Antibody to HER-2/neu receptor blocks DNA repair after cisplatin in human breast and ovarian cancer cells

Oncogene. 1994 Jul;9(7):1829-38.


Approximately 30% of human breast and ovarian cancers have amplification and/or overexpression of HER-2/neu gene which encodes a cell surface growth-factor receptor. Overexpression of this receptor, p185HER-2/neu, is associated with poor outcome and may predict clinical response to chemotherapy. Antibodies to HER-2/neu receptor have a cytostatic effect in suppressing growth of cells with overexpression of p185HER-2/neu. To elicit a cytocidal effect, therapy with antireceptor antibody was used in combination with the DNA-damaging drug, cisplatin, and this combined treatment produced a synergistic decrease in cell growth. In addition, antibody mediated an increased sensitivity to cisplatin in drug-resistant ovarian carcinoma cells containing multiple copies of HER-2/neu gene. To evaluate the mechanism for this synergy, unscheduled DNA synthesis was measured in cancer cells using incorporation of [3H]thymidine and autoradiography, and formation and repair of cisplatin-induced DNA adducts was also measured. Treatment with cisplatin led to a marked, dose-dependent increase in unscheduled DNA synthesis which was significantly reduced by combined treatment with antireceptor antibody in HER-2/neu-overexpressing cells. Therapy with antibody to HER-2/neu receptor also led to a 35-40% reduction in repair of cisplatin-DNA adducts after cisplatin exposure and, as a result, promoted drug-induced killing in target cells. This phenomenon which we term receptor-enhanced chemosensitivity may provide a rationale for more selective targeting and exploitation of overexpressed growth factor receptors in cancer cells, thus leading to new strategies for clinical intervention.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Antibodies, Neoplasm / immunology*
  • Biomarkers, Tumor / genetics
  • Biomarkers, Tumor / immunology
  • Breast Neoplasms / genetics
  • Breast Neoplasms / immunology
  • Breast Neoplasms / pathology*
  • Cisplatin / pharmacology*
  • DNA
  • DNA Adducts*
  • DNA Repair* / drug effects
  • DNA, Neoplasm / biosynthesis
  • DNA, Neoplasm / drug effects
  • Drug Resistance
  • ErbB Receptors / genetics
  • ErbB Receptors / immunology*
  • Female
  • Gene Expression
  • Humans
  • Mice
  • Mice, Nude
  • Ovarian Neoplasms / genetics
  • Ovarian Neoplasms / immunology
  • Ovarian Neoplasms / pathology*
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / immunology*
  • Receptor, ErbB-2
  • Tumor Cells, Cultured


  • Antibodies, Neoplasm
  • Biomarkers, Tumor
  • DNA Adducts
  • DNA, Neoplasm
  • Proto-Oncogene Proteins
  • cisplatin-DNA adduct
  • DNA
  • ErbB Receptors
  • Receptor, ErbB-2
  • Cisplatin