Gene therapy in pancreatic cancer

Pancreatic cancer(PC) is a highly lethal disease and notoriously difficult to treat. Only a small proportion of PC patients are eligible for surgical resection, whilst conventional chemoradiotherapy only has a modest effect with substantial toxicity. Gene therapy has become a new widely investigated therapeutic approach for PC.This article reviews the basic rationale, gene delivery methods, therapeutic targets and developments of laboratory research and clinical trials in gene therapy of PC by searching the literature published in English using the PubMed database and analyzing clinical trials registered on the Gene Therapy Clinical Trials Worldwide website(http://www. wiley.co.uk/genmed/ clinical). Viral vectors are main gene delivery tools in gene therapy of cancer, and especially, oncolytic virus shows brighter prospect due to its tumor-targeting property.Efficient therapeutic targets for gene therapy include tumor suppressor gene p53, mutant oncogene K-ras,anti-angiogenesis gene VEGFR, suicide gene HSK-TK,cytosine deaminase and cytochrome p450, multiple cytokine genes and so on. Combining different targets or combination strategies with traditional chemoradiother-apy may be a more effective approach to improve the efficacy of cancer gene therapy. Cancer gene therapy is not yet applied in clinical practice, but basic and clinical studies have demonstrated its safety and clinical benefits. Gene therapy will be a new and promising field for the treatment of PC.     

Gene therapy for gastric cancer： Is it promising？

Gastric cancer is one of the most common tumorsworldwide.The therapeutic outcome of conventionaltherapies is inefficient.Thus,new therapeutic strategiesare urgently needed.Gene therapy is a promisingmolecular alternative in the treatment of gastric cancer,including the replacement of defective tumor suppressorgenes,the inactivation of oncogenes,the introduction ofsuicide genes,genetic immunotherapy,anti-angiogeneticgene therapy,and virotherapy.Improved molecularbiological techniques and a better understanding ofgastric carcinogenesis have allowed us to validate avariety of genes as molecular targets for gene therapy.This review provides an update of the new developmentsin cancer gene therapy,new principles,techniques,strategies and vector systems,and shows how they maybe applied in the treatment of gastric cancer.     

Current gene therapy for stomach carcinoma

INTRODUCTIONGastric cancer is common in China,and its early diagnosis andtreatment in advanced stage are difficult.In recent years,genestudy in cancer is a hotspot,and great progress has beenachieved.Cancer gene therapy has shifted from the imaginationinto the laboratory and clinical trials.The“logic of how genesfunction”coupled with the connections of cell cycle processes tospecific gene actions is creating a promise of treating tumors by genetherapy.There have been significant advances against both local andmetastatic growths.The potential role of gene intervention extendsfrom diseases caused by single gene defects,through severe viralinfections,to polygenic disorders,such as diabetes mellitus andarteriosclerosis.However,gene therapy can be defined as the     

CDH1 germline mutation in hereditary gastric carcinoma

This paper provides a bird‘s-eye view both in preclinical and clinical aspects of E-cadherin germline gene (CDH1) in gastric cancer patients and their families. E-cadherin, a product of CDH1 gene, belonging to the functionally related trans-membrane glycoprotein family, is responsible for the Ca^2+-dependent cell-cell adhesion mechanism and contributes to dissociation followed by acquisition of cell motility, which usually occurs in the first step of cancer irwasion and metastasis. CDH1 gene germline mutation is common in many types of carcinoma, and occurs very frequent in hereditary gastric carcinoma (HGC) patients and their families. Recently, more and more researches support that E-cadherin plays an important role in the differentiation, growth and invasion of HGC. So it is of great value to clarify its mechanisms both for understanding HGC pathogenesis and for clinical therapy, especially in China, where there are a high risk population of gastric cancer and a high HGC incidence rate. In this paper, recent researches on CDH1 gene mutation, especially its role in tumor genesis and progress of HGC, are reviewed, and advances in evaluation of its mutation status for HGC diagnosis, therapy and prognosis, are also discussed briefly.     

Current status of tumor radiogenic therapy

Although tumor gene therapy falls behind its clinical use, the combination of irradiation and gene therapy is full of promise in cancer therapy based on traditional radiotherapy, chemotherapy and surgery. We have termed it as radiogenic therapy. This review focuses on the following aspects of radiogenic therapy in recent years: improvement of gene transfer efficiency by irradiation, radiotherapy combined with cytokine gene delivery or enhancement of the immunity of tumor cells by transgene, direct stimulation by radiation to produce cytotoxic agents, increase of tumor cell radiosensitivity in gene therapy by controlling the radiosensitivity genes and adjusting the fraction dose and interval of radiation so as to achieve the optimum antitumor effect while reducing the normal tissue damage, radioprotective gene therapy enhancing radiation tumor killing effect while protecting the normal tissue and organs with transgene using transfer vectors.     

