title: Interaction of dacarbazine and imexon, in vitro and in vivo, in human A375 melanoma cells.
abstract: OBJECTIVE
  We evaluated mechanisms of interaction between the alkyating agent dacarbazine (DTIC) and the pro-oxidant, imexon, in the human A375 melanoma cell line.
  
  
  METHODS
  The effect of DTIC and imexon, alone and in combination, was evaluated for growth inhibition (MTT), radiolabeled drug uptake, cellular thiol content (HPLC), and DNA strand breaks (Comet assay). Pharmacokinetic and antitumor effects were evaluated in mice.
  
  
  RESULTS
  Growth inhibition in vitro was additive with the two drugs. There was no effect on drug uptake or on the number of DNA strand breaks. There was a >75% reduction in cellular glutathione and cysteine with imexon but not DTIC. Co-administration of the two drugs in mice caused an increase in the area under the curve of both drugs, but the combination was not effective in reducing human A375 melanoma tumors in vivo.
  
  
  CONCLUSIONS
  Imexon and dacarbazine show additive effects in vitro but not in vivo in human A375 melanoma cells.
authors.affiliation: College of Medicine, Arizona Cancer Center, University of Arizona, Tucson, AZ 85724-5024, USA.
authors.forename: Betty K
authors.initials: BK
authors.lastname: Samulitis
authors.forename: Robert T
authors.initials: RT
authors.lastname: Dorr
authors.forename: H-H Sherry
authors.initials: HH
authors.lastname: Chow
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D019540:Area Under Curve; D045744:Cell Line, Tumor; D020552:Comet Assay; D003606:Dacarbazine / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D004347:Drug Interactions; D004354:Drug Screening Assays, Antitumor; D006588:Hexanones / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008545:Melanoma / Q000473:pathology*; D051379:Mice; D016513:Mice, SCID
chemical_list: D000970:Antineoplastic Agents; D006588:Hexanones; C014919:4-imino-1,3-diazabicyclo(3.1.0)hexan-2-one; D003606:Dacarbazine