Cancer surveys最新文献

Monoclonal antibodies coupled to drugs and toxic agents (immunotoxins) or radionuclides (radioimmunoconjugates) represent new tools for immunotherapy of haematological malignancies. Immunotoxins constructed with toxins of either plant or bacterial origin have shown a powerful antitumor activity both in vitro and in mice with severe combined immunodeficiency bearing various kinds of leukaemias and lymphomas. Preliminary clinical trials have shown an activity of these compounds at least in a proportion of patients. However, tumour responses have generally been partial and transient. The main problems with immunotoxin therapy remain the inability of immunotoxins to target tumour cells in the presence of a high burden of disease, the host immune response against both the antibody and the toxin moieties, which precludes repeated administration of immunotoxins, and the vascular leak syndrome. Targeting of tumour cells with specific antibodies armed with radionuclides (usually iodine-131 or yttrium-90) appears to be an even more attractive approach. Preliminary clinical studies have clearly demonstrated the ability of radioimmunoconjugates, especially when administered at high dose followed by bone marrow rescue, to induce durable complete remission in patients with non-Hodgkin's lymphomas refractory to conventional therapies. Radioimmunotherapy also overcomes the antigenic heterogeneity of the tumour cell population, since antigen negative tumour cells will be irradiated by the nearby targeted antigen-positive cells. Efforts should now be focused on defining more precisely the optimal clinical setting for administration of immunotoxin and radioimmunoconjugates (e.g. minimal residual disease), to reduce the immunogenicity of these compounds and solve the problem of vascular leak syndrome.

The DNA dependent protein kinase (DNA-PK) is a trimeric nuclear complex consisting of a large protein kinase and the Ku heterodimer that regulates kinase activity by its association with DNA. Recent findings have shown structural similarities between DNA-PK and a family of lipid and putative protein kinases (PIK family). DNA-PK is one of the PIK members known to be a protein kinase with clearly identified effector subunits. A broad range of observations link DNA-PK to dual roles in double strand DNA break (DSB) repair and transcription. Unlike its most closely related PIKs, DNA-PK is not required for activating cell cycle regulated DNA damage signalling mechanisms. Instead, the phenotypes and biochemical properties of DNA-PK are most consistent with functions in DSB repair and joining steps in recombination mechanisms. DNA-PK is associated with RNA polymerase II and RNA polymerase I transcription complexes, where it most frequently has a negative regulatory role.

The autosomal recessive disorder ataxia-telangiectasia (AT) is highly pleiotropic. It is characterized by gradual loss of Purkinje cells in the cerebellum, leading to progressive neuromotor deterioration, immunodeficiency, developmental defects in specific tissues, profound predisposition to malignancy and acute sensitivity to ionizing radiation. AT cells show chromosomal instability, premature senesence, radiosensitivity and defects in cell cycle checkpoints activated by ionizing radiation. Several radiation induced pathways that regulate the cell cycle seem to be defective in AT cells, at least one of which is mediated by TP53. Extensive characterization of the cellular defects of AT cells, together with the recent isolation of the ATM gene, has provided some insight into the possible physiological roles of the ATM protein. Several lines of evidence, including the nature of the agents that elicit the hypersensitivity of AT cells, point to the possibility of a defect in the response to damage induced by oxidative stress, which affects various cellular macromolecules. The ATM protein might have a role in activating defence mechanisms against oxidative stress. This hypothesis broadens the previous concept of the AT defect and explains several aspects of the AT phenotype that cannot be accounted for by defective processing of DNA damage.

The majority of low grade gastric lymphomas arise within acquired organized lymphoid tissue, which has all the features of MALT. This MALT is specifically acquired most commonly in response to infection of the gastric mucosa by H pylori. The lymphocytes within this MALT are therefore programmed to respond to this organism and the neoplastic cells of the lymphoma that may develop within this acquired MALT retain the ability to respond to the immunological proliferative drive associated with the continued presence of the organism. Following the removal of this immunological drive by eradication of the organism in vivo, the lymphoma shows clinical and histological regression. The time required to see this response is unknown and there are some lymphomas that fail to respond to simple Helicobacter eradication. In some cases, there is continued molecular evidence of the presence of the lymphoma clone in low levels and the significance of this remains unknown. These factors are presently under detailed examination, and several clinical trials to assess the response of a large series of low grade gastric MALT lymphomas to anti-Helicobacter therapy and the requirement for additional chemotherapy are at present in progress.

