Lymph node metastasis and effects of 1-beta-D-arabinofuranosylcytosine, 5-fluorouracil, and their lipophilic derivatives in an experimental model system using P388 leukemia.

Mouse P388 leukemic cells inoculated into the right forefootpad metastasized primarily to the right axillary lymph node. No significant metastasis to other lymph nodes or organs was detected on Day 12 after the inoculation of 10(6) P388 cells in the forefootpad, except that a lesser extent of metastasis was observed in some cases in the right inguinal lymph node, liver, and spleen. A quantitative estimation of metastasis in the axillary lymph node was accomplished by transferring the lymph node i.p. to the recipient mice (bioassay method). The metastasis of P388 cells to the axillary lymph node occurred linearly depending on the elapse of time after inoculation. In studying the chemotherapeutic effect on lymph node metastasis, two experimental models were established. Model 1, 10(6) P388 cells were inoculated into the right forefootpad, and drug was administered thereafter. The right axillary lymph node was removed on Day 8, and the extent of inhibition of lymph node metastasis was estimated by the bioassay method. In Model 2, P388 cells were inoculated, and the right forelimb including original tumor was amputated on Day 6 when the metastasis had already been established. The drug was given thereafter, and the extent of inhibition of metastasis was estimated on Day 12 by the bioassay method. In this experimental system, a lipophilic derivative N4-behenoyl-1-beta-D-arabinofuranosylcytosine was more effective than its parent compound 1-beta-D-arabinofuranosylcytosine; however, 5-fluorouracil was found to be more potent than its lipophilic derivative ftorafur for the inhibition of lymph node metastasis, suggesting an existence of various pharmacokinetic factors for the inhibition of lymph node metastasis.