Antibody to HER-2/neu receptor blocks DNA repair after cisplatin in human breast and ovarian cancer cells.
Antibody to HER-2/neu receptor blocks DNA repair after cisplatin in human breast and ovarian cancer cells.
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发表时间：
1994-07
期刊：
影响因子：
8
通讯作者：
R. Pietras;B. Fendly;V. Chazin;M. Pegram;S. Howell;D. Slamon
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作者：
R. Pietras;B. Fendly;V. Chazin;M. Pegram;S. Howell;D. Slamon
大约30%的人乳腺癌和卵巢癌具有编码细胞表面生长因子受体的HER-2/neu基因的扩增和/或过表达。该受体p185 HER-2/neu的过度表达与不良结局相关，并可能预测对化疗的临床反应。HER-2/neu受体的抗体在抑制p185 HER-2/neu过表达的细胞生长中具有细胞抑制作用。为了引起杀细胞作用，抗受体抗体治疗与DNA损伤药物顺铂联合使用，这种联合治疗产生了细胞生长的协同减少。此外，抗体介导了含有多拷贝HER-2/neu基因的卵巢癌耐药细胞对顺铂的敏感性增加。为了评估这种协同作用的机制，在癌细胞中使用掺入[3 H]胸苷和放射自显影测量了非程序性DNA合成，还测量了顺铂诱导的DNA加合物的形成和修复。顺铂治疗导致了一个显着的，剂量依赖性的增加，在非程序性DNA合成显着减少联合治疗HER-2/neu过表达细胞中的抗受体抗体。HER-2/neu受体抗体治疗也导致顺铂暴露后顺铂-DNA加合物修复减少35-40%，因此促进了靶细胞中药物诱导的杀伤。我们称之为受体增强化疗敏感性的这种现象可能为更有选择性地靶向和利用癌细胞中过表达的生长因子受体提供理论基础，从而导致临床干预的新策略。
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.