Cancer-specific gene therapy.
Cancer cells transcriptionally activate many genes that are important for uncontrolled proliferation and cell death. Deregulated transcriptional machinery in tumor cells usually consists of increased expression/activity of transcription factors. Ideally, cancer-specific killing can be achieved by delivering a therapeutic gene under the control of the DNA elements that can be activated by transcription factors that are overexpressed and/or constitutively activated in cancer cells. Additionally, tumor-specific translation of tumor-killing genes has been also exploited in cancer gene therapy. Based on these rationales, cancer-specific expression of a therapeutic gene has emerged as a potentially successful approach for cancer gene therapy. To achieve tumor-specific expression, cancer-specific vectors are generally composed of promoters, enhancers, and/or 5'-UTR that are responsive to tumor-specific transcription factors. A number of cancer-specific promoters have been reported, such as those of probasin, human telomerase reverse transcriptase, survivin, ceruloplasmin, HER-2, osteocalcin, and carcinoembryonic antigen. Evidences suggest that the enhancer element targeted by beta-catenin can be useful to target colon cancer cells. The 5'-UTR of the basic fibroblast growth factor-2 has been reported to provide tumor specificity. Moreover, a variety of therapeutic genes demonstrated direct antitumor effects such as those encoding proapoptotic proteins p53, E1A, p202, PEA3, BAX, Bik, and prodrug metabolizing enzymes, namely thymidine kinase and cytosine deaminase. As cancerous cells of different origins vary significantly in their genetic, transcriptional/translational, and cellular profiles, the success of a cancer gene therapy will not be promised unless it is carefully designed based on the biology of a specific tumor type. Thus, tremendous research efforts have been focused on the development of non-viral vectors that selectively target various tumors resulting in minimal toxicity in the normal tissues. Significant progresses were also made in the exploitation of various novel apoptotic, cytotoxic genes as therapeutic tools that suppress the growth of different tumors. Together, these recent advances provide rationales for future clinical testing of transcriptionally targeted non-viral vectors in cancer patients.
Lo
Hui-Wen
HW
Department of Molecular and Cellular Oncology The University of Texas M.D. Anderson Cancer Center Houston, Texas 77030, USA.
Day
Chi-Ping
CP
Hung
Mien-Chie
MC
D017500:Adenovirus E1A Proteins / Q000235:genetics; D000727:Androgen-Binding Protein / Q000235:genetics; D000818:Animals; D051017:Apoptosis Regulatory Proteins; D002570:Ceruloplasmin / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D005260:Female; D015870:Gene Expression; D016158:Genes, p53; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D008869:Microtubule-Associated Proteins / Q000235:genetics; D024101:Mitochondrial Proteins; D009363:Neoplasm Proteins / Q000235:genetics; D009369:Neoplasms / Q000235:genetics / Q000628:therapy*; D010051:Ovarian Neoplasms / Q000235:genetics / Q000628:therapy; D010750:Phosphoproteins / Q000235:genetics; D011401:Promoter Regions, Genetic; D011471:Prostatic Neoplasms / Q000235:genetics / Q000628:therapy; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D000077022:Survivin; D019098:Telomerase / Q000235:genetics; D000071857:Tumor Suppressor p53-Binding Protein 1; D051028:bcl-2-Associated X Protein
D017500:Adenovirus E1A Proteins; D000727:Androgen-Binding Protein; D051017:Apoptosis Regulatory Proteins; C494826:BAX protein, human; C096820:BIK protein, human; C107489:BIRC5 protein, human; D004268:DNA-Binding Proteins; D051034:Inhibitor of Apoptosis Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins; D024101:Mitochondrial Proteins; D009363:Neoplasm Proteins; D010750:Phosphoproteins; D019253:Proto-Oncogene Proteins c-bcl-2; D000077022:Survivin; C498301:TP53BP1 protein, human; D000071857:Tumor Suppressor p53-Binding Protein 1; D051028:bcl-2-Associated X Protein; C027519:probasin; D002570:Ceruloplasmin; D019098:Telomerase