Antibody to HER-2/neu receptor blocks DNA repair after cisplatin in human breast and ovarian cancer cells.
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.
Pietras
R J
RJ
Division of Hematology-Oncology, University of California, Los Angeles 90024.
Fendly
B M
BM
Chazin
V R
VR
Pegram
M D
MD
Howell
S B
SB
Slamon
D J
DJ
D000818:Animals; D000912:Antibodies, Neoplasm / Q000276:immunology*; D014408:Biomarkers, Tumor / Q000235:genetics / Q000276:immunology; D001943:Breast Neoplasms / Q000235:genetics / Q000276:immunology / Q000473:pathology*; D002945:Cisplatin / Q000494:pharmacology*; D004247:DNA; D018736:DNA Adducts; D004260:DNA Repair / Q000187:drug effects; D004273:DNA, Neoplasm / Q000096:biosynthesis / Q000187:drug effects; D004351:Drug Resistance; D066246:ErbB Receptors / Q000235:genetics / Q000276:immunology*; D005260:Female; D015870:Gene Expression; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D010051:Ovarian Neoplasms / Q000235:genetics / Q000276:immunology / Q000473:pathology*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000276:immunology*; D018719:Erb-b2 Receptor Tyrosine Kinases; D014407:Tumor Cells, Cultured
D000912:Antibodies, Neoplasm; D014408:Biomarkers, Tumor; D002945:Cisplatin; D004247:DNA; D018736:DNA Adducts; D004273:DNA, Neoplasm; D066246:ErbB Receptors; D011518:Proto-Oncogene Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases; C057270:cisplatin-DNA adduct