagoshi, S., Sakurai, Y., Ohishi, J., Ishida, T., Kobayashi, H.: N4-Behenoyl-1-β-D-arabinofuranosylcytosine, as a potential new antitumor agent. Cancer Res., 37, 2481–2486 (1977)PubMedGoogle Scholar
  3. 3.
    Bodey, G. P., Freireieh, R. W., Nonto, R. W., Hewlet, J. S.: Cytosine arabinoside therapy for acute leukemia in adults. Cancer Chemother. Rep., 53, 59–66 (1969)PubMedGoogle Scholar
  4. 4.
    Ellison, R. R., Holland, J. F., Silver, R. T., Bernard, J., Boiron, M.: Cytosine arabinoside: A new drug for induction of remissions in acute leukemia. Abstract, 9th Int. Cancer Congr., p. 645, 1966Google Scholar
  5. 5.
    Ellison, R. R., et al.: Arabinosylcytosine, a useful agent in the treatment of acute leukemia in adults. Blood 32, 507–523 (1968)PubMedGoogle Scholar
  6. 6.
    Evans, J. S., Musser, E. A., Bostwick, J. L., Mengel, G. D.: The effect of 1-β- D-arabinofuranosylcytosine hydrochloride on murine neoplasms. Cancer Res., 24, 1285–1293 (1964)PubMedGoogle Scholar
  7. 7.
    Fox, J. J., Falco, E. A., Wempen, D., Pomeroy, M. D., Dowling, M. D., Burchenal, J. H.: Oral and parenteral activity of 2,2′-anhydro-1-β- D-arabinofuranosyl-5-fluorocytosine (AAFC) against both intraperitoneally and intracerebrally inoculated mouse leukemia. Cancer Res. 32, 2269–2272 (1972)PubMedGoogle Scholar
  8. 8.
    Gray, G. D., Nichol, F. R., Michalson, M. M.: Immunosuppressive antiviral and antitumor activities of cytarbine derivatives. Biochem. Pharmacol. 27, 466–475 (1972)Google Scholar
  9. 9.
    Henze, A. R.: Nucleic acids. IV. The catalytic reduction of pyrimidine nucleosides (human lever deaminase inhibitors). J. Am. Chem. Soc. 89, 6720–6725 (1967)CrossRefGoogle Scholar
  10. 10.
    Ho, D. H. W., Freireich, E. J.: Clinical pharmacology of 1-β- D-arabinofuranosylcytosine. Clin. Pharmacol. Ther. 12, 944–954 (1971)PubMedGoogle Scholar
  11. 11.
    Ho, D. H. W., Rodriguez, V., Loo, T., Bodey, G. P., Freireich, E. J.: Clinical pharmacology of O2, 2′-eycloeytidine. Clin. Pharmacol. Ther. 17, 66–72 (1974)Google Scholar
  12. 12.
    Hoshi, A., Kanazawa, F., Kuretani, K.: Antitumor activity of cyclocytidine in a variety of tumors. Gann 63, 353–360 (1972)PubMedGoogle Scholar
  13. 13.
    Mehta, B. M., Meyers, M. B., and Hutchison, D. J., et al.: Microbiological assay for cytosine arabinoside. Cancer Chemother. Rep. 59, 515–522 (1975)PubMedGoogle Scholar
  14. 14.
    Schein, P. S.: Preclinical toxicology of anticancer agents. Cancer Res. 37, 1934–1937 (1977)PubMedGoogle Scholar
  15. 15.
    Skipper, H. E., Schabel, F. M., Wilcox, W. S.: Experimental evaluation of potential anticancer agents. XIII. On the criteria and kinetics associated with ‘curability’ of experimental leukemia. Cancer Chemother. Rep. 35, 1–111 (1964)PubMedGoogle Scholar
  16. 16.
    Sugi, T., Shigetome, T.: Hypotensive effect in dogs of surface active agent contained in a preparation for injection. Fukuoka J. Med. 62, 335–338 (1971) (in Japanese)Google Scholar
  17. 17.
    Tajima, T., Shoji, T., Kaneko, T., Yamanaka, T., Ohgoh, T.: General pharmacological effects of Manquinon-4. Pharmacometrics 5, 489–604 (1971) (in Japanese)Google Scholar
  18. 18.
    Walwick, E. R., Drecker, C. A., Roberts, W. K.: Cyclization during the phosphorylation of uridine and cytidine by phosphoric acid; a new route to the 0–2–2′-cyclonueleodisdes. Proc. Chem. Soc. 84 (1959)Google Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 1980

Authors and Affiliations

  • Kazumasa Yamada
    • 1
  • Kohei Kawashima
    • 1
  • Yukio Kato
    • 1
  • Yasuo Morishima
    • 1
  • Mitsune Tanimoto
    • 1
  • Ryuzo Ohno
    • 1
  1. 1.First Department of Internal MedicineNagoya University School of MedicineShowa-ku, NagoyaJapan

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