Oral antitumour activity in murine L1210 leukaemia and pharmacological properties of liposome formulations ofN 4-alkyl derivatives of 1-?-d-arabinofuranosylcytosine

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Abstract
The oral cytostatic activity in L1210 mouse leukaemia of the two newN 4-alkyl derivatives of 1-β-d-arabinofuranosylcytosine (AraC),N 4-hexadecyl- andN 4-octadecyl-1-β-d-arabinofuranosylcytosine (NH- AraC, NO-AraC) was investigated. In contrast to AraC, both derivatives were highly cytostatic after oral application as liposome formulations. With treatment schedules of five consecutive dosages or with two applications on days 1 and 4 after intravenous tumour cell inoculation with a total dose of 470–1000 mg/kg NH- AraC or NO-AraC, 70%–100% of the treated animals were cured. The lethal dose in healthy ICR mice after a single intraperitoneal application, corresponding to the LD50, was 524 mg/kg for NO-AraC, whereas NH- AraC proved to be less toxic. The haematological toxicity. remained moderate for both drugs with a mild leucopenia and a drop in platelet counts, which recovered 4–6 days after treatment. The erythrocytes were not affected and haemolytic toxicities were absent. As non-haematological toxicities, at high drug concentrations, a pronounced atrophy of the rapidly dividing epithelia of the small intestines and of the white pulp of the spleen were observed. The blood levels of NH-AraC given orally reached values comparable to those after parenteral application of a four-times lower dose of NH-AraC, suggesting a moderate bioavailability. Thus, these two lipophilic derivatives of AraC are compounds with a potential for the oral treatment of malignant diseases.

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