Silencing of gene expression by small interfering RNAs (siRNAs) is rapidly becoming a powerful tool for genetic analysis and represents a potential strategy for therapeutic product development. However, there are no reports of systemic delivery for siRNAs toward treatment of bone-metastatic cancer. Accordingly, we report here that i.v. injection of GL3 luciferase siRNA complexed with atelocollagen showed effective reduction of luciferase expression from bone-metastatic prostate tumor cells developed in mouse thorax, jaws, and͞or legs. We also show that the siRNA͞ atelocollagen complex can be efficiently delivered to tumors 24 h after injection and can exist intact at least for 3 days. Furthermore, atelocollagen-mediated systemic administration of siRNAs such as enhancer of zeste homolog 2 and phosphoinositide 3-hydroxykinase p110-␣-subunit, which were selected as candidate targets for inhibition of bone metastasis, resulted in an efficient inhibition of metastatic tumor growth in bone tissues. In addition, upregulation of serum IL-12 and IFN-␣ levels was not associated with the in vivo administration of the siRNA͞atelocollagen complex. Thus, for treatment of bone metastasis of prostate cancer, an atelocollagen-mediated systemic delivery method could be a reliable and safe approach to the achievement of maximal function of siRNA.bone metastasis ͉ prostate cancer R NA interference (RNAi) induced by small interfering RNA (siRNA) has recently emerged as a powerful technique that is capable of suppressing expression of individual genes with a high degree of specificity (1). The technique has been used for studies of gene function in vivo, primarily in mice. The first demonstration of RNAi-mediated repression in an adult animal showed effective repression of a luciferase reporter gene after hydrodynamic transfection of siRNA expression plasmids into mouse liver (2, 3). Subsequent studies have delivered siRNA by various methods, including viral vector-mediated delivery (4, 5) and lipid-based delivery (6, 7). A more recent study showed that chemically modified siRNAs can silence an endogenous gene after i.v. injection in mice (8). These findings provide hope for using RNAi technology in disease control.Many studies have used siRNAs as an experimental tool to dissect the cellular pathways that lead to uncontrolled cell proliferation and cancer. To develop siRNAs for cancer therapy, several researchers have investigated them in animal models (9-13). However, reports of RNAi-delivery strategies for bonemetastatic cancer are very limited. For example, in advanced prostate cancer, the sites most frequently affected by metastasis are the bones and regional lymph nodes. Patients with these metastases suffer pain and low limb edema, making it extremely important to explore avenues of treating such bone metastases.We previously demonstrated the efficacy of atelocollagen for delivery of nucleotides, such as plasmid DNA and antisense oligonucleotides, in vitro and in vivo (14)(15)(16)(17)(18)(19). Recently, we also reported that a...
We previously demonstrated expression of the HST-1/ FGF-4 gene in the testis of normal adult animals, which suggests its possible role in spermatogenesis. For an understanding of its functional signi®cance in the testis, conditional transgene expression was used. Precise genetic switches can be eciently generated in a straightforward manner using adenovirus-carrying Cre recombinase, which means our new strategies promise to contribute substantially to a better and prompt understanding of the functions of genes in vivo by controlling the expression of any gene to any organ at any desired time. Our new method demonstrated for the ®rst time that the speci®c gain of function of the HST-1/FGF-4 gene in the testis resulted in markedly enhanced spermatogenesis. To further investigate the function and therapeutic potency of HST-1/FGF-4, transgenic mice with enhanced HST-1/FGF-4 expression in the testis were exposed to adriamycin (ADR), an anticancer drug causing severe testicular toxicity. Degree of damage to spermatogenesis was assessed by sperm count, testicular weight, histology, and DNA ploidy. Induced expression of HST-1/FGF-4 markedly enhanced the recovery of ADR-induced testicular damage. Furthermore, adenoviruses carrying the HST-1/FGF-4 gene ameliorated testicular toxicity of ADR. These results with new adenovirus-mediated Cre/lox conditional mice indicated that HST-1/FGF-4 could be an important factor for spermatogenesis, presenting a new paradigm to treat impaired fertility.
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