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Gene therapy has the potential to provide cancer treatments based on novel mechanisms of action with potentially low toxicities. This therapy may provide more effective control of loco-regional recurrence in diseases such as non-small cell lung cancer (NSCLC), as well as systemic control of micrometastases. Despite current limitations, retroviral and adenoviral vectors can in certain circumstances provide an effective means of delivering therapeutic genes to tumour cells. Although multiple genes are involved in the process of carcinogenesis, mutations of the p53 gene are the most frequent abnormality identified in human tumours. Pre-clinical studies both in vitro and in vivo have shown that restoration of p53 function can induce apoptosis in cancer cells. Phase I clinical trials now show that p53 gene replacement therapy is feasible and safe using both retroviral and adenoviral vectors, and that it induces tumour regression in patients with advanced NSCLC and recurrent head and neck cancer. Other pre-clinical studies indicate that gene therapy may have useful synergy with cytotoxic and radiation therapy. This paper describes the different gene therapy strategies under investigation and the pre-clinical data that provides a rationale for the gene replacement approach, reviews clinical trial data and presents novel ideas for improving current vectors and gene delivery to tumours.

Today a "just" health policy is balanced between the problem of the allocation of scarce resources and the priority setting of services, care and cures. Despite technologies and molecular medicine, with their tendency to reach absolute prediction of disease or absence of disease and to cure with predicted efficacy, a large portion of the public refuse the results of experimental procedures and prefer to place trust in so-called alternative medicine or in drugs which are not in the official guide-lines following the principles of evidence-based medicine according to DL Sackett. Juridical problems arise between the rights of free choice of cure and social dimension of Governmental care programs, which include the maximum of benefits (i.e. effective therapies) for a pre-fixed total budget. An explicit rationing only on budgetary bases without rationalisation of medical procedures reduces the rights to care of citizens-patients. Thus, an explicit rationing-rationalisation seems to be the only procedure compatible with the interest of patients in a social security system allocating "scarce" resources.

A deeper understanding of the mechanisms underlying the regulation of immune responses together with the discovery of methods to identify tumour antigens have provided a strong foundation for the development of cancer immunotherapies. The recognition that multiple components of the immune system can effectuate tumour destruction has fostered the crafting of several strategies to augment anti-tumour immunity. These approaches involve the stimulation of tumour antigen-specific T lymphocyte and antibody responses, the augmentation of multiple components intrinsic to innate immune responses and the selective destruction of the tumour vasculature. A decisive factor in the crafting of these schemes has been the development of high efficiency gene transfer systems. These technologies render possible the genetic modification of a variety of cells playing critical roles in the evolution of anti-tumour immune responses; such modifications can dramatically enhance the levels of anti-tumour immunity. In this review, I will discuss the pre-clinical background underlying some of the current Phase I patient studies and highlight some of the intriguing early findings from these clinical investigations.

Gene engineering to enhance tumour immunogenicity and elicit curative responses against established tumours and tumour recurrences has become an attractive prospect. Gene engineering enables new genes to be selectively inserted into the genome of a tumour cell, or the construction of new fusion plasmids coding tumour antigens and immunomodulatory molecules. The rationale behind current research is to enhance the immune recognition of tumour antigens through their association with the molecules on which immune recognition depends. The immunotherapy data obtained in many experimental tumour systems provide a realistic assessment of the potential and limits of this technological approach. Experimental vaccination of rodents has been shown to induce a significant immune memory, even against poorly immunogenic tumours, that can prevent tumour growth and cure initial metastases, but is poorly effective against established tumours. Its use in tumour prevention is a fresh dawning perspective.

Investigation of the mechanism of relapse in patients receiving stem cell rescue as therapy for malignant disease has been facilitated by gene marking studies. These studies have shown the marker gene to be present in malignant cells in the patient at the time of relapse, indicating that infused stem cells can contribute to disease recurrence. As normal progenitor cells are also marked and can be tracked in vivo, these studies have also helped us learn how haemopoietic stem cells respond to manipulation, for example with growth factors. Second generation studies with multiple, modified vectors are beginning to provide information about a wider variety of clinical and biological issues, including the efficacy of purging. Although marker studies have been useful for haematological malignancy and for neuroblastoma, they are hampered by the low efficiency of marking achieved by retroviral vectors. For many malignancies, marking efficiencies are insufficient for useful information to be obtained. This problem may be overcome by the introduction of vectors that, unlike retroviruses, can stably integrate in cells that are not in cycle at the time of vector exposure. Other improvements will focus on the marker genes themselves, using marker elements that are simpler to track and will not produce any modification of the cells' behaviour. Finally, marker studies have proved safe so far, but follow-up of the treated patients continues.

