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Antitumor Effects and Pharmacology of Orally Administered N⁴-Palmitoyl-1-ß-D-arabinofuranosylcytosine in Mice¹

Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Toshima-ku, Tokyo 170, Japan

The antitumor activity and the pharmacological fate of N⁴-palmitoyl-1-ß-D-arabinofuranosylcytosine (N⁴-palmitoyl-ara-C) administered p.o. were examined in mice and were compared with those of the parent compound 1-ß-D-arabinofuranosylcytosine (ara-C). N⁴-Palmitoyl-ara-C administered p.o. showed chemotherapeutic effects superior to those of ara-C when used against P388 leukemia, L1210 leukemia, mammary adenocarcinoma 755, and colon 38 adenocarcinoma. The derivative also inhibited the spontaneous pulmonary metastasis of s.c.-inoculated Lewis lung carcinoma more efficiently than did ara-C. After a single p.o. injection of a suspension of N⁴-palmitoyl-[2-¹⁴C]ara-C at a therapeutic dose of 350 µmol/kg, a high concentration of the drug was found in the liver, lung, and plasma of portal venous blood. The level of the drug in other tissues and peripheral plasma was rather low. The two main metabolites, identified as ara-C and 1-ß-D-arabinofuranosyluracil, were found in plasma and various tissues. Plasma ara-C concentration was maintained for at least 6 hr in the range of 2.3 to 5.1 nmol/ml after p.o. administration of N⁴-palmitoyl-ara-C (350 µmol/kg). On the other hand, when an equimolar amount of ara-C was given, the plasma levels of the drug decreased rapidly; from 2 to 6 hr after administration, the level (1.0 to 4.1 nmol/ml) was less than that obtained with N⁴-palmitoyl-ara-C. These results suggested that N⁴-palmitoyl-ara-C administered p.o. is absorbed as an intact form from the gastrointestinal tract and that the absorbed compound is the depot form of ara-C, releasing ara-C over a prolonged period of time.

¹ This work was supported by Grant-in Aid (57-3) for Cancer Research from the Ministry of Health and Welfare, Japan.

² Research fellow from the Biological and Pharmacological Research Institute, Asahi Chemical Industry, Co., Ltd., Nobeoka, 882, Japan.

³ To whom requests for reprints should be addressed.

Received 11/18/82. Accepted 10/ 6/83.