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At least 163 records · Page 9Linked to original sources

PubMed1998

Cancer gene therapy by direct tumor injections of a nonviral T7 vector encoding a thymidine kinase gene.

Previously, we described a nonviral cytoplasmic gene therapy vector system based on the T7 autogene concept. This system has been shown to achieve rapid and high levels of gene expression in a variety of animal cells and tissues. To test the utility of the system in vivo tumor ablation, a T7 cancer gene therapy plasmid vector, pT7T7/T7TK, was constructed. This nonviral vector contains a T7 autogene, T7T7, and a human herpes simplex virus thymidine kinase (HSV-TK) gene driven by a second T7 promoter (T7TK). When co-transfected with T7 RNA polymerase (T7 RNAP) into cultured human osteosarcoma 143B cells, abut 10-20% of the cells were found to express HSV-TK, and more than 90% of the cells were killed in the presence of 1 microM ganciclovir (GCV) within 4 days after DNA transfection. The increase in killing above the transfection frequency is due to a "bystander" effect among transfected and untransfected 143B cells. Direct injections of pT7T7/T7TK into 143B tumors grown in nude mice resulted in TK gene expression in tumor cells located near the injection sites as revealed by the immunohistochemical staining. Repeated tumor injections of the pT7T7/T7TK vector and intraperitoneal (i.p.) injections of GCV resulted in inhibition of tumor growth and in tumor shrinkage in 6 out of 10 treated nude mice. Three of those six tumors fully regressed shortly after the end of the GCV injections. All of the full tumor regressions were found to be permanent and no apparent tumor relapses were observed for the rest of the lives of the treated nude mice after the initial tumor ablations. These results, combined with the nonviral and rapid cytoplasmic gene expression features, suggest that the T7 vector may be a good candidate for cancer gene therapy and other medical and biological applications.

Animals↗

PubMed2000

Cancer gene therapy: developments to 2000.

Cancer, at the molecular level, continues to be more thoroughly understood. With this understanding comes the opportunity for innovative therapeutic intervention. Gene therapy remains an attractive concept to treat cancer. However, a number of gene therapy clinical trials have now been reported and it is clear that barriers remain before gene therapy gains widespread clinical application. This article outlines current directions and novel developments in the field of cancer gene therapy, which attempt to overcome these obstacles.

Animals↗

PubMed2007

Clinicopathologic significance of EpCAM expression in squamous cell carcinoma of the tongue and its possibility as a potential target for tongue cancer gene therapy.

Epithelial adhesion molecule (EpCAM) is a transmembrane glycoprotein involved in intercellular adhesion. In particular, EpCAM appears to be overexpressed by the majority of human epithelial carcinomas, including colorectal, breast, head and neck, and hepatic carcinomas. We therefore hypothesized that EpCAM would be a good molecular target for cancer gene therapy. EpCAM protein expression in 48 primary tongue cancers and 10 normal oral mucosa was evaluated using anti-EpCAM immunohistochemistry, and correlation was examined with the clinicopathologic factors. In four human tongue cancer cell lines (SAS, HSC-2, OSC19 and OSC20), we investigated EpCAM expression by reverse transcription-polymerase chain reaction (RT-PCR). The invasive potential of cancer cells was evaluated using Matrigel invasion assay. Moreover, the effect of EpCAM inhibition was analyzed using RNA interference (RNAi). EpCAM overexpression was detected in 30 of 48 tongue cancers (62.5%), and was significantly higher in primary squamous cell carcinoma (SCC) of the tongue than in normal oral mucosa. The expression of EpCAM was significantly associated with tumor size, regional lymph node metastasis, histological differentiation and invasion pattern. Cancer cell lines with higher EpCAM expression had more invasive potential. Moreover, RNAi-mediated EpCAM reduction decreased the invasion potential and proliferation activity. These results indicated that the overexpression of EpCAM was correlated with a more aggressive phenotype of tongue cancer. Moreover, we suggested that EpCAM could be a molecular target, and that RNAi targeting EpCAM could be useful for tongue cancer gene therapy.

Aged↗

PubMed1997

Simultaneous genetic chemoprotection of normal marrow cells and genetic chemosensitization of breast cancer cells in a mouse cancer gene therapy model.

