Anti-leukemic action of the novel agent MGI 114 (HMAF) and synergistic action with topotecan

The illudin derivative MGI 114 (6-hydroxymethylacylfulvene or HMAF) is curr ently in phase II chemotherapeutic clinical trials for a variety of solid t umors. The illudins were originally thought to be potentially useful agents for myeloid leukemias, because hematopoietic tumor cells were markedly sen sitive whereas normal bone marrow progenitors were relatively resistant to the cytotoxic effects of illudins. Due to the marked preclinical efficacy o f MGI 114 against a variety of solid tumor xenografts, the current phase II human trials are restricted to solid tumor (breast, lung, colon, ovarian, pancreas, prostate, etc) malignancies. The present studies were undertaken to evaluate the efficacy of MGI 114 in the HL60/MRI myeloid leukemia xenogr aft, In addition, because of the reported synergistic cytotoxic activity be tween MGI 114 and the topoisomerase I inhibitor topotecan towards pediatric human tumor cell lines, we tested the activity of MGI 114 and topotecan co mbinations against HL60 cells in vitro and the HL60/MRI myelocytic xenograf t. Our results indicate that MGI 114 at maximum tolerated doses (MTD) of 7 mg/kg, five times per week for 3 weeks does display anti-myeloid leukemic p roperties in the HL60/MRI xenograft model which exceeds activity noted with other conventional agents (TGI > 70%), A marked therapeutic synergistic ac tion was observed with MGI 114 and topotecan combinations of 1/2 MTD of eac h agent producing complete tumor remission in 50% of animals, without devel opment of excessive or additive toxicity in animals. These results support further in vitro and clinical investigation into both the anti-myeloid leuk emic activity of MGI-114, and the cooperative pharmacologic interaction not ed between MGI-114 and topoisomerase I inhibitors.