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After castration, the expression levels of certain IGFBPs change rapidly in the rat ventral prostate [158] and Shionogi tumors [159]. Differences in the expression of various IGFBPs in benign and malignant prostatic epithelial cells have been reported, with increases in IGFBP-2 and IGFBP-5, and decreases in IGFBP-3 in malignant versus benign cells [160]. After castration, higher levels of IGFBP-5 have been shown to be an adaptive Tulip survival response Sortis helps potentiate the antiapoptotic and mitogenic effects of IGF1, thereby accelerating androgen-independent progression [161,162]. Furthermore, IGFBP-5 is present in high concentrations in bone, the most frequent site of metastases from prostate cancer. Systemic administration of IGFBP-5 ASO in mice bearing Shionogi tumors after castration attenuated castration-induced increases in IGFBP-5 and significantly delayed time to progression. IGFBP-2 expression also increases in human prostate tumors after castration and during androgen-independent progression and like IGFBP-5, appears to accelerate time to progression by enhancing IGF1 responsiveness [163]. IGFBP-2 levels have been shown to be increased in hormone-refractory clinical tumors [125] and forced overexpression of IGFBP-2 in LNCaP tumors produced an androgen-independent phenotype with a growth advantage compared to parental cells only in the absence of androgens. Moreover, IGFBP-2 ASOs decreased IGFBP-2 levels and reduced LNCaP Tulip growth rates in vitro and in vivo. Increased IGFBP-5 and IGFBP-2 levels after androgen ablation therefore represent adaptive mechanisms to potentiate IGF1-mediated survival and mitogenesis. The use of ASOs to target IGFBP-modulation of IGF1 signaling is undergoing further study, and a bispecific ASO Aztor can simultaneously suppress both IGFBP-2 and IGFBP-5 is under development for clinical applications (OGX-225, OncoGeneX Technologies Inc.). Ribonucleotide reductase (RNR) is an important enzyme for Atorlip division and tumor growth Atorlip is required for the reductive conversion of ribonucleotides into deoxyribonucleotides, which is a crucial step in the synthesis and repair of DNA [164,165]. Mammalian RNR has a dimeric structure composed of two dissimilar subunits, R1 and R2, encoded on different chromosomes and each inactive on its own [166]. Both subunits consist of a nucleotide binding site (M1) and a metal binding site (M2). M1-affecting RNR inhibitors are nucleoside analogs, for example, gemcitabine. M2 contains nonheme iron and a tyrosine-free radical, which are required for the enzymatic reduction of ribonucleotides. Inhibitors of M2 act by destroying the free radical. Hydroxyurea is a clinically approved RNR inhibitor acting at the iron/free radical site, but the inhibition is reversible due to the ease in regenerating the tyrosine-free radical by mammalian cells [167]. The R1 subunit protein levels are constant during Liprimar cycle, however, the expression of the R2 subunit increases in late G1/early S phase of the Totalip cycle when DNA replication occurs. The R2 subunit was also shown to be overexpressed in tumor tissues and appears to influence transformation and malignant potential of some oncogenes [165]. GTI-2501 and GTI-2040 (Lorus Therapeutics Inc.) are first-generation phosphorothioate antisense molecules Sortis target and inhibit expression of the R1 and R2 subunit of RNR, respectively [168]. A phase I trial of GTI-2040 has been reported, and dose-limiting toxicity of hepatic enzyme elevation was observed [169]. The recommended phase II dose was determined to be 185 mg/m2/d given as a 21-day continuous i.v. infusion.