Repeated exposures to high doses of chemotherapy are often required to eradicate solid tumors. The success of such high-dose therapy is often limited by the myelosuppressive and toxic effects of these drugs on bone marrow cells and by the intrinsic resistance of the cancer cells to chemotherapy. To test ways of using genetic modification of somatic cells to circumvent both of these problems, we first genetically modified normal bone marrow cells with multidrug resistance-1 (MDR-1) cDNA retroviral vectors to render these cells more resistant to p-glycoprotein-transported agents. Experiments conducted previously in a mouse model in our laboratory (E. G. Hanania et al., Cancer Gene Ther., 2: 251-261, 1995; E. G. Hanania and A. B. Deisseroth, Cancer Gene Ther., 1: 21-25, 1994), which involve transplantation of mouse marrow cells modified with the human MDR-1 cDNA, showed that the majority of the marrow cells of these animals were resistant to repetitive administration of myelotoxic doses of Taxol, a MDR-1-transported drug. Next, to test the effects of genetically modifying marrow cells to make them resistant to chemotherapy, and genetically modifying tumor cells to make them more sensitive to chemotherapy, a mouse breast cancer cell line was transfected with a plasmid expression vector that contained a wild-type p53 chemosensitization transcription unit. Others have shown that restoration of the p53 gene can lead to decreased proliferation, reduced tumorigenicity, and increased sensitivity to chemotherapy-induced apoptosis. In this animal model, the simultaneous use of both chemoprotection and chemosensitization vectors, which provided protection of the normal cells to the chemotherapy and at the same time sensitized the tumor cells to the toxic effects of the chemotherapy, resulted in levels of in vivo tumor reduction that were not possible when either genetic chemoprotection of marrow cells or chemosensitization of tumor cells was used alone. These data should be of interest to those who are studying ways of using genetic modification to improve the outcome of established chemotherapy treatment programs for solid tumors.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1996

Cancer gene therapy using tumor cells infected with recombinant vaccinia virus expressing GM-CSF.

The efficacy of a recombinant vaccinia virus (rvv-mGM-CSF) expressing murine granulocyte-macrophage colony stimulating factor (GM-CSF) for use in cancer gene therapy was evaluated. C57BL/6 mice with established B16-F10 melanoma were treated by s.c. injection of irradiated B16 cells infected with two different recombinant vaccinia virus (rvv) constructs. Mice treated with rvv-mGM-CSF vaccine survived longer (p < 0.05), were free of palpable tumors (> 4 mm) longer (p < 0.02), and had smaller mean tumor volumes (p < 0.005) compared to those treated with irradiated B16 cells infected with a control rvv (rvv-lacZ) expressing Escherichia coli beta-galactosidase or irradiated uninfected B16 cells. The vaccine appeared to be B16 tumor cell specific, because there was no therapeutic effect when heterologous but syngeneic (H-2b) colon adenocarcinoma cells, MC-38 infected with rvv-mGM-CSF were used as vaccine. In this model, rvv expressing interleukin-2 (IL-2) was ineffective. In addition, experimental lung metastasis of B16 tumor cells was significantly inhibited by rvv-mGM-CSF vaccine compared to several control vaccines when the vaccine was applied either by i.p. route (p < 0.006) or by s.c. injection (p < 0.0008). B16 cells expressing mGM-CSF after infection with rvv-mGM-CSF or transduction with a retroviral vector, were equally effective (p > 0.14) as vaccines against lung metastasis. Inhibition of metastasis was also B16 tumor cell specific. These data suggest that this approach of cancer gene therapy has a potential for use in cancer patients.

Adenocarcinoma↗

PubMed2000

Progress in cancer gene therapy.

The "First International Symposium on Genetic Anticancer Agents," which took place in Amsterdam on March 8-9, 2000, served as a forum to review the results of preclinical and clinical gene therapy studies for cancer endeavored to date. Despite the fact that gene therapy was initially conceptualized as an approach for inherited genetic disease, it is currently finding its widest employ for treating neoplastic disorders. In this regard, more than 70% of patients treated to date in human clinical gene therapy protocols have been in the context of anticancer regimens. Of note, the application of gene therapy for cancer has proceeded from the same rational basis as was originally conceptualized for inherited genetic disorders. Specifically, the molecular basis of these disorders is increasingly being understood, therapeutic genes are available, and alternative therapies are often lacking. Most recently, the field of gene therapy has enjoyed the realization of the first incontrovertible evidence of clinical benefit, for hemophilia and cardiovascular disease, in its first 15 years of human application. This recent recognition of the potential power of gene therapy, and the current lack of realizing such ends for neoplastic disease, has led to a reassessment of the field. Such a critical analysis is a necessary step in defining the means to progress the technology toward achieving the potential benefits of gene therapy for cancer.

Clinical Trials as Topic↗

PubMed2003

Integrated, molecular engineering approaches to develop prostate cancer gene therapy.

