Phase I clinical and pharmacokinetic study of orally administeredN 4-palmitoyl-1-β-d-arabinofuranosylcytosine
Tóm tắt
A phase I study ofN
4-palmitoyl-1-β-d-arabinofuranosylcytosine (PLAC) was conducted in 88 patients; 36 with solid tumors and 52 with hematological malignancies, using 2 different schedules. Schedule 1 employed a single oral administration and Schedule 2, 5-day consecutive daily oral administration. In Schedule 1, the daily dose was initiated with 1 mg kg−1 which was escalated up to 24 mg kg−1 according to the modified Fibonacci’s method. Side effects included nausea, vomiting and skin rashes, but myelosuppression was not seen within this dose range. In Schedule 2, the daily dose was started with 1 mg kg−1 which was escalated up to 24 mg kg−1. Major side effects were nausea, vomiting and amorexia, and mild myelosuppression was noted at 12 mg kg−1 or more. The dose-limiting toxicity was gastrointestinal toxicity, which appeared at 3.3 mg kg−1 or more and became frequent at 7 mg kg−1 or more. Pharmacokinetic study revealed that the plasma concentrations of PLAC and ara-C, obtained by the oral intake of 3.3 mg kg−1 or more of PLAC, were sufficient for these compounds to exert cytotoxic effects on various human leukemia cellsin vitro. Based on these observations and plausible mechanism of action of PLAC, further clinical study should be carried out in a treatment schedule of considerably prolonged administration period with 3.3–6 mg kg−1 day−1 of PLAC.
Tài liệu tham khảo
Chu M Y, Fischer G A: A proposed mechanism of action of 1-β-d-arabinofuranosylcytosine as an inhibitor of the growth of leukemic cells.Biochem Pharmac 11, 423 (1962).
Kim J H, Eidenoff L: Action of cytosine arabinoside on the nucleic acid metabolism and viability of HeLa cells.Fedn Proc 24, 331, (1965).
Ellison R R, Holland J F, Well M, Jacquillat C, Boiron M, Bernard J, Sawitsky A, Rosner F, Gussoff B, Silver R T, Karanas A, Cuttner J, Spurr C L, Hayes D M, Blom J, Leone L A, Haurani F, Kyle R, Hutchison J L, Forcier R J, Moon J H: Arabinosylcytosine, a useful agent in the treatment of acute leukemia in adults.Blood 32, 507 (1968).
Shimoyama M: Cytocidal action of anticancer agents: evaluation of the sensitivity of cultured animal and human cancer cells.Bibl Haemat 40, 711 (1975).
Akiyama M, Ohishi J, Shirai T, Akashi K, Yoshida K, Nishikido J, Hayashi H, Usubuchi Y, Nishimura D, Itoh H, Shibuya C, Ishida T: The synthesis of new derivatives of 1-β-d-arabinofuranosylcytosine.Chem Pharm Bull 26, 981 (1978).
Aoshima M, Tsukagoshi Y, Sakurai Y, Oh-ishi J, Ishida T, Kobayashi H: Antitumor activities of newly synthesizedN 4-acyl-1-β-d-arabinofuranosylcytosine.Cancer Res 36, 2726 (1976).
Aoshima M, Tsukagoshi S, Sakurai Y, Oh-ishi J, Ishida T, Kobayashi H:N 4-Behenoyl-1-β-d-arabinofuranosylcytosine, as a potential new antitumor agent.Cancer Res 37, 2481 (1977).
Asano T, Sugihara T, Mizuno M, Ohoka T, Toyoshima S: Studies on the biological fate of BH-AC.Proc Jap Cancer Ass 37th Ann Mtng Abstract No. 617, 167 (1978).
Kimura K, Ohno R, Amaki I, Hattori K, Hirota Y, Hoshino A, Ichimaru M, Ito M, Kimura I, Maekawa T, Masaoka T, Nakamura T, Ogawa M, Oguro M, Ohta K, Osamura S, Shimoyama M, Takaku F, Uzuka Y, Yamada K: Treatment of acute myelogenous leukemia in adults withN 4-behenoyl-1-β-d-arabinofuranosylcytosine.Cancer 56, 1913 (1985).