Treatment of hepatocellular carcinoma in patients with portal vein tumor thrombosis: Beyond the known frontiers

Hepatocellular carcinoma is one of the most frequent malignant tumors worldwide:Portal vein tumor thrombosis(PVTT)occurs in about 35%-50%of patients and represents a strong negative prognostic factor,due to the increased risk of tumor spread into the bloodstream,leading to a high recurrence risk.For this reason,it is a contraindication to liver transplantation and in several prognostic scores sorafenib represents its standard of care,due to its antiangiogenetic action,although it can grant only a poor prolongation of life expectancy.Recent scientific evidences lead to consider PVTT as a complex anatomical and clinical condition,including a wide range of patients with different prognosis and new treatment possibilities according to the degree of portal system involvement,tumor biological aggressiveness,complications caused by portal hypertension,patient’s clinical features and tolerance to antineoplastic treatments.The median survival has been reported to range between 2.7 and 4 mo in absence of therapy,but it can vary from 5 mo to 5 years,thus depicting an extremely variable scenario.For this reason,it is extremely important to focus on the most adequate strategy to be applied to each group of PVTT patients.     

Pharmacogenetics research on chemotherapy resistance in colorectal cancer over the last 20 years

During the past two decades the first sequencing of the human genome was performed showing its high degree of inter-individual differentiation,as a result of large international research projects(Human Genome Project,the 1000 Genomes Project International HapMap Project,and Programs for Genomic Applications NHLBI-PGA).This period was also a time of intensive development of molecular biology techniques and enormous knowledge growth in the biology of cancer.For clinical use in the treatment of patients with colorectal cancer(CRC),in addition to fluoropyrimidines,another two new cytostatic drugs were allowed:irinotecan and oxaliplatin.Intensive research into new treatment regimens and a new generation of drugs used in targeted therapy has also been conducted.The last 20years was a time of numerous in vitro and in vivo studies on the molecular basis of drug resistance.One of the most important factors limiting the effectiveness of chemotherapy is the primary and secondary resistance of cancer cells.Understanding the genetic factors and mechanisms that contribute to the lack of or low sensitivity of tumour tissue to cytostatics is a key element in the currently developing trend of personalized medicine.Scientists hope to increase the percentage of positive treatment response in CRC patients due to practical applications of pharmacogenetics/pharmacogenomics.Over the past 20 years the clinical usability of different predictive markers has been tested among which only a few have been confirmed to have high application potential.This review is a synthetic presentation of drug resistance in the context of CRC patient chemotherapy.The multifactorial nature and volume of the issues involved do not allow the author to present a comprehensive study on this subject in one review.     

Essential hypertension and oxidative stress:New insights

Essential hypertension is a highly prevalent pathological condition that is considered as one of the most relevant cardiovascular risk factors and is an important cause of morbidity and mortality around the world. Despite the fact that mechanisms underlying hypertension are not yet fully elucidated,a large amount of evidence shows that oxidative stress plays a central role in its pathophysiology. Oxidative stress can be defined as an imbalance between oxidant agents,such as superoxide anion,and antioxidant molecules,and leads to a decrease in nitric oxide bioavailability,which is the main factor responsible for maintaining the vascular tone. Several vasoconstrictor peptides,such as angiotensin Ⅱ,endothelin-1 and urotensin Ⅱ,act through their receptors to stimulate the production of reactive oxygen species,by activating enzymes like NADPH oxidase andxanthine oxidase. The knowledge of the mechanism described above has allowed generating new therapeutic strategies against hypertension based on the use of antioxidants agents,including vitamin C and E,N-Acetylcysteine,polyphenols and selenium,among others. These substances have different therapeutic targets,but all represent antioxidant reinforcement. Several clinical trials using antioxidants have been made. The aim of the present review is to provide new insights about the key role of oxidative stress in the pathophysiology of essential hypertension and new clinical attempts to demonstrate the usefulness of antioxidant therapy in the treatment of hypertension.     

Immunological treatment of liver tumors

Although multiple options for the treatment of liver tumors have often been described in the past, including liver resection, radiofrequency ablation with or without hepatic pump insertion, laparoscopic liver resection and the use of chemotherapy, the potential of immunotherapy and gene manipulation is still largely unexplored. Immunological therapy by gene manipulation is based on the interaction between virus-based gene delivery systems and dendritic cells. Using viruses as vectors, it is possible to transduce dendritic cells with genes encoding tumor-associated antigens, thus inducing strong humoral and cellular immunity against the antigens themselves. Both chemotherapy and radiation therapy have the disadvantage of destroying healthy cells, thus causing severe side-effects. We need more precisely targeted therapies capable of killing cancer cells while sparing healthy cells. Our goal is to establish a new treatment for solid liver tumors based on the concept of cytoreduction, and propose an innovative algorithm.     