Gene therapy is a translational science, with the ultimate goal of cancer gene therapy research being to develop effective and safe treatments for patients. In the new millennium, it is imperative to tailor a therapeutic strategy for a particular disease, based on clinical management issues. The desirable regulatory features and therapeutic strategies need to be fully considered before proceeding with molecular engineering of the gene delivery vector. Issues, such as cell-targeted expression, in vivo monitoring of gene delivery and expression, therapeutic strategies, and vector selection that targets the particular disease stage should be addressed. During the validation phase of the study, an objective evaluation in relevant animal models should determine whether the vector meets the desired specifications. Meeting the predetermined criteria should propel the product towards the clinical phase of evaluation. This review will present the conceptual framework that has been applied to developing an integrated and targeted gene therapy for prostate cancer.

Animals↗

PubMed2001

Studying cancer families to identify kidney cancer genes.

We studied families with multiple members affected with renal cancer to delineate clinically distinct forms of inherited renal cancer, and to identify and characterize the genes responsible for these disorders. Today, cancer geneticists recognize seven clinically distinct, inherited forms of epithelial renal cancer; genes responsible for five inherited predispositions have been found. Positional cloning efforts for one kidney cancer gene are nearing completion. These discoveries will provide diagnostic tests for these diseases, a foundation for studies of the relationship between genotype and phenotype, and a basis for studies of the pathophysiology of the diverse types of epithelial renal cancer.

Animals↗

PubMed1997

Cancer genes and cholangiocarcinoma.

Genes involved in cancer development include oncogenes and tumor suppressor genes. Ras oncogene and mutations in p53 tumor suppressor gene are commonly found in many types of cancer. In Thai patients with cholangiocarcinoma ras oncogenes occur less frequently than in other ethnic groups and furthermore, p53 mutations also occur with lower incidence when compared with Japanese subjects. It is unclear at this time the basis for these differences.

Bile Duct Neoplasms↗

PubMed1994

Demonstration of a rational strategy for human prostate cancer gene therapy.

The potential efficacy and clinical feasibility of gene therapy for prostate cancer were tested. Efficacy was tested using the Dunning rat prostate carcinoma model. Rats with anaplastic, hormone refractory prostate cancer treated with irradiated prostate cancer cells genetically engineered to secrete human granulocyte-macrophage colony-stimulating factor (GM-CSF) showed longer disease-free survival compared to either untreated control rats or rats receiving prostate cancer cell vaccine mixed with soluble human GM-CSF. A gene modified prostate cancer cell vaccine thus provided effective therapy for anaplastic, hormone refractory prostate cancer in this animal model. An evaluation of the clinical feasibility of gene therapy for human prostate cancer based on these findings was then undertaken. Prostate cancer cells from patients with stage T2 prostate cancer undergoing radical prostatectomy were first transduced with MFG-lacZ, a retroviral vector carrying the beta-galactosidase reporter gene. Efficient gene transfer was achieved in each of 16 consecutive cases (median transduction efficiency 35%, range 12 to 65%). Cotransduction with a drug-selectable gene was not required to achieve high yield of genetically modified cells. Histopathology confirmed malignant origin of these cells and immunofluorescence analysis of cytokeratin 18 expression confirmed prostatic luminal-epithelial phenotype in each case tested. Cell yields (2.5 x 10(8) cells per gram of prostate cancer) were sufficient for potential entry into clinical trials. Autologous human prostate cancer vaccine cells were then transduced with MFG-GM-CSF, and significant human GM-CSF secretion was achieved in each of 10 consecutive cases. Sequential transductions increased GM-CSF secretion in each of 3 cases tested, demonstrating that increased gene dose can be used to escalate desired gene expression in individual patients. These studies show a preclinical basis for proceeding with clinical trials of gene therapy for human prostate cancer.

Gene Transfer Techniques↗

PubMed2004

Parvovirus vectors for cancer gene therapy.

Parvoviruses comprise a group of single-stranded DNA viruses with greater potential for gene therapy applications. Unique characteristics of paroviruses, such as non-pathogenicity, antioncogenicity and methods of efficient recombinant vector production, have drawn more attention towards utilising parvovirus-based vectors in cancer gene therapy. Although > 30 different parvoviruses have been identified so far, recombinant vectors derived from adeno-associated virus (AAV), minute virus of mice (MVM), LuIII and parvovirus H1 have been successfully tested in many preclinical models of human diseases, including cancer. The present article will focus on the potential of non-replicating and autonomously replicating parvoviral vectors in cancer gene therapy, including strategies that target tumour cells directly or indirectly.

