Episome-Based Gene Therapy Strategy for Treatment of Human Breast Cancer

Abstract

Abstract : We have focussed our efforts on investigating the mechanisms by which antisense to type I insulin-like growth factor receptor (IGF-IR) inhibits cell growth and reduces tumorigenicity in human metastatic breast cancer cells. MDA-MB-4355 breast cancer cells carrying antisense IGF-IR displayed decreased expression of endogenous IGF-IR, reduced cell proliferation, loss of clonogenicity and enhanced apoptosis in vitro. There was a dramatic suppression in tumorigenesis and an absence of lung metastases in both nude and scid beige mice injected with MDA-MB-435s cells carrying anti sense IGF-IR. All animals injected with the control cells carrying the construct minus the antisense IGF-IR insert developed large tumors. The scid beige mice consistently exhibited pulmonary metastases whereas there were no apparent metastatic sites in the lungs of nude mice. We provide data that shows that the length of survival in scid beige mice injected with MDA-MB-435s cells carrying the antisense IGF-IR was dramatically increased compared to animals injected with cells carrying the construct minus the antisense IGF-IR insert. These results demonstrate that the IGF-IR plays a critical role in the progression of metastatic estrogen receptor negative human breast cancer. Therapies directed toward inhibiting the expression of this receptor may provide a new treatment strategy for patients with progressive metastatic breast cancer.