• M J Kelner, T C McMorris, M A Montoya, L Estes, S F Uglik, M Rutherford, K M Samson, R D Bagnell, and R Taetle.
• Department of Pathology, UCSD Medical Center, San Diego, CA 92103, USA. mkelner@ucsd.edu
• Cancer Chemother. Pharmacol. 1999 Jan 1; 44 (3): 235-40.

PurposeThe acylfulvenes are a class of antitumor agents derived from the fungal toxin illudin S. One acylfulvene derivative, MGI 114 (HMAF), demonstrates marked efficacy in xenograft carcinoma models when compared to the parent acylfulvene or related illudin compounds. The maximum tolerated dose (MTD) of the two analogs in animals, however, is similar. To help elucidate the basis of the increased therapeutic efficacy of MGI 114, we determined the in vitro cytotoxicity, cellular accumulation and DNA incorporation of this drug and compared the results with those from the parent acylfulvene analog.MethodsThe cytotoxicity of acylfulvene analogs was tested in vitro against a variety of tumor cell lines. Radiolabeled MGI 114 was used for cellular accumulation and DNA incorporation studies.ResultsMGI 114 retained relative histiospecific toxicity towards myeloid leukemia and various carcinoma cell lines previously noted with the parent acylfulvene compound. Markedly fewer intracellular molecules of MGI 114 were required to kill human tumor cells in vitro as compared to the parent acylfulvene, indicating that MGI 114 was markedly more toxic on a cellular level. At equitoxic concentrations, however, the incorporation of MGI 114 into genomic tumor cell DNA was equivalent to that of acylfulvene. Analysis of cellular accumulation of MGI 114 into tumor cells revealed a lower Vmax for tumor cells, and a markedly lower Vd for diffusion accumulation as compared to acylfulvene.ConclusionsThe addition of a single methylhydroxyl group to acylfulvene to produce MGI 114 results in a marked increase in cytotoxicity in vitro towards tumor cells as demonstrated by the reduction in IC50 values. There was a corresponding decrease in the number of intracellular molecules of MGI 114 required to kill tumor cells, but no quantitative alteration in covalent binding of the drugs to DNA at equitoxic concentrations. This indicates that cellular metabolism plays a role in the in vitro cytotoxicity of MGI 114. The equivalent incorporation into genomic DNA at equitoxic doses suggests that DNA damage produced by acylfulvene and MGI 114 is equivalent in regard to cellular toxicity and ability to repair DNA. This increased cellular toxicity, together with the decrease in diffusion rate, may explain the increased therapeutic efficacy of MGI 114 as compared to the parent acylfulvene analog.

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