Cytosine deaminase suicide gene therapy for peritoneal carcinomatosis

Abstract

Gene therapy is a novel therapeutic approach that might soon improve the prognosis of some cancers. We investigated the feasibility of cytosine deaminase (CD) suicide gene therapy in a model of peritoneal carcinomatosis. DHD/K12 colorectal adenocarcinoma cells transfected in vitro with the CD gene were highly sensitive to 5-fluorocytosine (5-FC), and a bystander effect could also be observed. Treating CD ϩ cells with 5-FC resulted in apoptosis as detected by terminal deoxynucleotidyltransferasemediated deoxyuridine triphosphate nick-end labeling. In vitro, several human cell lines derived from ovarian or colorectal carcinomas, as well as the rat glioblastoma 9 L cell line, responded to CD/5-FC and showed a very strong bystander effect. 5-FC treatment of peritoneal carcinomatosis generated in syngeneic BDIX rats by CD-expressing DHD/K12 cells led to a complete and prolonged response and to prolonged survival. Our study thus demonstrated the efficacy of CD suicide gene therapy for the treatment of peritoneal carcinomatosis. Cancer Gene Therapy (2000) 7, 20 -26

Transferrin lipoplex-mediated suicide gene therapy of oral squamous cell carcinoma in an immunocompetent murine model and mechanisms involved in the antitumoral response

“…[34][35][36][37] Therefore, we investigated the therapeutic potential of CD expression mediated by Tf-lipoplexes followed by 5-FC treatment in tumors established in the syngeneic mice C3H/HeOuJ. The results illustrated in Figure 3 show that CD gene delivery was also highly effective in reducing tumor size when mediated by Tf-lipoplexes.…”

Cellular and molecular events associated with the antitumor response induced by the cytosine deaminase/5-fluorocytosine suicide gene therapy system in a rat liver metastasis model

“…[25][26][27] In the present work, we investigated whether the tumor regression observed in the experi- Immune response induced by suicide gene therapy S Bertin et al mental model of liver metastasis, upon application of the different treatments, was associated with tumor cell apoptosis. TUNEL staining has been used extensively to identify cells with nuclear DNA fragmentation and, therefore, this assay was selected for these studies.…”

“…The absence of any enhancement in the therapeutic effect upon DNA complexation with the cationic liposomes suggests that the strong local bystander effect, associated with CD/5-FC suicide gene therapy system, 19,27 masks the benefit associated to an increased gene transfer efficiency. Application of this strategy also results in an antitumor immune response as evidenced by the concomitant volume decrease of the controlateral liver tumor.…”

Specific CEA-producing colorectal carcinoma cell killing with recombinant adenoviral vector containing cytosine deaminase gene

“…CD transforms nontoxic prodrug 5-fluorocytosine (5-FC) into an antitumor chemotherapeutic agent 5-fluorouracil (5-FU). This gene has already been tested in vitro as well as in several animal models; most of them being based on colorectal carcinoma cells [20][21][22][23][24] . If suicide gene wese delivered into cells, these cells, either target cells or normal cells, might be killed.…”