Monoclonal antibody to HER-2/neureceptor modulates repair of radiation-induced DNA damage and enhances radiosensitivity of human breast cancer cells overexpressing this oncogene.

摘要: The management of human breast cancer frequently includes radiation therapy as an important intervention, and improvement in the clinical efficacy is desirable. Overexpression HER-2 growth factor receptor occurs 25–30% cancers correlates with poor outcome, including earlier local relapse following conservative surgery accompanied by therapy. In cells overexpression receptor, recombinant humanized monoclonal antibodies (rhuMAbs) to receptors (rhuMAb HER-2) decrease cell proliferation vitro reduce tumor formation nude mice. Therapy rhuMAb enhances sensitivity at doses 1–5 Gy, exceeding remission rates obtained alone. This benefit specific does not occur without overexpression. Treatment (2–4 Gy) alone provokes a marked increase unscheduled DNA synthesis, measure repair, but HER-2-overexpressing treated combination demonstrate synthesis 25–44% controls. Using alternate test i.e., radiation-damaged or undamaged reporter DNA, we introduced cytomegalovirus-driven β-galactosidase into that had been control. At 24 h posttransfection, extent repair assayed measuring expression was high after exposure significantly lower combined To further characterize effects antibody on growth, analyses cycle phase distribution were performed. Antibody reduces fraction S 48 h. Radiation treatment also known promote arrest, predominantly G1, low S-phase presence HER-2, elicits similar reduction h, significant reversal this arrest appears begin postradiation exposure. level greater than found antibody-radiation therapy, suggesting early escape from antireceptor may allow sufficient time for completion cells. Because it well failure adequate p21WAF1 induction damage associated assessed activity critical mediator cellular response damage. results show transcripts protein product 6, 12, treatment; however, increased levels transcript are sustained exposed HER-2. Although 6–12 they both diminished Levels antibody. A basal occurred 12–24 effect be related tyrosine phosphorylation protein. Tyrosine alone, blocked radiation. dysregulation independent p53 correlate reduced mdm2 These data indicate damaged especially vulnerable injury if deprived essential signal transduction pathways provided pathway.