Content area
Full Text
The mainstay in the management of invasive bladder cancer continues to be radical cystectomy. With regard to improvement of quality of life, however, therapies that preserve the bladder are desirable. We investigated the use of intravesical PLK-1 small interfering RNA (siRNA) against bladder cancer. Patients with bladder cancers expressing high levels of PLK-1 have a poor prognosis compared with patients with low expression. Using siRNA/cationic liposomes, the expression of endogenous PLK-1 could be suppressed in bladder cancer cells in a time- and dose-dependent manner. As a consequence, PLK-1 functions were disrupted. Inhibition of bipolar spindle formation, accumulation of cyclin B1, reduced cell proliferation, and induction of apoptosis were observed. In order to determine the efficacy of the siRNA/liposomes in vivo, we established an orthotopic mouse model using a LUC-labeled bladder cancer cell line, UM-UC-3^sup LUC^. PLK-1 siRNA was successfully transfected into the cells, reduced PLK-1 expression, and prevented the growth of bladder cancer in this mouse model. This is the first demonstration, to our knowledge, of inhibition of cancer growth in the murine bladder by intravesical siRNA/cationic liposomes. We believe intravesical siRNA instillation against bladder cancer will be useful as a therapeutic tool.
Nonstandard abbreviations used: BCG, bacille Calmette-Guérin; DDS, drug delivery system; IVIS, in vivo imaging system; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; PLK-1, polo-like kinase-1; siRNA, small interfering RNA.
Introduction
Approximately 70% of bladder cancers are at a superficial stage at initial diagnosis (1,2). These lesions are usually managed with transurethral resection, followed by intravesical administration of agents including mitomycin C, adriamycin, and bacille Calmette-Guérin (BCG). Although these intravesical agents can prolong the length of progression-free survival after the cancers have been resected, long-term follow up has demonstrated that they infrequently cured patients of bladder cancer (1,2). Half of superficial lesions will recur, and as many as 10-30% will progress to a higher grade and/or stage and form local invasive cancers (1-3). The standard treatment for local invasive cancer is radical cystectomy, which may result in loss of urinary and sexual functions. Consequently, the current treatment often adversely affects the quality of life of these patients. Therefore, a novel therapeutic approach against superficial cancer has been eagerly desired.
RNA interference is a newly discovered cellular pathway for silencing genes in a sequence-specific manner at...