The illudin derivative
MGI 114 (6-hydroxymethylacylfulvene or HMAF) is currently in phase II chemotherapeutic clinical trials for a variety of solid
tumors. The illudins were originally thought to be potentially useful agents for
myeloid leukemias, because hematopoietic
tumor cells were markedly sensitive whereas normal bone marrow progenitors were relatively resistant to the cytotoxic effects of illudins. Due to the marked preclinical efficacy of
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 xenograft. In addition, because of the reported synergistic cytotoxic activity between
MGI 114 and the
topoisomerase I inhibitor topotecan towards pediatric human tumor cell lines, we tested the activity of
MGI 114 and
topotecan combinations against HL60 cells in vitro and the HL60/MRI myelocytic xenograft. 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 properties in the HL60/MRI xenograft model which exceeds activity noted with other conventional agents (TGI > 70%). A marked therapeutic synergistic action was observed with
MGI 114 and
topotecan combinations of (1/2) MTD of each agent producing complete
tumor remission in 50% of animals, without development of excessive or additive toxicity in animals. These results support further in vitro and clinical investigation into both the anti-myeloid leukemic activity of
MGI-114, and the cooperative pharmacologic interaction noted between
MGI-114 and
topoisomerase I inhibitors.
Leukemia (2000) 14, 136-141.