Targeting Anti-Apoptotic Genes Upregulated by Androgen Withdrawal Using Antisense Oligonucleotides to Enhance Androgen- and Chemo-Sensitivity in Prostate Cancer
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- Gleave, M.E., Zellweger, T., Chi, K. et al. Invest New Drugs (2002) 20: 145. doi:10.1023/A:1015694802521
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The main obstacle to improved survival ofadvanced prostate cancer is our failure toprevent its progression to its lethal anduntreatable stage of androgen independence. New therapeutic strategies designed toprevent androgen-independent (AI)progression must be developed beforesignificant impact on survival can beachieved. Characterization of changes ingene expression profiles after androgenablation and during progression toandrogen-independence suggest that thevarious therapies used to kill neoplasticcells may precipitate changes in geneexpression that lead to the resistantphenotype. Castration-induced increases inantiapoptosis genes, Bcl-2 and clusterin,help create a resistant phenotype, whileantisense oligonucleotides can inhibitthese adaptive cell survival mechanisms andenhance both hormone and chemotherapy. Ongoing efforts are necessary to identify additionalmolecular pathways mediating AI progressionand chemoresistance, since complexities oftumor heterogeneity and adaptabilitydictate that optimal control over tumorprogression will require multi-targetsystemic therapies.
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