title: Rational design of platinum chemotherapeutic drugs: hydrophobicity increases cytotoxicity.
abstract: BACKGROUND
  Malignant glioma are often resistant to cisplatin. Numerous chemical modifications have been made to overcome this limitation. Analyzing such novel compounds, we previously hypothesized, that hydrophobicity improves the cytotoxicity of NH3 substituted platinum agents.
  
  
  METHODS
  Testing this hypothesis, we synthesized further eight novel platinum agents, substituting the NH3 groups with various pyridyl ring systems. The cytotoxicity was measured in MTT tests using the cisplatin resistant human U25 1 malignant glioma cell line as a model. Solubility was measured in water using flameless atomic absorption spectroscopy.
  
  
  RESULTS
  Cytotoxicity correlated significantly with low water solubility. The relation of cells surviving 72-hours of 1 OuM drug exposure was best described by a logarithmic formula: Surviving cells (% of control) = 6.4 + 38.4 log (water solubility in mg Pt/L) Adding an oximgroup to the aromatic substitute decreased cytotoxicity.
  
  
  CONCLUSIONS
  These data confirmed that increased hydophobicity increases cytotoxicity in this group. This might be caused by better cellular penetration, or by shielding of DNA-adducts from repair processes. The data created a further hypothesis: A positive mesomeric effect as characteristic for the oxim-group might decrease DNA binding, a negative mesomeric might improve it.
authors.affiliation: Cancer Biology Research Group, University of Calgary, Faculty of Medicine, 3330 Hospital Drive NW, Calgary AB, T2N 4N1, Canada.
authors.forename: N
authors.initials: N
authors.lastname: Moeller
authors.forename: B S
authors.initials: BS
authors.lastname: Kangarloo
authors.forename: I
authors.initials: I
authors.lastname: Puscasu
authors.forename: C
authors.initials: C
authors.lastname: Mock
authors.forename: B
authors.initials: B
authors.lastname: Krebs
authors.forename: J E
authors.initials: JE
authors.lastname: Wolff
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology; D002470:Cell Survival; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008970:Molecular Weight; D017671:Platinum Compounds / Q000737:chemistry* / Q000494:pharmacology; D012995:Solubility; D014407:Tumor Cells, Cultured / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D017671:Platinum Compounds