Relationship between the exposure to cisplatin, DNA-adduct formation in leucocytes and tumour response in patients with solid tumours

Br J Cancer. 1996 Jun;73(12):1569-75. doi: 10.1038/bjc.1996.296.


The study was designed to investigate possible relationships between tumour response and exposure to cisplatin (area under the curve of unbound cisplatin in plasma, AUC) and DNA-adduct formation in leucocytes (WBC) in patients with solid tumours. Patients were treated with six weekly courses of cisplatin at a dose of 70 or 80 mg m-2. The AUC was determined during the first course and DNA-adduct levels in WBC during all courses at baseline, 1 h (A(max)) and 15 h after a 3 h infusion of cisplatin. The area under the DNA-adduct-time curve (AUA) was calculated. The tumour response was determined after six courses. Forty-five evaluable patients received 237 courses of cisplatin. Sixteen patients with head and neck cancer received a dose of 80 mg m-2 and 29 with various other tumour types received 70 mg m-2 plus daily 50 mg oral etoposide. There were 20 responders (partial and complete) and 25 non-responders (stable and progressive disease). The AUC was highly variable (mean +/- s.d. = 2.48 +/- 0.51 micrograms h-1 ml-1; range 1.10-3.82) and was closely correlated with the AUA (r = 0.78, P < 0.0001) and A(max) (r = 0.73, P < 0.0001). The AUC, AUA and A(max) were significantly higher in responders than in non-responders in the total population (P < 0.0001) and in the two subgroups treated at 70 or 80 mg m-2. In logistic regression analysis AUC, AUA and A(max) were important predictors of response. The magnitude of exposure to cisplatin is, through DNA-adduct formation, the major determinant of the response rate in this population. Hence, individualised dosing of cisplatin using AUC or DNA-adducts should lead to increased response rates.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Antineoplastic Agents / blood
  • Antineoplastic Agents / pharmacokinetics
  • Antineoplastic Agents / pharmacology*
  • Cisplatin / blood
  • Cisplatin / pharmacokinetics
  • Cisplatin / pharmacology*
  • DNA Adducts / biosynthesis*
  • DNA Adducts / blood*
  • DNA, Neoplasm / blood
  • DNA, Neoplasm / drug effects
  • Drug Screening Assays, Antitumor
  • Female
  • Humans
  • Individuality
  • Leukocytes / drug effects*
  • Leukocytes / metabolism*
  • Male
  • Middle Aged
  • Neoplasms / blood*
  • Neoplasms / drug therapy*
  • Prospective Studies


  • Antineoplastic Agents
  • DNA Adducts
  • DNA, Neoplasm
  • Cisplatin