Clinicopathological studies have identified CD30+ ALCL as a clinicopathological entity with heterogeneous morphology and a frequent translocation involving t(2;5), with a better prognosis than most other T cell neoplasms and a different natural history and prognosis than Hodgkin's disease. Because of the different natural history and prognosis of CD30+ ALCL, it is important to recognize this entity and its morphological variants. Further studies are indicated to determine whether specific clinical management(s) and therapies are necessary for variants of ALCL such as HD like ALCL and the small cell predominant type.

Enteropathy associated T cell lymphoma (EATCL) is the most serious complication of coeliac disease. HLA genotyping shows that patients with EATCL have the coeliac disease associated DQA1*0501, DQB1*0201 phenotype. Other HLA-DR/DQ alleles that may be associated with adult onset coeliac disease appear to represent additional risk factors for lymphoma development. Increased numbers of small intestinal intraepithelial cytotoxic T cells are found in the small intestinal mucosa of patients with coeliac disease and in the enteropathic bowel of patients with EATCL. The neoplastic cells of EATCL have the immunophenotype of intraepithelial cytotoxic T cells and may exhibit epitheliotropism. Analysis of T cell receptor genes and immunohistochemistry have shown that the intestinal mucosa distant from the tumour contains clonal populations of small T cells, often of the same clone as the high grade T cell lymphoma. Most cases of chronic ulcerative enteritis are probably part of the same disease process. The ulceration seen in chronic ulcerative enteritis and in enteropathy associated T cell lymphoma may be due to the release of cytolytic enzymes by cytotoxic T cells and tumour cells. These findings suggest that EATCL arises in the setting of coeliac disease and evolves from intraepithelial lymphocytosis through low grade lymphoma to a high grade tumour, possibly under antigen drive from gliadin peptides. These peptides may be presented to the intraepithelial cytotoxic T cells directly by epithelial cells bearing the coeliac disease associated HLA-DQ alleles.

Despite our advances, much remains to be elucidated about the molecular mechanisms of damage inducible mutagenesis. Although some aspects of the intricate protein interactions that lead to the formation of the mutasome have been determined, the precise nature of the interactions between pol III and the UmuD'C-RecA proteins remains entirely speculative. Further progress will depend on the development of a completely reconstituted, cell free lesion bypass system in vitro, as well as structural modelling of the mutasome in its entirety before we understand how error prone translesion DNA synthesis is achieved. Even if a structural homologue of the Escherichia coli mutasome does not exist in higher organisms, it seems quite likely that a functionally homologous mutagenic pathway will indeed be found. Such an active mutagenic process in animal cells would certainly have significant implications for our understanding of the mechanisms of genetic instability, as well as of human carcinogenesis and other pathologies associated with the formation of mutations in DNA.

Translational control has a key role in regulating cell growth. The mRNA binding translation factors (eIF4s) selectively modulate the translation of different mRNAs based on their differing properties, especially the extent of inhibitory secondary structure in their 5' untranslated regions. The mRNA 5' cap is recognized by eIF4E, which can then recruit other translation factors including the helicase cIF4A. Overexpression of eIF4E leads to cell transformation or disordered growth. It also enhances the translation of certain mRNAs, including that for cyclin D1. Decreased expression of eIF4E leads to reduced rates of cell growth. Transformed cells express elevated levels of eIF4E. eIF4E is subject to phosphorylation, which is increased by agents that stimulate translation. However, the role of eIF4E phosphorylation and the signalling pathways through which it is controlled remain to be elucidated. Oncogenic ras leads to increased phosphorylation of eIF4E, and the ability of ras to transform cells is diminished when eIF4E expression is decreased, implying that eIF4E is a key mediator of ras mediated transformation. The recent discovery of inhibitors of eIF4E (eIF4E binding proteins, 4EBP1/2) adds another regulatory component to the system. Although a role for 4EBP1 in cell transformation (or rather in impeding it) has yet to be established, this is an exciting and likely possibility. It should also be noted that 4EBP1 seems to be under the control of the p70S6K pathway, which has a role in cell cycle progression.