title: Overcoming cisplatin resistance: design of novel hydrophobic platinum compounds.
abstract: BACKGROUND
  The anticancer activity of cisplatin derives from its ability to crosslink DNA. Cisplatin-resistance is partially caused by enhanced nucleotide excision repair (NER). Major 1,2-intrastrand crosslinks can create a hydrophobic notch at the damage site, which can be specifically bound by damage-recognition proteins, thus shielded from NER-activity. We aimed at preventing resistance by enhancing this mechanism using more hydrophobic platinum compounds.
  
  
  METHODS
  We synthesized three platinum analogs with increased hydrophobic characteristics. Performing MTT-assays, the efficacy of cisplatin and the novel agents was compared in a fibroblast and eight brain tumour cell lines.
  
  
  RESULTS
  Among the novel compounds, the most hydrophobic molecule, methylpyridineplatinum, was most cytotoxic (LC50 = 5.84 x 10(-5) M), followed by methylpyrazineplatinum, the second most hydrophobic (LC50 = 1.79 x 10(-4) M), and pyridineplatinum (LC50 = 2.76 x 10(-4) M). Overall, cisplatin revealed highest cytotoxicity (LC50 = 8.77 x 10(-6) M).
  
  
  CONCLUSIONS
  Comparison of the novel compounds supports the hypothesis that increased hydrophobicity contributes to higher antitumour-activity. Other advantageous characteristics of cisplatin might relate to its remaining highest efficacy.
authors.affiliation: Pediatric Oncology Program, Alberta Children's Hospital, University of Calgary, AB, Canada.
authors.forename: G
authors.initials: G
authors.lastname: Tallen
authors.forename: C
authors.initials: C
authors.lastname: Mock
authors.forename: S B
authors.initials: SB
authors.lastname: Gangopadhyay
authors.forename: B
authors.initials: B
authors.lastname: Kangarloo
authors.forename: B
authors.initials: B
authors.lastname: Krebs
authors.forename: J E
authors.initials: JE
authors.lastname: Wolff
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D001562:Benzimidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001932:Brain Neoplasms / Q000473:pathology; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D002945:Cisplatin / Q000737:chemistry / Q000494:pharmacology*; D003432:Cross-Linking Reagents / Q000138:chemical synthesis / Q000494:pharmacology*; D004260:DNA Repair / Q000235:genetics; D015195:Drug Design; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D004354:Drug Screening Assays, Antitumor; D005347:Fibroblasts / Q000187:drug effects; D005910:Glioma / Q000473:pathology; D006801:Humans; D008527:Medulloblastoma / Q000473:pathology; D015394:Molecular Structure; D009944:Organoplatinum Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D001562:Benzimidazoles; D003432:Cross-Linking Reagents; D009944:Organoplatinum Compounds; C407505:dichloro((1H-4,5--dimethylbenzimidazol-2-yl)pyrazine)platinum(II); C407504:dichloro((1H-4,5-dimethylbenzimidazol-2-yl)pyridine)platinum(II); C407506:dichloro((1H-benzimidazol-2-yl)pyridine)platinum(II); D002945:Cisplatin