Colorectal cancer (CRC) is the second most common type of cancer in the Western world. Despite improvements in treatment, CRC recurs in up to 50% of patients and ultimately proves to be fatal.
CRC lends itself to various gene-therapy approaches, which include gene correction, virus-directed enzyme–prodrug therapy, immunogenetic manipulation and virotherapy.
CRC can be confined to organs (liver) or compartments (peritoneal cavity) for most of its natural history, allowing regional administration of the gene vector.
Gene-replacement trials have been initiated combining adenoviral TP53, which can act as a cytotoxic sensitizer, and conventional chemotherapy.
Virus-directed enzyme–prodrug therapy involves viral delivery of a transgene encoding an enzyme that can convert a non-toxic prodrug to a cytotoxic species. Early-phase clinical trials have been initiated with cytosine deaminase/fluorocytosine, herpes simplex virus thymidine kinase/gancyclovir and nitroimidazole reductase/CB1954.
Adenoviral transduction of allogeneic CRC cells with the gene encoding interleukin-2, vaccinia and fowl-pox vaccines aimed at inducing T-cell responses to carcinoembryonic antigen, and manipulation of MHC expression have all produced clinical immune responses in trials of immunogenetic therapies.
Virotherapy, with replication-competent adenoviruses engineered to proliferate in CRC cells with mutant p53 or RB, has been used to treat patients with hepatic metastases, in combination with 5-fluorouracil.
Randomized clinical trials are required to show the added value of gene therapy in the management of CRC; it is probable that combination gene therapy will be required to complement conventional chemotherapy.
Colorectal cancer (CRC) is the second most common type of malignancy in Western nations. Improvements in surgical and radiotherapeutic techniques and the increased availability of new cytotoxic drugs have improved outcome, but 50% of patients still die from recurrent or metastatic disease. Several features of its natural history render CRC a good candidate for gene therapy. Techniques include gene replacement, virus-directed enzyme–prodrug therapy, immune manipulation and virotherapy, all of which have entered clinical trials.
Subscribe to Journal
Get full journal access for 1 year
only $4.92 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Ferlay, J., Bray, F., Pisani, P. & Parkin, D. M. Globocan 2000. Cancer incidence, mortality and prevalence worldwide, version 1.0. IARC Cancer Base No. 5. (IARC Press, Lyon, 2001).
Fearon, E. R. & Vogelstein, B. A genetic model for colorectal tumorigenesis. Cell 61, 759–767 (1990). Excellent summary of the pattern of mutations that characterize the transition from normal colon epithelium to adenoma and then adenocarcinoma.
Bodmer, W. F. et al. Localisation of the gene for familial adenomatous polyposis on chromosome 5. Nature 328, 614–616 (1987).
Cottrell, S., Bicknell, D., Kaklamanis, L. & Bodmer, W. F. Molecular analysis of APC mutations in familial adenomatous polyposis and sporadic colon carcinomas. Lancet 340, 626–630 (1992).
Midgley, R. & Kerr, D. J. Seminar in colorectal cancer. Lancet 353, 391–399 (1999). General background introduction to the natural history and modern management of colorectal cancer.
Douillard, J. Y. et al. Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: a multicentre randomised trial. Lancet 355, 1041–1047 (2000).
Todryk, S. M., Chong, H., Vile, R. G., Pandha, H. & Lemoine, N. R. Can immunotherapy by gene transfer tip the balance against colorectal cancer? Gut 43, 445–449 (1998).
Mendelsohn, J. & Baselga, J. The EGF receptor family as targets for cancer therapy. Oncogene 19, 6550–6565 (2000).
Papamichael, D. Prognostic role of angiogenesis in colorectal cancer. Anticancer Res. 21, 4349–4354 (2001).
Thompson, J. A., Grunert, F. & Zimmermann, W. Carcinoembryonic antigen gene family: molecular biology and clinical perspectives. J. Clin. Lab. Anal. 5, 344–366 (1991).
Kinzler, K. W. & Vogelstein, B. The colorectal cancer gene hunt: current findings. Hosp. Prac. 27, 51–58 (1992).