Antibiotics and probiotics in treatment of inflammatory bowel disease

Many experimental and clinical observations suggest that intestinal microflora plays a potential role in the pathogenesis of inflammatory bowel disease (IBD). Manipulation of the luminal content using antibiotics or probiotics represents a potentially effective therapeutic option. The available studies do not support the use of antibiotics in ulcerative colitis (UC). Antibiotics are effective in treating septic complications of Crohn's disease (CD) but their use as a primary therapy is more controversial, although this approach is frequently and successfully adopted in clinical practice. There is evidence that probiotic therapy may be effective in the prevention and treatment of mild to moderate UC. In contrast, a lack of successful study data at present precludes the widespread use of probiotics in the treatment of CD. Both antibiotics and probiotics appear to play a beneficial role in the treatment and prevention of pouchitis and further trials are warranted to fully quantify their clinical efficacy.     

Perspectives for gene therapy in renal diseases

Somatic cell gene therapy has made considerable progress last five years and has shown clear success in some clinical trials. In the field of nephrology, both the elucidation of pathophysiology of renal diseases and the development of gene transfer technique have become driving force for new therapy of incurable renal diseases, such as Alport syndrome and polycystic kidney disease. Gene therapy of renal cancer, although its application is limited to advanced cancer, is the front-runner of clinical application. Erythropoietin gene therapy has provided encouraging results for the treatment of anemia in uremic rats and recently progressed to the inducible one in response to hypoxia. Gene therapy for glomerulonephritis and renal fibrosis showed prominent impact on experimental models, although the safety must be confirmed for prolonged treatment. Transplant kidney is an ideal material for gene modification and induction of tolerance in the transplant kidney is an attractive challenge. Emerging techniques are becoming available such as stem cell technology and messenger RNA silencing strategies. We believe that the future of gene therapy research is exciting and promising and it holds an enormous potential for clinical application.     

Therapeutic angiogenesis for peripheral artery disease: gene therapy

Peripheral artery disease is a highly prevalent disease which is characterised by a high unmet medical need particularly in the more advanced stages of disease. Recent advances in the knowledge of the complex regulation of angiogenesis and arteriogenesis and ways to its induction offer hope for a novel strategy that is based on the generation of such new vessels. This strategy termed "therapeutic angiogenesis" is a concept based on the use of angiogenic factors or stem cells or their combination to promote neovascularisation for the treatment of ischaemic tissues. This article reviews both regulation of angiogenesis and the development of therapeutic strategies based on this knowledge using gene therapy. This includes knowledge from animal experiments as well as from phase I and phase II clinical trials. This information may be particularly important at a time when angiogenesis gene therapy enters the stage of phase III clinical testing hopefully leading to the first time approval of this completely new class of drug in the near future. Following articles of this series will review therapeutic angiogenesis approaches based on cytokine therapy and stem cell therapy.     

Gene therapy of hepatocellular carcinoma

The extraordinary versatility of gene therapy opens new possibilities for the treatment of incurable diseases, including hepatocellular carcinoma. Gene therapy strategies against tumors include prodrug activation therapy by the transfer of suicide genes, immunogene therapy, tumoral cell phenotype correction by the inhibition of oncogenes or the transfer of tumor suppressor genes, antiangiogenesis and transfer of oncolytic viruses. The experience accumulated during the last decade of clinical gene therapy indicates that genes can be expressed inside the tumor tissue, but the overall results of the studies conducted so far are still disappointing, mainly due to the poor performance of the currently available gene therapy vectors. This review covers the general aspects of gene therapy vectors, preclinical data available in animal models of hepatocellular carcinoma, and finally a brief summary of the gene therapy clinical trials aimed at the treatment of liver cancer.     

Gene therapy for gastrointestinal tract cancer: a review

Carcinomas of the gastrointestinal tract count as one of the most common causes of cancer-related death in the world. Despite improvement of conventional treatment modalities, the prognosis of patients with gastrointestinal tract cancer remains poor. Progress in understanding the molecular mechanism of gastrointestinal carcinogenesis may facilitate development of gene therapy strategies for the treatment of gastrointestinal tumors. This review describes new developments in vectors (tools for gene transfer) for gene therapy, possible therapeutic genes and the early clinical results of gastrointestinal tract cancer gene therapy. Results of current preclinical studies are promising for the future clinical application of gene therapy for gastrointestinal cancer. The first clinical trials have been initiated recently, the preliminary results reflecting low toxicity and clinical responses. Further clinical studies will be required to confirm the feasibility of gene therapy in the treatment of gastrointestinal cancer. In future, the greatest potential will probably lie in the field of combination strategies of gene therapy and existing treatment modalities, such as surgery combined with molecular chemotherapy.     

