Inhibition of ovarian cancer metastasis by adeno-associated virus-mediated gene transfer of nm23H1 in an orthotopic implantation model

Abstract

Ovarian cancer is one of the most threatening malignant tumors in females due to the frequent occurrence of metastasis that precedes diagnosis. The present study explored the possibility of preventing ovarian cancer metastasis by promoting nm23H1 expression through adeno-associated virus (AAV)-mediated gene transfer. A cell line of high metastatic potential, SW626-M4, was derived by in vivo selection and used to establish an ovarian cancer metastasis model in the mouse. Liver metastasis and animal survival time were measured after transfer of a recombinant adeno-associated viral vector expressing nm23H1 (AAV-nm23H1) into the aforementioned model. Intraperitoneal injection of AAV-nm23H1 into this orthotopic implantation model of ovarian cancer resulted in (1) expression of the exogenous gene in more than 95% of tumor cells in situ in nude mice; (2) a 60% reduction in the number of animals developing liver metastases; and (3) a 35-day prolongation of median survival time compared with the untreated host group. In conclusion, the results support the feasibility of induction of nm23H1 expression through gene transfer as a therapeutic strategy for preventing metastases and prolonging host survival time, and indicate that AAV vectors deserve attention in the design of future gene therapy approaches to achieving long-term expression of curative genes in vivo.

Targeting Tumor Metastasis by Regulating Nm23 Gene Expression

“…Using AAV gene therapy vector, an Nm23-H1 construct was delivered into an ovarian carcinoma model of peritoneal metastasis. It was expressed by the tumor cells and significantly extended mouse survival (Li et al, 2006). The metastasis suppressive effects of Nm23-H1 were confirmed when Lacombe and colleagues developed an Nm23 knockout mouse.…”

“…The expression of Nm23-H1 gene can be used to determine response treatment following radiotherapy for nasopharyngeal carcinomas and in ovarian cancer (Kapoor, 2009). Transfer of Nm23-H1 gene through adeno virus to prevent metastasis can be a rapid emerging and an improved version in therapeutic tool (Li et al, 2006;Kapoor, 2009). Modulating in Nm23-H1 gene expression can be used to draw to meet metastasis in malignant tumor because tumor metastasis is the leading cause of death in cancer patients (Marshall et al, 2009).…”

“…Nm23 is a reasonable target to attempt gene therapy for its multidisciplinary role in preventing metastasis. The evidence reveals that high efficient gene transfer accomplished by two or three intra peritoneal injection of adeno associated virus (AAV) increases Nm23 expression that leads to reduction in the development of liver metastasis that increased 35-days of survival time in ovarian cancer animals (Li et al, 2006).…”

NM23 et les genès Suppresseurs de métastases

“…Welch propose l'injection de Kisspeptines pour inhiber la colonisation métastatique [20]. Il a été montré que l'injection intra-péri-tonéale d'un vecteur adénoviral exprimant NM23-H1 réduit l'incidence des métastases hépatiques d'un modèle orthotopique de cancer de l'ovaire [40]. Très récemment, une équipe japonaise rapporte que l'administration intra-trachéale d'un vecteur adénoviral exprimant KAI1 réduit de façon majeure la masse des métastases ganglionnaires d'un modèle orthotopique de cancer du poumon [41].…”

Progress on Nme (NDP kinase/Nm23/Awd) gene family-related functions derived from animal model systems: studies on development, cardiovascular disease, and cancer metastasis exemplified

“…An inhibition of the Nme enzymatic activity by small molecule inhibitors was initially intended, but the available polyphenols such as ellagic acid (Buxton 2008), although widely discussed to be beneficial in cancer therapy, are unspecific kinase inhibitors and show low potency. Gene therapy approaches were successful preclinically (Li et al 2006;Li et al 2009) but remain clinically intractable. A variety of alternative approaches have been pursued.…”