Epidermal Growth Factor Receptor Overexpression as a Target for Auger Electron Radiotherapy of Breast Cancer
Abstract
The epidermal growth factor receptor (EGFR) is overexpressed in the majority of estrogen receptor-negative, hormone-resistant and poor prognosis breast cancers. Our objective is to evaluate a new form of targeted radiotherapy for EGFR-positive breast cancer. Our approach is to exploit the normal internalization and nuclear translocation of human EGF following binding to the EGFR to introduce the Auger electron-emitting radionuclide, indium-111 (111)In into breast cancer cells, where the Auger electrons are damaging to DNA causing cell death. We constructed a novel human serum albumin-human EGF bioconjugate (HSA-hEGF) substituted with multiple DTPA metal chelators for (111)In for targeted Auger electron radiotherapy of breast cancer. (111)In-DTPA-HSA-hEGF was specifically bound by EGFR positive MDA-MB-468 human breast cancer cells and was internalized and translocated to the cell nucleus. (111)In-DTPA-HSA-hEGF was radiotoxic to MDA-MB-468 cells in vitro and localized effectively in MDA-MB-468 breast cancer xenografts in vivo achieving a tumor/blood ratio of >7:1 at 72 hours post-injection. Concurrent studies demonstrated that (111)In-DTPA-hEGF was 30 to 500-fold more cytotoxic in vitro (on a molar basis) than conventional chemotheraputic agents used to treat breast cancer. Studies are planned to evaluate the efficacy and toxicity of targeted Auger electron radiotherapy of MDA-MB-468 breast cancer xenografts in vivo.
Document Details
- Document Type
- Technical Report
- Publication Date
- Aug 01, 2000
- Accession Number
- ADA389569
Entities
People
- Raymond Reilly
Organizations
- Toronto General Hospital