Animals↗

PubMed1996

Anaerobic bacteria as a delivery system for cancer gene therapy: in vitro activation of 5-fluorocytosine by genetically engineered clostridia.

Certain species of anaerobic bacteria have been shown to localise and germinate specifically in the hypoxic regions of tumours, resulting in tumour lysis. We propose an innovative approach to cancer gene therapy in which genetically engineered anaerobic bacteria of the genus Clostridium are used to achieve tumour-specific gene delivery. Our strategy involves enzyme/prodrug therapy, in which the Escherichia coli enzyme cytosine deaminase is used to convert the non-toxic prodrug 5-fluorocytosine to the active chemotherapeutic agent 5-fluorouracil. The E. coli gene encoding cytosine deaminase has been cloned into a clostridial expression vector and transformed into Clostridium beijerinckii, resulting in constitutive expression of cytosine deaminase and significant levels of active enzyme in the bacterial medium. When added to an in vitro clonogenic survival assay, supernatant from clostridia expressing cytosine deaminase increased the sensitivity of murine EMT6 carcinoma cells to 5-fluorocytosine approximately 500-fold. This high level of prodrug activation, combined with the specificity of clostridia for hypoxic regions of tumours, indicates a potential use in cancer gene therapy.

Animals↗

PubMed2002

Alphavirus vectors as tools in cancer gene therapy.

Alphavirus vectors, particularly those based on the replicon of Semliki Forest virus, have shown great potential as gene delivery vehicles for various applications in cancer gene therapy. The rapid production of high-titer recombinant SFV particles, which show impressive transduction rates in various mammalian cell lines, primary cultures and in vivo, results in high levels of transgene expression. Additionally, SFV vectors induce apoptosis in transduced host cells, which can further increase their efficiency in tumor therapy. Because of the broad host range some attempts to target the gene delivery have been engineered for Sindbis virus vectors, where IgG binding domains of protein A have been introduced into the envelope structure of the recombinant particles to allow attachment of virus to host cells through the interaction of protein A with monoclonal antibodies. SFV vectors have also been employed for the production of retrovirus-like particles for establishment of long-term gene expression. Tumor vaccine approaches have been taken by injection of SFV vectors as naked RNA molecules, DNA plasmids or recombinant particles to achieve both therapeutic and prophylactic efficacy. The continuous improvement of alphavirus vectors will further expand the application range in the future.

Alphavirus↗

PubMed1997

Probability of carrying a mutation of breast-ovarian cancer gene BRCA1 based on family history.

BACKGROUND: Heritable mutations of the breast cancer gene BRCA1 are rare, occurring in fewer than 1% of women in the general population, and therefore account for a small proportion of cases of breast and ovarian cancers. Nevertheless, the presence of such mutations is highly predictive of the development of these cancers. PURPOSE: We developed and applied a mathematic model for calculating the probability that a woman with a family history of breast and/or ovarian cancer carries a mutation of BRCA1. METHODS AND RESULTS: As a basis for the model, we use Mendelian genetics and apply Bayes' theorem to information on the family history of these diseases. Of importance are the exact relationships of all family members, including both affected and unaffected members, and ages at diagnosis of the affected members and current ages of the unaffected members. We used available estimates of BRCA1 mutation frequencies in the general population and age-specific incidence rates of breast and ovarian cancers in carriers and noncarriers of mutations to estimate the probability that a particular member of the family carries a mutation. This probability is based on cancer statuses of all first- and second-degree relatives. We first describe the model by considering single individuals: a woman diagnosed with breast and/or ovarian cancer and also a woman free of cancer. We next considered two artificial and two actual family histories and addressed the sensitivity of our calculations to various assumptions. Particular relationships of family members with and without cancer can have a substantial impact on the probability of carrying a susceptibility gene. Ages at diagnosis of affected family members and their types of cancer are also important. A woman with two primary cancers can have a probability of carrying a mutation in excess of 80%, even with no other information about family history. The number and relationships of unaffected members, along with their current ages or ages at death, are critical determinants of one's carrier probability. An affected woman with several cancers in her family can have a probability of carrying a mutation that ranges from close to 100% to less than 5%. CONCLUSION: Our model gives informative and specific probabilities that a particular woman carries a mutation. IMPLICATIONS: This model focuses on mutations in BRCA1 and assumes that all other breast cancer is sporadic. With the cloning of BRCA2, we now know that this assumption is incorrect. We have adjusted the model to include BRCA2, but the use of this version must await publication of penetrance data for BRCA2, including those for male breast cancer that are apparently associated with BRCA2 but not with BRCA1. The current model is, nevertheless, appropriate and useful. Of principal importance is its potential and that of improved versions for aiding women and their health care providers in assessing the need for genetic testing.

