title: Cellular accumulation determines the activity of three novel tricyclic platinum agents.
abstract: BACKGROUND
  Cisplatin (CDDP) is a very useful chemotherapeutic agent, but cellular resistance limits its efficacy in malignant glioma. In order to analyze and overcome this resistance, we synthesized three novel platinum compounds; aminoplatin, methylplatin and oxiplatin, using tricyclic DNA intercalating molecules as models.
  
  
  METHODS
  The novel compounds differ only in one chemical group, which is positioned opposite to the DNA binding site. DNA binding, cellular penetration, and cytotoxicity were compared in three human glioma cell lines (T98G, U87-MG, and U25 IN) and a human fibroblast cell strain (HS 68). 2
  
  
  RESULTS
  Binding to isolated DNA was most effective in aminoplatin, followed by methylplatin and oxiplatin. It differed by factors I. I, 0.35, 0.23, from the DNA binding of CDDP (factor I) for the three compounds, respectively. The cellular penetration, however, was fastest with oxiplatin (factor 10.1) followed by CDDP (1), aminoplatin (0.55), and methylplatin (0.27). The cytotoxicity of the three novel compounds followed the pattern of their cellular penetration with oxiplatin being the most active. U87-MG cells were resistant to CDDP, and in this cell line oxiplatin was more effective than CDDP in overcoming the resistance.
  
  
  CONCLUSIONS
  This indicates cellular penetration to be an important feature and the ketogroup of oxiplatin to be beneficial in tricyclic platinum compounds.
authors.affiliation: Division of Pediatric Oncology, University of Calgary, AB, Canada.
authors.forename: S B
authors.initials: SB
authors.lastname: Gangopadhyay
authors.forename: A
authors.initials: A
authors.lastname: Roendigs
authors.forename: S B
authors.initials: SB
authors.lastname: Kangarloo
authors.forename: B
authors.initials: B
authors.lastname: Krebs
authors.forename: J E
authors.initials: JE
authors.lastname: Wolff
mesh_terms: D000631:Aminopyridines / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001665:Binding Sites; D001932:Brain Neoplasms / Q000188:drug therapy; D002470:Cell Survival; D004247:DNA / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005347:Fibroblasts / Q000378:metabolism; D005910:Glioma / Q000188:drug therapy; D006801:Humans; D008956:Models, Chemical; D009944:Organoplatinum Compounds / Q000494:pharmacology; D010957:Plasmids / Q000378:metabolism; D017671:Platinum Compounds / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology; D013997:Time Factors; D014407:Tumor Cells, Cultured
chemical_list: D000631:Aminopyridines; D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D017671:Platinum Compounds; D011725:Pyridines; C433935:aminoplatin; C433936:methylplatin; C431073:oxiplatin; D004247:DNA