Treatment of murine L1210 lymphoid leukemia and melanoma B16 with lipophilic cytosine arabinoside prodrugs incorporated into unilamellar liposomes
✍ Scribed by W. Rubas; A. Supersaxo; H. G. Weder; H. R. Hartmann; H. Hengartner; H. Schott; R. Schwendener
- Publisher
- John Wiley and Sons
- Year
- 1986
- Tongue
- French
- Weight
- 661 KB
- Volume
- 37
- Category
- Article
- ISSN
- 0020-7136
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✦ Synopsis
Lipophilic prodrugs of I-P-D-arabinofuranosyl cytosine (Ara-C), namely N4-and 5'-oleyl-I -P-D-arabinofuranosyl cytosine (N4-oleyl-ara-C, 5'-oleyl-ara-C) and N4palmitoyl-I-P-D-arabinofuranosyl cytosine (N4-palmara-C) were incorporated into liposomes of various lipid compositions. The phospholipid vesicles were prepared by controlled dialysis of lipid/prodrug/detergent micelles yielding homogeneous and stable unilamellar liposomes. The liposome size ranged from 70 to I20 nm depending on the lipid composition and the amounts of prodrug incorporated. Depending on the total amount of micellized Ara-C prodrugs, a maximal incorporation rate of 250 pg prodrug per mg egg phosphatidylcholine was achieved. The incorporation efficiency was in the ran e of 85 to 97%. The in vivo antitumor activity o f the liposome preparations against LIZ10 lymphoid leukemia was clearly superior by factors of 2-8 depending on the therapy schedule and route of drug application. The treatment of melanoma B16 with free Ara-C as well as with the prodrug-liposornes exhibit rather weak antitumor activity. Drug application by means of prodrug-liposomes yields equal or higher tumor-inhibitory effects at drug concentrations which were 2 -4 times lower than those of free Ara-C. Although drug tolerance and myelosuppression studies with Swiss albino mice revealed that the prodrug-liposomes were 5-10 times more toxic than free Ara-C, a substantial improvement of efficiency could be observed. The incorporation of the ara-C prodrugs into liposomes provides protection against fast degradation and systemic elimination which might be an explanation for the im- proved antitumor effect of these preparations.
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