Gene therapy of cancer

OBJECTIVE: To provide a review of the basic concepts and terminology of human genetics, the clinical application and risks of gene therapy, and ethical and societal issues. DATA SOURCES: Review articles, research studies, and book chapters related to genetics and human gene therapy. CONCLUSIONS: The genetic changes that play a role in the development of cancer have begun to be elucidated, and these discoveries have led to strategies to destroy cancers by correcting genetic defects or manipulating genes to induce tumoricidal activities. Gene therapy is a novel investigational intervention that is constantly evolving. IMPLICATIONS FOR NURSING PRACTICE: Oncology nurses will need an increased understanding of cellular biology, genetics, and genetics engineering. Major considerations for nursing practice include patient and family education, informed consent, side effects, and ethical and societal issues.     

Gene therapy for lung cancer

Gene therapy has received considerable attention and some speculation as to its value. Although few patients have been treated, the preliminary results of the phase I lung cancer gene therapy clinical trials are very promising. Clinically relevant basic research in the molecular pathogenesis and immunology of lung cancer is progressing. As improved vector technologies are developed, new opportunities will be available to initiate lung cancer gene therapy trials that are based on a more detailed understanding of lung cancer biology. In conclusion, although important biologic and technical questions remain unanswered, recent research suggests that gene therapy will have a profound impact on lung cancer treatment.     

Gene therapy for colon cancer

The enormous number of newly diagnosed cases of colorectal cancer that occur each year and the lack of agents that are highly effective for all patients underscore the need for novel approaches to combating the disease. Gene therapy as a developing treatment modality is already well established, with a number of trials ongoing and a vast range of other approaches being assessed in animal and cell culture experiments. In this brief review, we have discussed five gene therapy trials in colon carcinoma that are ongoing or in the approval process in the United States. The gene therapy approaches being employed can be divided into three major categories: (1) enzyme/prodrug systems (HSVtk/ganciclovir; CD/5-fluorocytosine); (2) tumor suppressor gene replacement therapy with wild-type p53; and (3) immune-gene therapy which is based on cytokine or tumor antigen expression to induce tumor immunity (e.g., CEA). Replication-deficient recombinant adenoviral vectors are predominantly used for colon cancer gene therapy, because they can be produced at high titer and they readily infect a number of different cell types. One trial uses polynucleotide therapy for antitumor immunization with intramuscular injection. All of these studies are phase I trials, principally designed to evaluate safety, but they will also provide data on gene delivery. Some trials may provide some insight into potential therapeutic effects. We have alluded to some of the concerns on toxicity related to the use of adenovirus, risks and side effects from transgenes, lack of tumor-specificity of transgene expression, and potential problems with efficient gene delivery to solid tumors. The clinical trials, however, will provide insight that will inform design of future studies with respect to dose, form, and frequency of administration, as well as to the value of biologic and clinical endpoints. The molecular analysis of the fundamental basis of colon cancer has moved at a remarkable pace and that progress seems set to continue. Thus, the basic foundations for gene therapy are undoubtedly in place: a clinical need; growing understanding of basic tumor biology; and ever-improving delivery systems. The field is at a very early stage in its evolution, and one concern is that the considerable hurdles that must be overcome are seen as examples of the failure of cancer gene therapy; however, we believe these challenges will be overcome. The authors also believe that colon cancer gene therapy is likely to take new directions, such as use as adjuvant to radical surgery, rather than attempts to treat end-stage disease when the liver is replaced by metastases. Other new directions might include prophylactic gene-based immunization against a panel of well-characterized tumor antigens, at least for persons shown to be at high risk of colon cancer because of genetic or other predisposition. A marriage between gene therapy approaches and conventional anticancer treatments such as radiotherapy and chemotherapy also seems likely. There is already evidence of this move with demonstration of synergism between p53 replacement and radiotherapy and chemotherapy. It is also likely that therapies will be developed that combine elements from the cancer gene therapies discussed previously, namely, suicide gene transfer, immune modulation, and modulation of defective cancer genes. Perhaps one of the main concerns is not that researchers in cancer gene therapy want to walk before they can run, but that the public and government agencies believe they can. The next 10 years will be an interesting time in the development of novel treatments against colon cancer.     

Gene therapy for breast cancer

Gene therapy for breast cancer is still in the very early stages of development. Many of the molecular strategies that have been proposed are also being developed for other cancers. Their application to breast cancer, however, needs to address several issues specific to this disease such as the widespread nature of metastases, the indolent growth of the tumor cells, and the production by the tumor of immunosuppressive agents. Nonetheless, these approaches appear promising, particularly those that employ a combination of strategies. Gene therapies that affect the biology of breast cancer cells or regulate host immune mechanisms have been most successful and may be paired with existing therapies for breast cancer.     

Gene transfer therapy in cancer

Gene transfer techniques have now achieved clinical realization in the wake of recent advances in recombinant DNA technology, together with increased understanding of the molecular biology and immunology of cancer. These novel treatments, and their applications and limitations merit intensive study.     