Review: Gene Therapy for Cancer:

Gene therapy is a new form of therapeutic intervention with applications in many areas of medical treatment. There are still many technical difficulties to be overcome, but recent advances in the molecular and cellular biology of gene transfer have made it likely that gene therapy will soon start to play an increasing role in clinical practice and particularly in the treatment of cancer. The first clinical gene transfer in an approved protocol took place exactly 10 years ago, and it was for the transfer of gene-marked immune cells into patients with advanced cancer. Now there are 218 active clinical protocols in the United States, and they have involved over 2000 patients worldwide. Among the conditions and diseases for which gene transfer is being tried as treatment, cancer comes first with 130 clinical trials. Fundamental research in the mechanisms of cancer and the development of molecular biology tools are crucial for the success of the treatments in the future. The identification of tumor rejection antigens from a variety of cancers and the immune response that is defective in cancer patients are important topics for future studies. The evaluation of gene therapy combinations involving use of tumor suppressor genes and constructs that inactivate oncogenes is also another important area for future research. The future improvement of present viruses as well as the use of new viral vectors will likely expand the applicability and efficacy of gene therapy. During the next decade technological developments, particularly in the areas of gene delivery and cell transplantation, will be critical for the successful clinical practice of gene therapy.     

Gene transfer with ultrasound and microbubbles (optison) as a potential treatment for cardiovascular diseases

Cardiovascular diseases are the leading causes of mortality and morbidity in developed countries. Most conventional therapy is inefficient and tends to treat the symptoms rather than the underlying causes of the disorder. Gene therapy based on ultrasound with microbubbles offers a novel approach for the prevention and treatment of cardiovascular diseases. The major development of gene transfer has importantly contributed to intense investigation of the potential of gene therapy in cardiovascular medicine. The amazing advances in molecular biology have provided a dramatic improvement of the technology that is necessary to transfer target genes into somatic cells. Gene transfer methods have been surprisingly improved. In fact, some of them (retroviral vectors, adenoviral vectors or liposome based vectors, etc) have been used in clinical trials already. However, some severe side effects were reported in clinical gene therapy using such viral vector, so people wish for safe and efficient clinical gene therapy. Transfection with ultrasound and microbubbles has been reported as a new powerful tool in a new class for gene therapy.     

Cardiovascular gene therapy: angiogenesis and beyond

Recent advances in understanding the mechanisms of disease have produced many new targets for gene therapy. However, it has been difficult to convert these new insights into clinically useful applications. In the field of cardiovascular medicine, most clinical studies of gene therapy have focused on angiogenesis as a treatment for ischemia. Initial enthusiasm was supported by small, uncontrolled, phase 1 trials. However, several large efficacy studies have recently been published that have not shown clinically significant improvement, and a few well-publicized complications of gene therapy have cast a pall over the entire field. In this review, we will summarize specific technical aspects of cardiovascular gene therapy, examine the recent series of clinical studies, and explore the direction of future work for the principal cardiovascular diseases.     

Gene therapy for pulmonary diseases

Gene therapy has not yet met the high expectations of "the early days." However, it is a promising new treatment for lung diseases. Not only single gene disorders such as CF are potential candidates for gene therapy, but also cancer and chronic lung diseases characterized by an imbalance of damaging and protective mechanisms. This review summarizes the recent advances in the development of more efficient gene transfer systems and highlights areas of clinical application of gene therapy.     

Gene therapy for severe combined immunodeficiency caused by adenosine deaminase deficiency: improved retroviral vectors for clinical trials

Severe combined immunodeficiency (SCID) caused by adenosine deaminase deficiency (ADA-) is the first genetic disorder to be treated with gene therapy. Since 1990 when the first trial started for 2 patients with ADA- SCID, five clinical trials enrolling 11 patients have been conducted with different clinical approaches and the results obtained from these trials have recently been reported. According to these reports, T cell-directed gene transfer was useful in the treatment of ADA- SCID whereas the retroviral-mediated gene transfer to hematopoietic stem cells was insufficient for achievement of clinical benefits. This chapter reviews several crucial problems inherent in the current retroviral technology based on the clinical data observed in these pioneering ADA gene therapy trials and presents our new retroviral vector system for the next stem cell gene therapy.