Matsushima Masashi, Horinaga Minoru, Fukuyama Ryuichi, Yanaihara Hitoshi, Kikuchi Eiji, Kawachi Makoto, Iida Masahiro, Nakahira Yoko, Oya Mototsugu, Asakura Hirotaka
Department of Urology, Saitama Medical School, Saitama 350-0495.
Oncol Lett. 2011 Jan;2(1):13-19. doi: 10.3892/ol.2010.217. Epub 2010 Nov 23.
Intravesical immunotherapy with bacillus Calmette-Guerin (BCG) is currently the most successful adjuvant agent for the treatment and/or prophylaxis of non-muscle-invasive bladder cancer (NMIBC). However, NMIBCs recur in 60-70% of cases and 30% of these recurrent tumors present with a higher grade and more invasive properties. Patients that do not respond to intravesical BCG therapy are considered to be a challenge for urologists. Thus, novel conservative possibilities should be explored. To test the efficacy of a novel therapeutic approach, we examined the antitumor effect of combination therapy by intravesical administration of mitomycin C (MMC) plus BCG, infusing the two drugs simultaneously, in an orthotopic bladder cancer model. Intravesical BCG and MMC administration showed a dose-dependent survival (n=8 per group). The combination of MMC and BCG provided a significant survival advantage compared to the BCG-alone (p=0.035) and MMC-alone groups (p=0.040) (n=8 per group). The group with combined MMC/BCG exhibited a survival period similar to that achieved with an amount eight times higher that of BCG (n=10 per group). Ki-67 labeling index of cancer cells, showing tumor proliferation, was significantly lower in the combined group compared to the BCG-alone (p<0.05), MMC-alone (p<0.01) and control groups (p<0.01). No difference was detected between the combined group and the BCG-alone group with regard to CD3, T-cell infiltration and CD68 macrophage activity. The combined MMC/BCG treatment decreased the tumor appearance rate, improved the survival period and reduced the cellular proliferation rate in tumors compared to the BCG-alone treatment. The results suggest that the combined intravesical MMC/BCG treatment induced an enhanced antitumor effect against bladder tumors. The combined MMC/BCG treatment also showed a survival period similar to that achieved using a dose eight times higher of BCG-alone.
卡介苗（BCG）膀胱内免疫疗法是目前治疗和/或预防非肌层浸润性膀胱癌（NMIBC）最成功的辅助药物。然而，60-70%的NMIBC病例会复发，其中30%的复发性肿瘤具有更高的分级和更强的侵袭性。对膀胱内BCG治疗无反应的患者被认为是泌尿外科医生面临的挑战。因此，应探索新的保守治疗方法。为了测试一种新治疗方法的疗效，我们在原位膀胱癌模型中研究了丝裂霉素C（MMC）联合BCG膀胱内给药的抗肿瘤作用，两种药物同时注入。膀胱内BCG和MMC给药显示出剂量依赖性生存（每组n=8）。与单独使用BCG组（p=0.035）和单独使用MMC组（p=0.040）相比，MMC与BCG联合使用具有显著的生存优势（每组n=8）。MMC/BCG联合组的生存期与单独使用BCG剂量高八倍时的生存期相似（每组n=10）。显示肿瘤增殖的癌细胞Ki-67标记指数在联合组中显著低于单独使用BCG组（p<0.05）、单独使用MMC组（p<0.01）和对照组（p<0.01）。联合组与单独使用BCG组在CD3、T细胞浸润和CD68巨噬细胞活性方面未检测到差异。与单独使用BCG治疗相比，MMC/BCG联合治疗降低了肿瘤出现率，改善了生存期，并降低了肿瘤细胞增殖率。结果表明，MMC/BCG联合膀胱内治疗对膀胱肿瘤具有增强的抗肿瘤作用。MMC/BCG联合治疗的生存期也与单独使用BCG剂量高八倍时的生存期相似。