Adult↗

PubMed1994

Intron splice acceptor site sequence variation in the hereditary non-polyposis colorectal cancer gene hMSH2.

Common but weakly penetrant mutations of certain genes may confer an increased susceptibility to colorectal cancer and account for a proportion of 'sporadic' cases. We analysed DNA from 111 colorectal cancer cases and 114 controls for a specific candidate sequence variation in the hereditary non-polyposis colorectal cancer gene hMSH2. The variant sequence was found in a quarter of individuals, and there was no difference between cancer cases and controls, according to age of development of cancer or presence of family history. It thus appears that this particular sequence variation is a polymorphism rather than a mutation which increases cancer susceptibility.

Adolescent↗

PubMed2001

Methioninase cancer gene therapy with selenomethionine as suicide prodrug substrate.

In this study, we report a novel approach to gene-directed enzyme prodrug therapy for cancer. This gene therapy strategy exploits the toxic pro-oxidant property of methylselenol, which is released from selenomethionine (SeMET) by cancer cells with the adenoviral-delivered methionine alpha,gamma-lyase (MET) gene cloned from Pseudomonas putida. In MET-transduced tumor cells, the cytotoxicity of SeMET is increased up to 1000-fold compared with nontransduced cells. A strong bystander effect occurred because of methylselenol release from MET gene-transduced cells and uptake by surrounding tumor cells. Methylselenol damaged the mitochondria via oxidative stress and caused cytochrome c release into the cytosol, thereby activating the caspase cascade and apoptosis. Adenoviral MET-gene/SeMET treatment also inhibited tumor growth in rodents and significantly prolonged their survival. Recombinant adenovirus-encoding MET gene-SeMET treatment thereby offers a new paradigm for cancer gene therapy.

Adenoviridae↗

PubMed2004

EpCAM is overexpressed in breast cancer and is a potential target for breast cancer gene therapy.

EpCAM (epithelial cell adhesion molecule) is a cell surface molecule that is known to be highly expressed in colon and other epithelial carcinomas. EpCAM is involved in cell-to-cell adhesion and has been the target of antibody therapy in several clinical trials. To assess the value of EpCAM as a novel target for breast cancer gene therapy, we performed real-time reverse transcription-PCR to quantify the level of EpCAM mRNA expression in normal breast tissue and primary and metastatic breast cancers. We found that EpCAM is overexpressed 100- to 1000-fold in primary and metastatic breast cancer. Silencing EpCAM gene expression with EpCAM short interfering RNA (siRNA) resulted in a 35-80% decrease in the rate of cell proliferation in four different breast cancer cell lines. EpCAM siRNA treatment decreased cell migration by 91.8% and cell invasion by 96.4% in the breast cancer cell line MDA-MB-231 in vitro. EpCAM siRNA treatment was also associated with an increase in the detergent-insoluble protein fraction of E-cadherin, alpha-catenin, and beta-catenin, consistent with the known biology of EpCAM as a regulator of cell adhesion. Our hypothesis is that modulation of EpCAM expression can affect cell migration, invasion, and proliferation by enhancing E-cadherin-mediated cell-to-cell adhesion. These data provide compelling evidence that EpCAM is a potential novel target for breast cancer gene therapy and offer insights into the mechanisms associated with EpCAM gene silencing.

Antigens, Neoplasm↗

PubMed2006

Adenoviral vectors--how to use them in cancer gene therapy?

Gene therapy is most often described as a technique for introducing the foreign genetic material into cells with a correction of a dysfunctional gene as its final goal. Today, it is well known that cancer is one of the leading causes of mortality in the world. Besides classical methods for cancer treatment new strategies against cancer are needed. Although originally being designed as a treatment for monogenetic illness, soon after, gene therapy appeared as a potential new strategy in cancer therapy. One of the widely used vectors for cancer gene therapy is adenovirus. In this review we have described molecular biology of adenoviruses and basis for construction of adenoviral vectors. We have also described concepts for cancer gene therapy including their in vitro and in vivo application. Special attention is drawn toward retargeting of adenovirus as a new approach in vector design for cancer gene therapy, in order to restrict transgene expression in tumor tissue. This approach uses biophysical as well as genetic characteristics of tumor itself and its supporting tissue, allowing new "bypass" in cancer gene therapy.

Adenoviridae↗