Combined effects of differentiation-apoptosis inducers on mice inoculated with human leukemia cells.

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We have found that geranylgeraniol (GGO) is a potent inducer of apoptosis in various tumor cell lines including human myeloid leukemia, lymphoblastic, and adenocarcinoma. Upon treatment of HL-60 cells with 50 muM GGO, 85% of DNA was fragmented in 3 h. [^3H] GGO was taken up by HL-60 cells in 3 h and was incorporated into several proteins with molecular masses from 10.5 to 20.1 kDa, suggesting these proteins were geranylgeranylated. The expression of c-myc and bc1-2 decreased significantly within 3 h.To explore agents for differentiation-apoptosis therapy of leukemia, various combinations of differentiation-and apoptosis-inducers were examined for the strongest apoptosis-inducing activity for human HL-60 cells. The strongest apotosis-inducing acitvity on HL-60 cells were obtained by combining with retinoic acid, bufalin, and VP16. Administration of the combination of retinoic acid, bufalin, and VP16 to mice inoculated with HL-60 cells was makedly effective in prolongation of survival.