title: Characterization of acylfulvene histiospecific toxicity in human tumor cell lines.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  The combination of higher Vmax and lower Vd may explain the increased in vivo efficacy of acylfulvene.
authors.affiliation: Department of Pathology, UCSD Medical Center, San Diego, CA 92103, USA. mkelner@ucsd.edu
authors.forename: M J
authors.initials: MJ
authors.lastname: Kelner
authors.forename: T C
authors.initials: TC
authors.lastname: McMorris
authors.forename: M A
authors.initials: MA
authors.lastname: Montoya
authors.forename: L
authors.initials: L
authors.lastname: Estes
authors.forename: S F
authors.initials: SF
authors.lastname: Uglik
authors.forename: M
authors.initials: M
authors.lastname: Rutherford
authors.forename: K M
authors.initials: KM
authors.lastname: Samson
authors.forename: R D
authors.initials: RD
authors.lastname: Bagnell
authors.forename: R
authors.initials: R
authors.lastname: Taetle
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D000081223:Polycyclic Sesquiterpenes; D012717:Sesquiterpenes / Q000378:metabolism / Q000494:pharmacology*; D013141:Spiro Compounds / Q000378:metabolism / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured / Q000187:drug effects* / Q000378:metabolism
chemical_list: D000903:Antibiotics, Antineoplastic; D000081223:Polycyclic Sesquiterpenes; D012717:Sesquiterpenes; D013141:Spiro Compounds; C079422:acylfulvene; C008105:illudin S