Antisense targets to enhance hormone and cytotoxic therapies in advanced prostate cancer.
The main obstacle to improved survival of advanced prostate cancer is our failure to prevent or treat its progression to its lethal and untreatable stage of androgen independence. New therapeutic agents designed to prevent androgen-independent progression are required. Accelerated identification and characterization of cancer-relevant molecular targets has sparked considerable interest in the development of new generations of anti-cancer 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 more 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 anti-cancer regimens. The status of antisense targeting of several genes, including bcl-2, bcl-xL, clusterin, androgen receptor and IGFBPs, relevant to prostate and other cancers, are reviewed.
Gleave
Martin
M
The Prostate Centre at Vancouver General Hospital, Division of Urology, University of British Columbia, D9, 2733 Heather Street, Vancouver, BC, Canada V6H 3Z3. gleave@interchange.ubc.ca
Nelson
Colleen
C
Chi
Kim
K
D000726:Androgen Antagonists / Q000494:pharmacology / Q000627:therapeutic use; D059002:Androgen Receptor Antagonists; D000728:Androgens / Q000172:deficiency; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D002986:Clinical Trials as Topic; D051152:Clusterin; D015870:Gene Expression / Q000187:drug effects; D006023:Glycoproteins / Q000037:antagonists & inhibitors / Q000235:genetics; D006801:Humans; D018969:Insulin-Like Growth Factor Binding Proteins / Q000235:genetics; D007334:Insulin-Like Growth Factor I / Q000037:antagonists & inhibitors / Q000235:genetics; D008297:Male; D018832:Molecular Chaperones / Q000037:antagonists & inhibitors / Q000235:genetics; D016376:Oligonucleotides, Antisense / Q000494:pharmacology / Q000627:therapeutic use*; D011471:Prostatic Neoplasms / Q000188:drug therapy*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D011944:Receptors, Androgen / Q000235:genetics; D051020:bcl-X Protein
D000726:Androgen Antagonists; D059002:Androgen Receptor Antagonists; D000728:Androgens; D000970:Antineoplastic Agents; C494811:BCL2L1 protein, human; C495242:CLU protein, human; D051152:Clusterin; D006023:Glycoproteins; D018969:Insulin-Like Growth Factor Binding Proteins; D018832:Molecular Chaperones; D016376:Oligonucleotides, Antisense; D019253:Proto-Oncogene Proteins c-bcl-2; D011944:Receptors, Androgen; D051020:bcl-X Protein; D007334:Insulin-Like Growth Factor I