Cytocidal effect and DNA damage of nedaplatin in vitro by simulating pharmacokinetic parameters

K. Kawanishi, Y. Miyagi, J. Yamamoto, Y. Miyagi, Keiichiro Nakamura, J. Kodama, A. Hongo, M. Yoshinouchi, T. Kudo

Research output: Contribution to journalArticle

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Abstract

Purpose: 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: T1/2α 1.20 h and T1/2β 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. Conclusion: 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.

Original languageEnglish
Pages (from-to)303-308
Number of pages6
JournalCancer Chemotherapy and Pharmacology
Volume47
Issue number4
DOIs
Publication statusPublished - 2001

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Pharmacokinetics
DNA Damage
Area Under Curve
Pharmacodynamics
DNA
Cells
Pharmaceutical Preparations
Crosslinking
Assays
nedaplatin
In Vitro Techniques
Platinum
Serum
Antineoplastic Agents
Ovarian Neoplasms
Cell Survival
Cell Cycle

Keywords

  • 254-S
  • AUC
  • Crosslink
  • DNA
  • Nedaplatin
  • Simulation

ASJC Scopus subject areas

  • Cancer Research
  • Pharmacology
  • Oncology

Cite this

Cytocidal effect and DNA damage of nedaplatin in vitro by simulating pharmacokinetic parameters. / Kawanishi, K.; Miyagi, Y.; Yamamoto, J.; Miyagi, Y.; Nakamura, Keiichiro; Kodama, J.; Hongo, A.; Yoshinouchi, M.; Kudo, T.

In: Cancer Chemotherapy and Pharmacology, Vol. 47, No. 4, 2001, p. 303-308.

Research output: Contribution to journalArticle

Kawanishi, K, Miyagi, Y, Yamamoto, J, Miyagi, Y, Nakamura, K, Kodama, J, Hongo, A, Yoshinouchi, M & Kudo, T 2001, 'Cytocidal effect and DNA damage of nedaplatin in vitro by simulating pharmacokinetic parameters', Cancer Chemotherapy and Pharmacology, vol. 47, no. 4, pp. 303-308. https://doi.org/10.1007/s002800000238
Kawanishi, K. ; Miyagi, Y. ; Yamamoto, J. ; Miyagi, Y. ; Nakamura, Keiichiro ; Kodama, J. ; Hongo, A. ; Yoshinouchi, M. ; Kudo, T. / Cytocidal effect and DNA damage of nedaplatin in vitro by simulating pharmacokinetic parameters. In: Cancer Chemotherapy and Pharmacology. 2001 ; Vol. 47, No. 4. pp. 303-308.
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AU - Miyagi, Y.

AU - Yamamoto, J.

AU - Miyagi, Y.

AU - Nakamura, Keiichiro

AU - Kodama, J.

AU - Hongo, A.

AU - Yoshinouchi, M.

AU - Kudo, T.

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N2 - Purpose: 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: T1/2α 1.20 h and T1/2β 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. Conclusion: 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.

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