Kinzler, K. W. & Vogelstein, B. Lessons from hereditary colorectal cancer. Cell 87, 159–170 (1996).
Houlston, R. S. & Tomlinson, I. P. M. Polymorphisms and colorectal tumour risk. Gastroenterology 121, 282–301 (2001).
Harris, M. P. et al. Adenovirus-mediated p53 gene transfer inhibits growth of human tumour cells expressing mutant p53 protein. Cancer Cell Ther. 3, 121–130 (1996).
Opalka, B., Dickopp, A. & Kirch, H. C. Apoptotic genes in cancer therapy. Cells Tissues Organs 172, 126–132 (2002).
Venook, P. et al. Gene therapy of colorectal liver metastasis using recombinant adenovirus encoding wt p53 (SCH58500) via hepatic artery infusion: a phase I study. Proc. Am. Soc. Clin. Oncol. 17, 431 (1998).
Van Etten, B. et al. Prerequisites for effective adenovirus mediated gene therapy of colorectal liver metastases in that rat using an intracellular neutralizing antibody of p21-Ras. Br. J. Cancer 86, 436–442 (2002).
Chung-Faye, G. A. et al. In vivo gene therapy for colon cancer using adenovirus-mediated, transfer of the fusion gene cytosine deaminase and uracil phosphoribosyltransferase. Gene Ther. 8, 1547–1554 (2001).
Rogulski, K. R., Kim, J. H., Kim, S. H. & Freytag, S. O. Glioma cells transduced with an Echerichia coli CD/HSV-1 TK fusion gene exhibit enhanced metabolic suicide and radiosensitivity. Hum. Gene Ther. 8, 73–85 (1997).
Green, N. K. et al. Sensitization of colorectal and pancreatic cancer cell lines to the prodrug 5 (aziridin-1-yl)-2, 4-dinitrobenzamide (CB1954) by retroviral transduction and expression of the E. coli nitroreductase gene. Cancer Gene Ther. 4, 229–238 (1997).
Green, N. K. et al. Gene therapy for cancer: in vivo killing of tumour cells expressing E-coli nitroreductase following administration of the prodrug CD1954. Gene Ther. 6, 33 (1999).
Burrows, F. J. et al. Purified herpes simplex virus thymidine kinase retroviral particles: III. Characterisation of bystander killer mechanisms in transfected tumour cells. Cancer Gene Ther. 9, 87–95 (2002).
Sung, M. W. et al. Intratumoural adenovirus-mediated suicide gene transfer for hepatic metastases from colorectal adenocarcinoma: results of a phase I clinical trial. Mol. Ther. 4, 182–191 (2001).
Huber, B. E., Austin, E. A., Richards, C. A., Davis, S. T. & Good, S. S. Metabolism of 5-fluorocytosine to 5-fluorouracil in human colorectal tumour cells transduced with cytosine deaminase gene: significant antitumour effects when only a small percentage of tumour cells express cytosine deaminase. Proc. Natl Acad. Sci. USA 91, 8302–8306 (1994). Early demonstration of the utility of virus-directed enzyme–prodrug therapy and the importance of the bystander effect in vivo.
Crystal, R. G. et al. Phase I study of direct administration of replication deficient adenovirus vector containing the E. coli cytosine deaminase gene to metastatic colon carcinoma of the liver in association with the oral administration of the pro-drug 5-fluorocytosine. Hum. Gene Ther. 8, 985–1001 (1997).
McNeish, I. A. et al. Virus directed enzyme prodrug therapy for ovarian and pancreatric cancer using retrovirally delivered E. coli nitroreductase and CB1954. Gene Ther. 5, 1061–1069 (1998).
Chung-Faye, G. et al. Virus-directed, enzyme prodrug therapy with nitroimidazole reductase: a phase I and pharmacokinetic study of its prodrug, CB1954. Clin. Cancer Res. 7, 2662–2668 (2001).
Palmer, D. H. et al. Virus-directed enzyme prodrug therapy (VDEPT) clinical trials with adenoviral nitroimidazole reductase (ad–ntr). Br. J. Cancer 86, S30 (2002).
