Characterization of acylfulvene histiospecific toxicity in human tumor cell lines

Cancer Chemotherapy and Pharmacology
M J KelnerR Taetle

Abstract

Acylfulvene derivatives demonstrate marked efficacy in xenograft carcinoma models as compared with the parent illudin compounds. To elucidate the increased therapeutic efficacy of acylfulvene analogs, we compared them with the illudin compounds in terms of their in vitro cytotoxicity, cellular accumulation and DNA incorporation. The cytotoxicity of various acylfulvene analogs was tested in vitro against a variety of tumor cell lines. Radiolabelled acylfulvene analog was prepared and used for cellular accumulation and DNA incorporation studies. The prototype acylfulvene analog retained selective histiospecific toxicity towards myeloid leukemia and various carcinoma cell lines. In vitro killing of tumor cells by acylfulvene required up to a 30-fold increase in molecules per cell, as compared with illudin S, indicating that acylfulvene was less toxic on a cellular level. At equitoxic concentrations, acylfulvene incorporation into genomic tumor cell DNA was equivalent to illudin S suggesting that cellular metabolism has a role in acylfulvene cytotoxicity. Analysis of cellular accumulation of acylfulvene into tumor cells revealed a markedly higher Vmax for tumor cells, and a lower Vd for diffusion accumulation into other cells. The ...Continue Reading

Citations

Sep 24, 2011·Chemical Research in Toxicology·Kathryn E PietschShana J Sturla
Dec 12, 2012·Chemical Research in Toxicology·Kathryn E PietschShana J Sturla
Apr 2, 2019·Analytical Sciences : the International Journal of the Japan Society for Analytical Chemistry·Yuki UtoKoichi Inoue
Sep 5, 2014·Journal of Cellular Biochemistry·Young-Tae JuSoon-Chan Hong
Dec 2, 2000·Cell Proliferation·K HelmbrechtL Rensing
Jul 28, 1999·Biochemical Pharmacology·M C HerzigJ M Woynarowski
Apr 10, 2012·Chemical Reviews·Marina Tanasova, Shana J Sturla

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