Characterization of acylfulvene histiospecific toxicity in human tumor cell lines

• Published in: Cancer chemotherapy and pharmacology Vol. 41; no. 3; pp. 237 - 242
• Main Authors: KELNER, M. J, MCMORRIS, T. C, MONTOYA, M. A, ESTES, L, UGLIK, S. F, RUTHERFORD, M, SAMSON, K. M, BAGNELL, R. D, TAETLE, R
• Format: Journal Article
• Language: English
• Published: Berlin Springer 1998
• Subjects: Antibiotics, Antineoplastic - metabolism; Antibiotics, Antineoplastic - pharmacology; Antineoplastic agents; Biological and medical sciences; Chemotherapy; Humans; Medical sciences; Pharmacology. Drug treatments; Sesquiterpenes - metabolism; Sesquiterpenes - pharmacology; Spiro Compounds - metabolism; Spiro Compounds - pharmacology; Structure-Activity Relationship; Tumor Cells, Cultured - drug effects; Tumor Cells, Cultured - metabolism; Fungi; Antineoplastic agent; Terpenoid; Sesquiterpenes; Established cell line; Plant origin; Basidiomycetes; Cytotoxicity; In vitro; Tumor cell; Thallophyta
• ISSN: 0344-5704; 1432-0843

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 combination of higher Vmax and lower Vd may explain the increased in vivo efficacy of acylfulvene.