ABSTRACT
Virus-directed enzyme prodrug therapy (VDEPT) utilising cytosine deaminase (CD) converts 5-fluorocytosine (5-FC) into the chemotherapy agent, 5-fluorouracil (5-FU), and has entered into a clinical trial for metastatic colon cancer. To improve this system, a replication-deficient adenovirus, containing a bifunctional fusion gene, CD:uracil phosphoribosyltransferase (UPRT), was constructed (AdCDUPRT). UPRT enhances the conversion of 5-FU into its active metabolites, which inhibit DNA and RNA synthesis. In vitro, AdCDUPRT infection of colon cancer cells resulted in a marked increase in sensitisation to 5-FU, compared with AdCD-infected or uninfected cells. The corollary is a approximately 100-fold and approximately 10 000-fold increase in sensitisation to 5-FC in AdCDUPRT-infected cells, compared to AdCD-infected and uninfected cells, respectively. There was a strong bystander effect in vitro, 70% of tumour cells were killed by 5-FC when only 10% of cells expressed CDUPRT. In vivo, athymic mice with colon cancer xenografts treated with intratumoral AdCDUPRT and intraperitoneal 5-FC, significantly reduced tumour growth rates compared with untreated controls (P = 0.02), whereas AdCD/5-FC treated mice did not. At higher AdCDUPRT virus doses, 5-FC and 5-FU were equally effective at delaying tumour growth compared with controls. In summary, VDEPT for colon cancer utilising AdCDUPRT is more effective than AdCD and the bifunctional CDUPRT gene enables the use of either 5-FC or 5-FU as prodrugs.
Subject(s)
Colonic Neoplasms/therapy , Genetic Therapy/methods , Nucleoside Deaminases/genetics , Pentosyltransferases/genetics , Prodrugs/therapeutic use , Transfection/methods , Adenoviridae/genetics , Analysis of Variance , Animals , Artificial Gene Fusion/methods , Bystander Effect , Cytosine Deaminase , Flucytosine/metabolism , Flucytosine/therapeutic use , Fluorouracil/metabolism , Genetic Vectors/administration & dosage , Humans , Injections, Intralesional , Mice , Mice, Nude , Neoplasm Transplantation , Random Allocation , Transplantation, Heterologous , Tumor Cells, CulturedABSTRACT
Colorectal cancer is a leading cause of cancer mortality in Western countries. Gene therapy has been proposed as a potential novel treatment modality for colorectal cancer, but it is still in an early stage of development. The preclinical data have been promising and numerous clinical trials are underway. This brief review aims to summarise the current status of clinical trials of different gene therapy strategies, including immune stimulation, mutant gene correction, prodrug activation and oncolytic virus therapy, for patients with colorectal cancer. Data from phase I trials have proven the safety of the reagents but have not yet demonstrated significant therapeutic benefit. In order to achieve this and extend the scope of the treatment, continuing efforts should be made to improve the antitumour potency, efficiency of gene delivery and accuracy of gene targeting.
Subject(s)
Colorectal Neoplasms/therapy , Genetic Therapy , Adenoviridae/genetics , Antigen Presentation , Aziridines/metabolism , Carcinoembryonic Antigen/immunology , Clinical Trials as Topic , Flucytosine/metabolism , Ganciclovir/metabolism , Genes, p53 , Humans , T-Lymphocytes, Cytotoxic/immunologyABSTRACT
Colorectal cancer is the second most common cause of cancer mortality in Western countries. Gene therapy represents a novel approach to the treatment of colorectal cancer, and this review addresses the current strategies and ongoing clinical trials, including gene correction, immunomodulatory approaches and virus-directed enzyme-prodrug systems. Although the pre-clinical results for these strategies have been encouraging, clinical trials have not yet reflected these data. However, gene therapy for colorectal cancer is still in the early stages of development, and its potential, particularly in combination with conventional cancer therapies, warrants further investigation.
