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

Antisense oligonucleotides (oligos) are artificial sequences of nucleotide bases which may be synthesized complementary to known regions within specif ic mRNAs. When these constructed oligos interact with protein encoding mRNA they may regulate expression of various growth factors and/or their recept ors. Oligos directed against transforming growth factor-alpha (TGF-alpha) a nd its binding site, the epidermal growth factor receptor (EGFR), were empl oyed : A) in vitro to affect the growth of hormone insensitive human derive d PC-3 prostate cancer cells as well as the human derived UACC-893 breast c ancer cell line; and B) in vivo to treat tumors established by these cell l ines in athymic nude mice. The in vitro results for each oligo, and their c ombination, produced significant inhibition of both prostate and breast cel l lines. In addition, the combination of oligos most efficiently diminished the immunohistochemical expression of both TGF-alpha and EGFR in PC-3 cell s. Direct in vivo inoculation of oligos into established PC-3 or UACC-893 t umors in nude mice produced hemorrhagic necrosis within 2-3 days. Such ther apy could represent a new tier of therapy for recurrent, hormone insensitiv e, tumors based upon the concept of growth factor deprivation. (C) 1998 Pro us Science. All rights reserved.