Efficacy of adenovirus-mediated CD/5-FC and HSV-1 thymidine kinase/ganciclovir suicide gene therapies concomitant with p53 gene therapy.
Efficacy of adenovirus-mediated CD/5-FC and HSV-1 thymidine kinase/ganciclovir suicide gene therapies concomitant with p53 gene therapy.
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发表时间：
1999-12
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通讯作者：
Y. Xie;J. D. Gilbert;J. H. Kim;S. Freytag
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作者：
Y. Xie;J. D. Gilbert;J. H. Kim;S. Freytag
最近的证据表明，具有野生型P53状态的肿瘤细胞比缺乏功能性P53的细胞对化疗药物和辐射更敏感。野生型P53细胞的高敏感性被认为是由于它们在损伤后倾向于经历P53介导的细胞凋亡。鉴于自杀基因治疗本质上是肿瘤靶向化疗，我们检验了野生型p53共表达可以提高腺病毒介导的自杀基因治疗效果的假说。用表达胞嘧啶脱氨酶/单纯疱疹病毒胸苷激酶(CD/HSV-1 TK)融合基因的复制缺陷型腺病毒感染p53缺失的人Hep3B和SK-OV-3细胞，但不携带融合基因非复制型腺病毒(FGNR)或野生型人P53基因(FGNRp53)。体外和体内测定细胞对CD/5-氟胞嘧啶(CD/5-FC)和HSV-1 TK/更昔洛韦(GCV)酶/前药系统的敏感性。共表达P53不能增强CD/5-FC或HSV-1 TK/GCV系统的体外细胞毒作用。未能观察到P53的作用不能解释为P53表达不足或暂时的基础上，因为FGNRP53感染的细胞在G1期停止生长，诱导Bax，并在前药物治疗后以更快的速度发生凋亡，特别是当腺病毒E1a蛋白存在时。瘤内注射FGNRp53结合单或双亲药物治疗导致的肿瘤生长延迟等于或小于观察到的FGNR病毒。我们的结果表明，P53的共表达并不一定能提高腺病毒介导的CD/5-FC和HSV-1 TK/GCV自杀基因治疗的体内疗效。
Recent evidence has suggested that tumor cells having a wild-type p53 status are more sensitive to chemotherapeutic agents and radiation than cells that lack functional p53. The heightened sensitivity of wild-type p53 cells is thought to be attributable to their propensity to undergo p53-mediated apoptosis after insult. Given that suicide gene therapy is essentially tumor-targeted chemotherapy, we examined the hypothesis that coexpression of wild-type p53 could enhance the efficacy of adenovirus-mediated suicide gene therapy. Human Hep3B and SK-OV-3 cells, which are null for p53, were infected with a pair of replication-deficient adenoviruses that expressed a cytosine deaminase/herpes simplex virus thymidine kinase (CD/HSV-1 TK) fusion gene without (fusion gene nonreplicative adenovirus, FGNR) or with (FGNRp53) the wild-type human p53 gene. The sensitivity of cells to the CD/5-fluorocytosine (CD/5-FC) and HSV-1 TK/ ganciclovir (GCV) enzyme/prodrug systems was determined in vitro and in vivo. Coexpression of p53 did not enhance the cytotoxicity of either the CD/5-FC or HSV-1 TK/GCV system in vitro. The failure to observe an effect of p53 could not be explained on the basis of insufficient or transient p53 expression, because FGNRp53-infected cells growth arrested in G1, induced Bax, and underwent apoptosis at an increased rate after prodrug treatment, particularly when the adenovirus E1A protein was present. Intratumoral injection of FGNRp53 concomitant with single or double pro-drug therapy resulted in a tumor growth delay that was equal to or less than that observed with the FGNR virus. Our results indicate that coexpression of p53 may not necessarily improve the efficacy of adenovirus-mediated CD/ 5-FC and HSV-1 TK/GCV suicide gene therapies in vivo.