Schedule-dependent pharmacodynamic effects of gemcitabine and cisplatin in mice bearing Lewis lung murine non-small cell lung tumours

C. J A Van Moorsel, H. M. Pinedo, K. Smid, E. M. Comijn, D. A. Voorn, G. Veerman, B. Lakerveld, W. J F Van der Vijgh, G. Giaccone, P. E. Postmus, G. J. Peters

Research output: Contribution to journalArticle

Abstract

The combination of 2',2'-difluorodeoxycytidine (gemcitabine, dFdC) and cis-diammine-dichloroplatinum(II) (cisplatin, CDDP) is increasingly applied in clinical oncology. We studied the underlying mechanisms of the in vivo schedule dependency and supra-additive interaction between dFdC and CDDP in C57/Bl6 mice bearing Lewis lung (LL) tumours. Mice were treated with CDDP (6 mg/kg) and dFdC (60 mg/kg) either simultaneously or in a 4 or 24 h interval with dFdC preceding CDDP or vice versa. Four, 8 (in some cases 12) and 24 h after treatment mice were sacrificed and tumours, kidneys, blood and bone marrow (BM) were collected. Since CDDP acts by formation of Platinum (Pt)-DNA adducts and dFdC by incorporation of its triphosphate (dFdCTP) into DNA, we measured total Pt levels, dFdCTP accumulation and Pt-DNA adducts by atomic absorption spectrometry (AAS), high performance liquid chromatography (HPLC) and 32P-postlabelling, respectively. These levels were related to the previously determined antitumour efficacy and toxicity of the dFdC/CDDP combination. Peak dFdCTP accumulation in tumours (11 pmol/mg) was found 4 h after dFdC treatment, while CDDP tended to reduce this in a time-dependent way. Peak levels of total Pt in tumours were found 4 h after CDDP treatment (581 fmol/mg) and dropped 1.8-fold after simultaneous treatment with dFdC (P = 0.04). Treatment with dFdC 4 h after or simultaneously with CDDP increased Pt retention (level 24 h after CDDP treatment) 1.4- and 1.6-fold (P = 0.04 and P = 0.03, respectively). Peak Pt-DNA adduct levels in tumours were also found 4 h after CDDP treatment (7 fmol/μg DNA) and were decreased 3-fold by dFdC treatment 24 h prior to CDDP (P = 0.04). Pt-DNA adduct retention was only decreased when dFdC was given 4 h before CDDP (8-fold (P <0.01)). The retention and the area-under the concentration-time curve of Pt-DNA adducts were related to decreased tumour doubling time (linear regression coefficient (R) = 0.95; P <0.05, 0.96 P = 0.04 and 0.90; P = 0.04. Pt-DNA adduct levels in the BM cells reached a plateau level 4-24 h after CDDP treatment (approximately 10 fmol/μg DNA), which was increased by dFdC when given either simultaneously with, 4 h before or 4 h after CDDP (6-, 3- and 5-fold at 28 h, 8 h and 28 h, respectively (P ≤ 0.04)). Peak Pt-DNA adduct formation (24 h: 8 fmol/μg DNA) in kidneys was enhanced by dFdC when given simultaneously with or 4 h before CDDP (4 h timepoint) (P <0.01). However, retention was 4- and 6-fold decreased when dFdC was given 4 or 24 h after CDDP, respectively (P≤0.01). dFdC given 24 h before CDDP decreased all Pt-DNA adduct levels in kidneys 3-fold or more (P≤0.03). Pt-DNA adduct levels were inversely related to kidney toxicity when the most toxic schedule was excluded from the analysis. Peak levels of total Pt in kidneys were reached 24 h after CDDP treatment (4.3 fmol/mg) and the 8 h levels were increased 2-fold by dFdC when given 4 h after CDDP (P = 0.07). (C) 2000 Elsevier Science Ltd.

Original languageEnglish (US)
Pages (from-to)2420-2429
Number of pages10
JournalEuropean Journal of Cancer
Volume36
Issue number18
DOIs
StatePublished - 2000
Externally publishedYes

Keywords

  • Cisplatin
  • Gemcitabine
  • Murine
  • Non-small cell lung cancer
  • Pharmacodynamics
  • Pharmacokinetics
  • Schedule

ASJC Scopus subject areas

  • Cancer Research
  • Hematology
  • Oncology

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  • Cite this

    Van Moorsel, C. J. A., Pinedo, H. M., Smid, K., Comijn, E. M., Voorn, D. A., Veerman, G., Lakerveld, B., Van der Vijgh, W. J. F., Giaccone, G., Postmus, P. E., & Peters, G. J. (2000). Schedule-dependent pharmacodynamic effects of gemcitabine and cisplatin in mice bearing Lewis lung murine non-small cell lung tumours. European Journal of Cancer, 36(18), 2420-2429. https://doi.org/10.1016/S0959-8049(00)00345-2