Connexin 26 gene therapy of human bladder cancer: Induction of growth suppression, apoptosis, and synergy with cisplatin
Connexin 26 gene therapy of human bladder cancer: Induction of growth suppression, apoptosis, and synergy with cisplatin
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DOI：
10.1089/10430340152710568
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发表时间：
2001-12-10
影响因子：
4.2
通讯作者：
Grossman, HB
中科院分区：
文献类型：
--
作者：
Tanaka, M;Grossman, HB
连接蛋白26（Cx 26）基因编码的蛋白质参与间隙连接细胞间通讯，是一个假定的肿瘤抑制因子。我们构建了Cx 26腺病毒载体（Ad-Cx 26），并将其用于感染人膀胱癌细胞系UM-UC-3、UM-UC-6、UM-UC-14和T24。Ad-Cx 26感染在体外抑制了这些细胞系的生长，并阻止了体内肿瘤的形成。在UM-UC-3细胞中观察到细胞周期积累或停滞在G（1）期，在UM-UC-6、UM-UC-14和T24细胞中观察到细胞周期积累或停滞在G（2）/M期。UM-UC-3、UM-UC-6和UM-UC-14细胞在体外和体内均观察到凋亡。对照腺病毒（Ad-CTR）或模拟感染未观察到这些效应。Ad-Cx 26对人膀胱癌细胞株SV-HUC的生长无明显影响。将Ad-Cx 26直接注射到已建立的UM-UC-3和UM-UC-14裸鼠肿瘤中，与Ad-CTR处理的肿瘤相比，导致Cx 26表达、凋亡和显著降低的生长。肿瘤生长的延迟恢复与Cx 26表达的丧失相关。与单独使用任何一种药物相比，Ad-Cx 26和顺铂的联合治疗导致体外生长减少。我们探索了联合治疗与Ad-Cx 26和顺铂，以提高体内Cx 26基因治疗的疗效。在体内治疗与Ad-Cx 26和顺铂导致肿瘤生长的长期抑制。这些数据表明，基因和化疗的组合可以在体内产生显著的协同作用。
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.