Gene therapy

In recent years, there have been a number of technological breakthroughs that have allowed for clinical trials in gene therapy to be initiated. In combination with the genome initiative, the potential for new therapeutics is limitless. Although an enormous amount of information has been obtained in a relatively short period of time, gene therapy is not yet ready for wide-scale practice. Some of the successes and obstacles that remain are summarized in this report.     

Gene therapy

In the last years there has been much progress in our understanding of molecular mechanisms in the pathogenesis of disease. In this review we provide an overview of gene therapy, its most actualized techniques for gene delivery, and we give specific examples of laboratory and clinical achievements to date. The development of methods for delivering genes to mammalian cells has stimulated great interest in the possibility of treating human disease by gene-based therapies. As a result, concepts and methods that would have been considered purely science fiction 50 years ago are now used in the treatment of diseases. The widespread application of gene therapy technology to many diseases is already breaking down the traditional boundaries of modern medicine. However, despite its progress, several key technical drawbacks need to be overcome before gene therapy can be used safely and effectively in clinical settings. Technological developments, particularly in the areas of gene delivery and cell transplantation, will be critical for the successful practice of gene therapy.     

Gene therapy

Analyzing the duration and efficiency of treatment of 95 inpatients with first detected pulmonary tuberculosis indicated that the mean hospital stay of patients without and with decay was 205 and 291 days, respectively. Medical and social aspects should be considered while defining indications and hospital stay periods in patients with tuberculosis. Long-term hospitalization of the patients is justifiable only in complicated tuberculosis and special circumstances which require direct continuous follow-up.     

Gene therapy of neoplastic meningosis

Gene therapy of neoplastic meningosis is a promising new approach that relies on introduction of 'suicide' genes into cancer cells. The most commonly used gene has been the herpes virus thymidine kinase gene (HSV-tk) which has been delivered to cancer cells via retroviral or adenoviral vectors. A bystander cytocidal effect to non-transduced tumor cells has been documented and is dependent upon intercellular communication via gap junctions. A variety of gene therapy approaches using the HSV-tk system have been used in experimental models of neoplastic meningosis with promising results. Optimizing vector design and bystander cytotoxicity is a prerequisite for successful gene therapy in patients with neoplastic meningosis.     

Gene therapy for primary immunodeficiency

The mechanisms by which monocytes from patients infected with human immunodeficiency virus (HIV) have reduced growth inhibitory activity against Cryptococcus neoformans was examined. Monocyte-enriched peripheral blood mononuclear cells from 12 HIV-seropositive donors with CD4 cell counts of 10-210 cells/mm3 (median, 85) and HIV-seronegative donors were compared in assays to determine the binding and phagocytosis of C. neoformans and the respiratory burst and degranulation in response to C. neoformans and zymosan. Monocytes from HIV-infected and uninfected persons bound and ingested C. neoformans equally well; however, generation of hydrogen peroxide and specific release of beta-glucuronidase in response to C. neoformans was significantly reduced in monocyte-enriched cells from the HIV-infected donors. The impaired anticryptococcal activity of monocytes from persons with HIV may be related to defects in both oxidative and nonoxidative effector pathways that occur after the binding and internalization of the organism.     

Gene therapy for hematological malignancies

The management of avascular necrosis of the capitellum of the adolescent elbow continues to be a dilemma. This article is a critical retrospective analysis of 12 pediatric patients (mean age at surgery 14.5 years) who underwent arthroscopic debridement alone followed by early range of motion. Follow-up at a mean of 3.2 years (range, 2.0 to 5.7 years) indicated that the average flexion contracture improved from 23 degrees preoperatively to 10 degrees postoperatively. All patients had remodeling of the capitellum by plain radiographs; however, five patients had associated enlargement of the radial head. Eleven patients had minimal mechanical symptoms after the procedure and were highly satisfied. One patient had substantial enlargement of the radial head with continued loss of supination and mechanical symptoms requiring radial head resection 2 years after the index procedure. Five patients had a triangular avulsion fragment present off the lateral capsule. A statistically significant worse subjective outcome was associated with the presence of this fragment (P < .005). There were no complications.     

Gene therapy for malignant gliomas

Malignant gliomas are attractive targets for gene therapy because of their relatively well-localized distribution. Several new strategies have been devised that target different aspects of glioma biology. Gene transfer can be used to synthesize chemotherapy drugs that block DNA synthesis within these highly mitotic tumors. New genes can be introduced that restore the functions of mutated tumor suppressor genes or block the molecular pathways needed for tumor angiogenesis. Alternatively, the immune response to these tumors can be augmented by the local production of cytokines. Finally, viruses themselves can be used as tumoricidal agents by designing viruses that selectively replicate and destroy tumor cells. The advantages and limitations of these approaches are discussed in the context of their possible application to the treatment of these highly lethal malignancies.