Clusterin and IGFBPs as antisense targets in prostate cancer

The primary hurdle to improved survival of advanced prostate cancer is our failure to prevent or treat the tumor's progression to its lethal and untreatable stage of androgen independence. Novel treatment modalities designed to prevent androgen-independent progression including prostate cancer metastasis are required. Accelerated identification and characterization of cancer-relevant molecular targets has sparked considerable interest in the development of new generations of anticancer agents that specifically inhibit a progression-relevant target. Antisense oligonucleotides, short synthetic stretches of chemically modified DNA capable of specifically hybridizing to the mRNA of a chosen cancer-relevant target gene, promise to show enhanced specificity for malignant cells with a favorable side-effect profile due to well-defined and tailored modes of action. Although not all of the challenges have been met to date, emerging clinical evidence supports the premise that antisense oligonucleotides stand a realistic chance of emerging as major partners of rationally designed anticancer regimens. The rationale and status of antisense targeting of the treatment resistance factor clusterin and of insulin-like growth factor binding protein (IGFBP) 2 and 5 are discussed.