Cytotoxic effects of histone deacetylase inhibitor FK228 (depsipeptide, formally named FR901228) in combination with conventional anti-leukemia/lymphoma agents against human leukemia/lymphoma cell lines

FK228 is a novel antitumor depsipeptide that inhibits histone deacetylases and restores the expression of genes aberrantly suppressed in cancer cells. This agent was shown to have broad antitumor activity in preclinical studies, and is currently under phase I/II evaluations. Because of its wide spectrum of actions, it is reasonable to consider the combination with other anticancer drugs in clinical application. We studied the cytotoxic interaction of FK228 in combination with conventional antileukemic agents using human promyelocytic leukemia HL60, Philadelphia chromosome-positive (Ph+) chronic myelogenous leukemia KU-812, T-cell lymphoblastic leukemia MOLT3 and Burkitt's lymphoma Raji cell lines. For the combination of FK228 and imatinib, Ph+ leukemia KU812, K562 and TCC-S cell lines were used. The cells were exposed simultaneously to FK228 and other agents for 4 days. Cell growth inhibition was determined by using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. We used the isobologram method of Steel and Peckham to evaluate the cytotoxic interaction at the concentration of drugs that produced 80% cell growth inhibition (IC80). FK228 showed an additive effect with cytarabine, carboplatin, doxorubicin, etoposide, 4-hydroperoxy-cyclophosphamide, 6-mercaptopurine and SN-38 (active metabolite of irinotecan) in all cell lines studied. FK228 with methotrexate and vincristine showed an antagonistic effect in three and one of the four cell lines, respectively. FK228 was additive with imatinib in all three Ph+ leukemia cells. Our findings suggest that FK228 is a promising candidate for combining with most anticancer agents except for methotrexate and vincristine, which produce suboptimal effects.