Aim: Stathmin is a microtubule destabilizing protein that is important for the regulation of the mitotic spindle. Stathmin, which is expressed at high levels in a wide variety of human cancers, is an attractive molecule to target in therapies that disrupt the mitotic apparatus. We selected prostate cancer as a model for the development of local anti-stathmin-based therapy since the disease is localized in its early stages. Our published studies show that stathmin inhibition can suppress the malignant phenotype of prostate cancer cells in vitro. We designed new experiments to determine if inhibition of stathmin would suppress the growth of human prostate cancer in vivo. Methods: We developed a bicistronic adenoviral vector (Ad.Rz.GFP) that coexpresses green fluorescent protein (GFP) and a ribozyme (Rz) that targets human stathmin mRNA. Results & Discussion: We first examined the effects of ex vivo gene transfer of anti-stathmin ribozyme on tumorigenicity of human prostate cancer cells in nude mice. The mice were divided into three groups. Group I was injected subcutaneously at eight different sites with 1x107 uninfected LNCaP cells. Group II and group III mice were injected subcutaneously at eight different sites with 1x107 cells that were pre-infected with control Ad.GFP and Ad.Rz.GFP adenovirus, respectively. After 6-8 weeks, group I and group II mice formed tumors at all four injection sites that ranged from 0.3 to 1.4 cm in size. In contrast, the group III mice that were injected with cells infected with the anti-stathmin adenovirus failed to form tumors at any of the injection sites. We also examined the therapeutic efficacy of the anti-stathmin adenovirus in established tumors derived from uninfected LNCaP cells. Eight animals were injected subcutaneously at four different sites, each with 5x106 LNCaP cells/site. We initiated treatment by intratumoral injections after the mice developed tumors that ranged from 0.4-0.7 cm in diameter. Two tumors on one side were injected with either PBS or with the control Ad.GFP virus (108 viral particles, once every 5 days, for a total of 3 injections) while the two tumors on the other side were injected with anti-stathmin adenovirus (108 viral particles, once every 5 days, for a total of 3 injections). Seventy percent of the tumors injected with the ribozyme carrying adenovirus regressed completely and 30% stopped growing during the 60-day period of observation. In contrast, tumors that were injected with PBS or the control adenovirus continued to grow and reach larger sizes. Thus, inhibition of stathmin expression provides a new strategy for prostate cancer gene therapy. Since anti-tumor drugs like taxol that is widely used against prostate cancer, also exert its effect through the microtubule pathway, anti-stathmin therapy could be combined with taxol to provide synergistic anti-tumor effects.

[Proc Amer Assoc Cancer Res, Volume 47, 2006]