Connexin 26 gene therapy of human bladder cancer: induction of growth suppression, apoptosis, and synergy with Cisplatin.
The connexin 26 (Cx26) gene encodes a protein involved in gap junctional intercellular communication and is a putative tumor suppressor. We constructed a Cx26 adenovirus vector (Ad-Cx26) and used it to infect human bladder cancer cell lines UM-UC-3, UM-UC-6, UM-UC-14, and T24. Infection with Ad-Cx26 suppressed the growth of these cell lines in vitro and prevented tumor formation in vivo. Cell cycle accumulation or arrest at the G(1) phase was noted in UM-UC-3 cells and at the G(2)/M phase in UM-UC-6, UM-UC-14, and T24 cells. Apoptosis was noted in UM-UC-3, UM-UC-6, and UM-UC-14 cells both in vitro and in vivo. These effects were not seen with control adenovirus (Ad-CTR) or mock infection. Ad-Cx26 did not significantly alter the growth of the immortalized normal human bladder cell line SV-HUC. Direct injection of Ad-Cx26 into established UM-UC-3 and UM-UC-14 tumors in nude mice resulted in Cx26 expression, apoptosis, and significantly decreased growth compared with Ad-CTR treated tumors. Delayed resumption of tumor growth was associated with loss of Cx26 expression. Combination therapy with Ad-Cx26 and cisplatin resulted in decreased growth in vitro compared with either agent alone. We explored combination therapy with Ad-Cx26 and cisplatin to improve the in vivo efficacy of Cx26 gene therapy. In vivo therapy with Ad-Cx26 and cisplatin resulted in long-term suppression of tumor growth. These data demonstrate that combining gene and chemotherapy can result in dramatic synergy in vivo.
Tanaka
M
M
Department of Urology, University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, USA.
Grossman
H B
HB
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis; D002455:Cell Division; D002945:Cisplatin / Q000627:therapeutic use*; D003131:Combined Modality Therapy; D000072259:Connexin 26; D017630:Connexins / Q000235:genetics*; D004195:Disease Models, Animal; D004357:Drug Synergism; D016147:Genes, Tumor Suppressor; D015316:Genetic Therapy; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000628:therapy; D014407:Tumor Cells, Cultured; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy / Q000628:therapy*
D000970:Antineoplastic Agents; D017630:Connexins; C000607042:GJB2 protein, human; C000607043:Gjb2 protein, mouse; D000072259:Connexin 26; D002945:Cisplatin