Chang, T. K., Weber, G. F., Crespi, C. L. & Waxman, D. J. Differential activation of cyclophosphamide and ifosphamide by cytochromes P-450 2B and 3A in human liver microsomes. Cancer Res. 53, 5629–5637 (1993).
Marais, R., Spooner, R. A., Light, Y., Martin, J. & Springer, C. J. Gene-directed enzyme prodrug therapy with a mustard prodrug/carboxypeptidase G2 combination. Cancer Res. 56, 4735–4742 (1996).
Kojima, A., Hackett, N. R., Ohwada, A. & Crystal, R. G. In vivo human carboxylesterase cDNA gene transfer to activate the prodrug CPT-11 for local treatment of solid tumours. J. Clin. Invest. 101, 1789–1796 (1998).
Nabel, G. J. et al. Direct gene transfer with DNA-liposome complexes in melanoma: expression, biologic activity, and lack of toxicity in humans. Proc. Natl Acad. Sci. USA 90, 11307–11311 (1993).
Rubin, J. et al. Phase I study of immunotherapy of hepatic metastases of colorectal carcinoma by direct gene transfer of an allogeneic histocompatability antigen, HLA-B7. Gene Ther. 4, 419–425 (1997).
Fakhrai, H. et al. Cytokine gene therapy with interleukin-2 transduced fibroblasts: effects of IL-2 dose on anti-tumour immunity. Hum. Gene Ther. 6, 591–601 (1995).
Galanis, E. et al. Immunotherapy of advanced malignancy by direct gene transfer of an interleukin-2 DNA/DMRIE/DOPE lip complex: phase I/II experience. J. Clin. Oncol. 17, 3313–3323 (1999).
Sobol, R. E. et al. Interleukin 2 gene therapy of colorectal carcinoma with autologous irradiated tumour cells and genetically engineered fibroblasts: a phase I study. Clin. Cancer Res. 5, 2359–2365 (1999).
Schmidt-Wolf, I. G. et al. Phase I clinical study applying autologous immunological effector cells transfected with the interleukin-2 gene in patients with metastatic renal cancer, colorectal cancer and lymphoma. Br. J. Cancer 81, 1009–1016 (1999).
Tsang, K. Y. et al. Generation of human cytotoxic T cells specific for human carcinoembryonic antigen epitopes from patients immunized with recombinant vaccinia-CEA vaccine. J. Natl Cancer Inst. 87, 982–990 (1995). High-quality Phase I trial of a carcinoembryonic antigen (CEA) vaccine, showing that it was possible to detect human cytotoxic T cells specific for CEA epitopes.
Conry, R. M. et al. Phase I trial of a recombinant vaccinia virus encoding carcinoembryonic antigen in metastatic adenocarcinoma: comparison of intradermal versus subcutaneous administration. Clin. Cancer Res. 5, 2330–2337 (1999).
Conry, R. M. et al. Human autoantibodies to carcinoembryonic antigen (CEA) induced by a vaccinia-CEA vaccine. Clin. Cancer Res. 6, 34–41 (2000).
Hodge, J. W., McLaughlin, J. P., Kantor, J. A. & Scholm, J. Diversified prime and boost protocols using recombinant vaccinia virus and recombinant non-replicating avian pox virus to enhance T-cell immunity and antitumour responses. Vaccine 15, 759–768 (1997).
Marshall, J. L. et al. Phase I study in cancer patients of a replication-defective avipox recombinant vaccine that expresses human carcinoembryonic antigen. J. Clin. Oncol. 17, 332–337 (1999).
Zhu, M. Z., Marshal, J., Cole, D., Scholm, J. & Tsang, K. Y. Specific cytolytic T-cell responses to human CEA from patients immunized with recombinant avipox-CEA vaccine. Clin. Cancer Res. 6, 24–33 (2000).
Horig, H. et al. Phase I clinical trial of a recombinant canarypoxvirus (ALVAC) vaccine expressing human carcinoembryonic antigen and the B7.1 co-stimulatory molecule. Cancer Immunol. Immunother. 49, 504–514 (2000).