In recent years, surgical treatment of cerebral gliomas has made significant technical advances (e.g. microsurgery and neuronavigation) and has also benefitted from improvement in diagnostic techniques and biopathology. Thanks to this progress, there has been a reduction in the surgical mortality and morbidity of highly malignant neoplasms such as glioblastoma multiforme and medulloblastoma, although there has not been any significant improvement in survival. On the other hand, for a specific group of circumscribed and resectable brain gliomas, modern neurosurgery is potentially curative in a high proportion of cases, even if the gliomas are located in deep and previously inaccessible brain regions. These "benign" variants of cerebral gliomas occur mainly in children and young adults, i.e., in subjects with a long life-expectancy. Astrocytoma, oligodendroglioma and ependymoma are a third group of cerebral gliomas for which modern neurosurgery offers interesting new possibilities.

Radiation was conclusively proved to be of value in the treatment of malignant gliomas in the late 1970's where it enabled an approximate doubling of the survival time. Further study defined a number of prognostic factors which provide a basis for selecting patients for treatment. The introduction of computer tomography (and later magnetic resonance) scanning allowed a more rational approach to target volume definition and a reduction in radiation-related morbidity. Dose-ranging studies defined a standard approach to treatment (60 Gray in 30 fractions). Since then numerous attempts have been made to improve on these results. Marginal benefits have been claimed for altered fractionation schemes, limited volume dose escalation (implants and stereotaxy), radiation sensitisers and particle therapies. However none has become routine in clinical practice. Advances in planning technology have allowed a further reduction in the volume of normal brain irradiated and the potential for dose escalation. Low grade astrocytoma has not been examined in the same way and great doubt exists with respect to optimal treatment. There is a great opportunity for research to realise the potential in the new techniques for improving the outlook for patients with malignant glioma and in clarifying the role of radiation in low grade tumours.

The aim of this study was to investigate the impact of L-arginine (nitric oxide synthase substrate), L-NG-nitro-L-arginine (nitric oxide synthase inhibitor), and heparin on the pancreas microcirculation, serum IL-6 level and microscopic alterations of the pancreas in acute pancreatitis in rats. Acute pancreatitis was induced by 4 i.p. injections of cerulein (15mg/kg). Microcirculatory values were measured by means of laser Doppler flowmetry 5 h after the first cerulein injection. Remarkable histopathological changes in the pancreas, including parenchymal necrosis, an elevation of serum IL-6 level, and a significant drop of pancreatic capillary perfusion was observed in rats with nitric oxide synthase inhibition. L-arginine improved the pancreatic microcirculation but worsened the microscopic alterations within the pancreas. Heparin had a beneficial effect on the microcirculatory values, serum IL-6 concentration, and morphologic changes. Authors conclude that inhibition of nitric oxide synthase aggravates acute pancreatitis. L-arginine treatment improves pancreatic perfusion but potentiates morphological alterations. Heparin, improving the microcirculation and inflammatory changes within the pancreatic gland, may be considered as a promising therapeutic agent in acute pancreatitis.

The prognosis of patients with malignant gliomas remains dismal despite the development of a multidisciplinary approach to their treatment. There is a strong need for novel therapeutic approaches that can make a definite impact in the clinical course of these tumours. Although there have been several advances in diagnostic modalities, surgical techniques and cytotoxic therapies, the development of newer therapies has been hampered by the limited understanding of the factors that determine the biological nature of gliomas. However, inroads are now being made into the understanding of the genetic make-up, biological behaviour and therapeutic response of these tumours, which are expected to pave the way for new modes of treatment. In this article, we review the advances made in the identification of potential targets for glioma therapy and the recent clinical trials utilising biological therapies and newer cytotoxic agents.