Hori K, Tsuruo T, Naganuma K, Tsukagoshi S, Sakurai Y: Antitumor effects and pharmacology of orally administeredN 4-palmitoyl-1-β-d-arabinofuranosylcytosine in mice.Cancer Res 44, 172 (1984).
Unpublished data, by Kagoshima University and Asahi Chemical Industry Co. Ltd.
Kanabayashi T, Hori K, Isaka H, Tsuruo T, Tsukagoshi S. Sakurai Y: Effect ofN 4-palmitoyl-ara-C (PLAC) on hematopoietic and gastro-intestinal systems in mouse and monkey.Proc Jap Cancer Ass 41st Ann Mtng Abstract No. 798, 238 (1982).
Carter D K: In Staquet M (ed):The Design of Clinical Trials in Cancer Therapy, p. 242. Brussels, Scientifiques Européenes (1972).
Miller A B, Hoogstraten B, Staquet M, Winkler A: Reporting results of cancer treatment.Cancer 47, 207 (1981).
Hanze A R: Nucleic acid IV The catalytic reduction of pyrimidine nucleosides (human liver deaminase inhibitors).J Am Chem Soc 89, 6720 (1967).
Shimada N, Ueda T, Yokoshima T, Ohishi J, Ohoka T: A sensitive and specific radioimmunoassay for 1-β-d-arabinofuranosylcytosine.Cancer Lett 24, 173 (1984).
Makino Y, Matsubara Y, Watanabe K, Hirobe M: The simultaneous determination of ara-U and ara-C, urinary metabolites ofN 4-behenoyl-1-β-d-arabinofuranosylcytosine by mass fragmentography.Yakugaku Zasshi 102, 49 (1982).
Frei E III, Bickers J N, Howlett J S, Lane M, Leary W V, and Talley R W: Dose schedule and antitumor studies of arabinosyl cytosine (NSC 63878)Cancer Res 29, 1325–1332 (1969).
Kimura K, Ohno R, Amaki I, Hattori K, Hirota Y, Hoshino A, Ichimaru M, Ito M, Kimura I, Maekawa T, Masaoka T, Nakamura T, Ogawa M, Oguro M, Ohta K, Osamura S, Simoyama M, Takaku F, Uzuka Y, Yamada K: Phase I Clinical and pharmacokinetic study ofN 4-behenoyl-1-β-d-arabinofuranosylcytosine.Med Oncol and Tumor Pharmacother 3, 15 (1986).
Ho D H W, Frei III E: Clinical Pharmacology of 1-β-d-arabinofuranosylcytosine.Clin Pharmac Ther 12, 944 (1971).
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 (1964).
Gray G D, Nichol F R, Mickelson M M, Camiener G W, Gish D T, Kelly G R, Wechter W J, Moxley T E, Neil G L: Immunosuppressive, antiviral and antitumor activities of cytarabine derivatives.Biochem Pharmac 21, 465 (1972).
Hoshi A, Kanzawa F, Kuretani K, Saneyoshi M, Arai Y: 2, 2′-O-Cyclocytidine, an antitumor, cytidine analogue resistant to cytidine deaminase.Gann 62, 145 (1971)
Tsuruo T, Iida H, Tsukagoshi S, Sakurai Y: Comparison of cytotoxic effect and cellular uptake of 1-β-d-arabinofuranosylcytosine and itsN 4-acyl derivatives, using cultured KB cells.Cancer Res 39, 1063 (1979).
Griffin J, Munroe D, Major P, Kufe D: Induction of differentiation of human myeloid leukemia cells by inhibitors of DNA synthesis.Exp Hemat 10, 774 (1982).
Sachs L: The differentiation of myeloid leukemia cells: new possibilities for therapy.Br J Hemat 40, 509 (1978).