Kirn, D. H. & McCormick, F. Replicating viruses as selective cancer therapeutics. Mol. Med. Today 2, 519–527 (1996).
Smith, E. R. & Chiocca, E. A. Oncolytic viruses as novel anticancer agents: turning one scourge against another. Exp. Opin. Invest. Drugs 9, 311–327 (2000).
Bischoff, J. R. et al. An adenovirus mutant that replicates selectively in p53-deficient human tumour cells. Science 274, 373–376 (1996). First description of tumour-specific replication-competent adenovirus in cancer cells with mutant TP53.
Reid, T. et al. Intra-arterial administration of a replication-selective adenovirus (dl1520) in patients with colorectal carcinoma metastatic to the liver: a phase I trial. Gene Ther. 8, 1618–1626 (2001).
Reid, T. et al. Hepatic arterial infusion of replication-selective adenovirus (dl1520): phase II viral, immunologic and clinical endpoints. Cancer Res. 62, 6070–6079 (2002).
Richards, C. A., Austin, E. A. & Huber, B. E. Transcriptional regulatory sequences of carcinoembryonic antigen: identification and use with cytosine deaminase for tumour-specific gene therapy. Hum. Gene Ther. 6, 881–893 (1995).
Bisland, A. E. et al. Selective ablation of human cancer cells by telomerase specific adenoviral suicide gene therapy vectors expressing bacterial nitroreductase. Oncogene 22, 370–380 (2003).
Fisher, K. D. et al. Polymer-coated adenovirus permits efficient retargeting and evades neutralizing antibodies. Gene Ther. 8, 341–348 (2001).
Maruta, F. et al. Identification of FGF receptor-binding peptides for cancer gene therapy. Cancer Gene Ther. 9, 543–552 (2002).
Benson, A. B. et al. Bevacizumab (anti–VEGF) plus FOLFOX 4 in previously treated advanced colorectal cancer patients. Proc. Am. Soc. Clin. Oncol. A39, A975 (2003).
Humbley, Y. et al. Cituximab alone or in combination with irinotecan in patients with epidermal growth factor receptor positive, irinotecan refractory colorectal cancer. Proc. Am. Soc. Clin. Oncol. A39, A1012 (2003).
Fearnhead, N. S., Wilding, J. L. & Bodmer, W. F. in Advances in Colorectal Cancer British Medical Bulletin Vol. 64 (eds Kerr, D. J., Bodmer, W. F., McArdle, C. S. & Pignatelli, M.) 27–43 (Oxford Univ. Press, Oxford, 2002).
- ONCO-FETAL ANTIGENS
Cell-surface-associated antigens that are normally expressed during specific phases of embryogenesis but are not expressed at significant levels in adults. These can be dysregulated during carcinogenesis.
- ASYMPTOMATIC TRANSAMINITIS
The increase of liver enzymes (such as aspartate and alanine aminotransferases) that are measurable in the blood in response to tissue damage.
- MAJOR HISTOCOMPATIBILITY COMPLEX
(MHC). A genetic region encoding proteins that are involved in antigen presentation to T cells. MHC class I molecules bound to peptide are recognized by the T-cell receptors of CD8+ T cells.
- CAPILLARY LEAK SYNDROME
Involves damage to vascular endothelial cells, and the extravasation of fluids and proteins, resulting in weight gain and, in its most severe form, kidney damage and pulmonary oedema.
- PHAGE DISPLAY
Technology for displaying a protein (or peptide) on the surface of a bacteriophage, which contains the gene(s) that encodes the displayed protein(s), thereby physically linking the genotype and phenotype.
The process of separating target-binding clones from nonbinding clones for a phage display library.
About this article
Development of a prognostic index and screening of potential biomarkers based on immunogenomic landscape analysis of colorectal cancer
Downregulation of STK4 promotes colon cancer invasion/migration through blocking β‐catenin degradation
Molecular Oncology (2020)
Combination of targeting CD24 and inhibiting autophagy suppresses the proliferation and enhances the apoptosis of colorectal cancer cells
Molecular Medicine Reports (2019)
Human Gene Therapy (2019)
Advanced Materials (2019)