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Experimental Therapeutics

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

Leukemia volume 14, pages 136–141 (2000)Cite this article

Abstract

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 ½ 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.

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Acknowledgements

This work was supported by funds provided by the Cigarette and Tobacco Tax Fund of the State of California through the Tobacco-Related Disease Research Program of the University of California Award 7RT-0002 (MJK) and by funds provided by MGI PHARMA Co., Minnetonka, MN USA (TCM).

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Authors and Affiliations

  1. Department of Pathology, University of California, San Diego, CA, USA

    MJ Kelner, L Estes, KM Samson & NA Trani

  2. Department of Chemistry and Biochemistry, University of California, San Diego, CA, USA

    TC McMorris

  3. MGI PHARMA, Minneapolis, MN, USA

    JR MacDonald

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  1. MJ Kelner
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Kelner, M., McMorris, T., Estes, L. et al. Anti-leukemic action of the novel agent MGI 114 (HMAF) and synergistic action with topotecan. Leukemia 14, 136–141 (2000). https://doi.org/10.1038/sj.leu.2401611

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