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Combined effect of N-[4-(5-bromo-2-pyrimidinyloxy)-3-chlorophenyl]-N'-(2-nitrobenzoyl ) urea, HO-221, with various antitumor agents was studied using L 1210 leukemia in vivo and in vitro. Ten anticancer drugs were chosen from alkylating agents, antitumor antibiotics, antimetabolites and plant alkaloids each. The combined effect was assessed by comparing ILS (increase of life span) in the combined group with the sum of ILS of each single agent. Synergistic effect was considered to exist if ILS of the combination-treatment group exceeds the sum of those in 2 single-treatment groups. The two-drug combination of HO-221 with cyclophosphamide (CPA), adriamycin (ADM), mitomycin C (MMC), vindesine (VDS), vincristine (VCR) or etoposide showed remarkable synergistic effects with 60-days survivors. However, the combination chemotherapy with antimetabolites, 5-fluorouracil (5-FU) and methotrexate (MTX) showed competitive effects. Moreover, the synergistic cytocidal effect in vitro by the clonogenic assay was observed in combination of HO-221 with the same drug using in vivo test. The present results indicate that HO-221 seems to be a useful antitumor agent in combination chemotherapy.
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