title: Cytocidal effect and DNA damage of nedaplatin in vitro by simulating pharmacokinetic parameters.
abstract: OBJECTIVE
  The pharmacodynamic effects of cis-diammine(glycolato)platinum (nedaplatin, 254-S) in vitro have been reported, but the dosage and exposure time in vitro have not always been based on clinical observations of the drug's actions in vivo. Regardless of the actual exposure conditions used, the effect of cell-cycle nonspecific anticancer agents such as nedaplatin is believed to depend on the area under the drug concentration-time curve (AUC). In this study, we evaluated the pharmacodynamics of nedaplatin in vitro, especially in relation to its AUC dependency, in terms of cell survival and DNA crosslinking.
  
  
  METHODS
  BG-1 human ovarian cancer cells were treated with various concentrations of nedaplatin to simulate the pharmacokinetics of administration in a clinical setting. The BG-1 cells were exposed to nedaplatin dissolved in medium containing serum using constant concentration conditions, either high (maximum 7.69 mg/l) or low (average 1.33 mg/l). These concentrations were based on doses used in clinical studies. We then adjusted the exposure conditions in vitro to simulate the elimination of the drug from serum in vivo as follows: T1/2 alpha 1.20 h and T1/2 beta 2.70 h. The AUC values were set at 4, 8, 16, 25 and 40 mg.h/l for all exposure conditions. A colony-formation assay for the surviving fraction and an alkaline-elution assay for DNA crosslink measurement were done for the pharmacodynamic evaluation with comparison on the basis of the AUC value.
  
  
  RESULTS
  Exposure to a low concentration for a long time was the most effective of the exposure conditions at the same AUC value. The greater the AUC value, the higher the crosslink index under all exposure conditions. This index tended to increase particularly after exposure to the low concentration. The natural logarithm of the surviving fraction (Y') was a linear function of the crosslink index regardless of the drug-exposure condition: ln(Y') = -87.2x + ln(5.79), R2 = 0.89. The threshold cytocidal effect was associated with a crosslink index of 0.02.
  
  
  CONCLUSIONS
  There was a strong correlation between the cytocidal effect of nedaplatin and DNA crosslink formation. The cytocidal effect and DNA crosslinking in vitro depended on the exposure conditions used to define the AUC. Therefore, a new pharmacokinetic-pharmacodynamic model for nedaplatin must be constructed to investigate the most effective administration procedure in vivo.
authors.affiliation: Department of Obstetrics and Gynecology, Okayama University Medical School, Shikata-cho 2-5-1, Okayama City, Okayama 700-8558, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Kawanishi
authors.forename: Y
authors.initials: Y
authors.lastname: Miyagi
authors.forename: J
authors.initials: J
authors.lastname: Yamamoto
authors.forename: Y
authors.initials: Y
authors.lastname: Miyagi
authors.forename: K
authors.initials: K
authors.lastname: Nakamura
authors.forename: J
authors.initials: J
authors.lastname: Kodama
authors.forename: A
authors.initials: A
authors.lastname: Hongo
authors.forename: M
authors.initials: M
authors.lastname: Yoshinouchi
authors.forename: T
authors.initials: T
authors.lastname: Kudo
mesh_terms: D000970:Antineoplastic Agents / Q000493:pharmacokinetics* / Q000494:pharmacology*; D019540:Area Under Curve; D002470:Cell Survival / Q000187:drug effects; D003114:Colony-Forming Units Assay; D003432:Cross-Linking Reagents / Q000494:pharmacology; D003470:Culture Media; D004249:DNA Damage / Q000187:drug effects*; D004273:DNA, Neoplasm / Q000187:drug effects / Q000378:metabolism; D005260:Female; D006207:Half-Life; D006801:Humans; D009944:Organoplatinum Compounds / Q000493:pharmacokinetics* / Q000494:pharmacology*; D010051:Ovarian Neoplasms / Q000473:pathology; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D003432:Cross-Linking Reagents; D003470:Culture Media; D004273:DNA, Neoplasm; D009944:Organoplatinum Compounds; C053989:nedaplatin