Growth factor deprivation therapy of hormone insensitive prostate and breast cancers utilizing antisense oligonucleotides.

Abstract

Antisense oligonucleotides (oligos) are artificial sequences of nucleotide bases which may be synthesized complementary to known regions within specific mRNAs. When these constructed oligos interact with protein encoding mRNA they may regulate expression of various growth factors and/or their receptors. Oligos directed against transforming growth factor-alpha (TGF-alpha) and its binding site, the epidermal growth factor receptor (EGFR), were employed: A) in vitro to affect the growth of hormone insensitive human derived PC-3 prostate cancer cells as well as the human derived UACC-893 breast cancer cell line; and B) in vivo to treat tumors established by these cell lines in athymic nude mice. The in vitro results for each oligo, and their combination, produced significant inhibition of both prostate and breast cell lines. In addition, the combination of oligos most efficiently diminished the immunohistochemical expression of both TGF-alpha and EGFR in PC-3 cells. Direct in vivo inoculation of oligos into established PC-3 or UACC-893 tumors in nude mice produced hemorrhagic necrosis within 2-3 days. Such therapy could represent a new tier of therapy for recurrent, hormone insensitive, tumors based upon the concept of growth factor deprivation.