Tumor suppressor genes in human lung cancer

Lung cancer is the most common cause of cancer death in Japanese males, the incidence having increased markedly in recent years. Carcinogen exposure such as to tobacco-smoke and air pollution are associated with the probability of developing lung cancer. Aquired somatic mutations play an important role in the pathogenesis of environmentally induced lung cancers. Cytogenetic and molecular analysis of lung tumors has made it possible to examine this hypothesis and to search for candidate genes that may be targeted by chronic exposure to these carcinogens. Early studies implicate several distinct chromosomal loci (3p, 9p, 13q, 17p, and others) and suggest sequential genetic events occur during the initiation and progression of lung carcinogenesis. Several suppressor genes including Rb (13q), P53 (17p), and P16 (9p) have been identified and cloned at these chromosomal loci. The identification of putative tumor suppressor gene at chromosome 3p is still under work. Understanding the interaction of P53, RB, cyclins, and protein kinase inhibitors including P16 will be essential to the development of the next generation of diagnostic and therapeutic studies for lung cancer

Protease-induced leukocyte chemotaxis and activation: roles in host defense and inflammation

The migration of leukocytes such as neutrophils, monocytes and lymphocytes into inflamed lesions is one of the critical events of inflammation. Although the traditional function of neutrophil-derived antimicrobial proteases is to ingest and kill bacteria, some neutrophil serine proteases have been shown to induce leukocyte migration and activation. Mast cell-derived chymase also has the chemotactic activity for leukocytes. During the acute phase of inflammatory and allergic diseases, the predominantly migrated cells are neutrophils and mast cells, respectively, and in the subsequent chronic phase, monocytes and lymphocytes are mainly migrated. The chemotactic activity for monocytes and lymphocytes of neutrophil-derived serine proteases and mast cell-derived chymase may have a role in switching acute inflammation to chronic inflammation and delayed-type hypersensitivity. Recently, aminopeptidase N and endothelin were shown to induce chemotactic migration of leukocyes. Thus, protease-induced leukocyte chemotaxis and activation may play an important role in immunologic events of inflammatory and allergic diseases

ナンジセイ コケイガン ニ タイスル ガン コウゲン ペプチドパルス ジュジョウ サイボウ オ モチイタ ガン ワクチン リョウホウ : トランスレーショナル リサーチ トシテノ テンカイ

Dendritic cells (DCs) are the most potent antigen-presenting cells. DCs pulsed with peptides of tumor-associated antigens (TAA) have been used in cancer immunotherapy. An early clinical study demonstrated the safety of these trials, but the clinical effect was not sufficient. Most studies have used immature DCs generated from peripheral blood monocytes with granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-4 (IL-4). Here, we conducted phase I clinical trial of active immunotherapy using mature DCs induced by a streptococcus derivatives OK-432. DCs were generated from blood monocytes by culturing with GM-CSF and IL-4 for 6 days and then GM-CSF, IL-4 and OK-432 for 2 days. Before injection, DCs were pulsed with MAGE-3 peptide (IMPKAGLLI), which is restricted for HLA-A*2402, and keyhole limpet hemocyanin (KLH) as a control antigen. We selected HLA-A*2402-positive patients who had advanced solid tumors expressing MAGE-3 mRNA. DC vaccine was administered subcutaneously every 2 weeks for a total of four vaccinations in a dose-escalation design at the dose level per cohort of 0.1 (Group 1), 0.3 (Group 2) and 1 (Group 3) ×10８DCs/injection. Immunological monitoring with delayed type hypersensitivity (DTH) reaction and MHC tetramer was performed. Three patients with advanced solid tumor (two lung cancer and one melanoma patients) were so far enrolled in Group 1 of this study. This protocol was well tolerated. A mild fever (Grade 1 to 2) and local reaction of injection site (erythema and induration : Grade 1) were found in all patients. DTH for MAGE-3 peptide became to be positive after forth vaccination in one patient. The decrease of tumor marker (CEA) was found in one patient. However, clinical responses in all three patients were not observed. These results indicated that vaccination with mature DCs (0.1×10８DCs/injection) was safe and feasible, but further analysis using the higher dose of DCs was required to assess the immunological and clinical responses

Genetic modification of dendritic cells and its application for cancer immunotherapy

Dendritic cells (DCs) are the most potent antigen-presenting cells (APCs). DCs pulsed with peptides of tumor-associated antigens (TAA) and tumor lysate have been used in cancer immunotherapy. An early clinical study demonstrated the safety of the use of DCs, but the clinical response was not sufficient. The gene-modification of DCs with TAA and soluble factor genes such as cytokine and chemokine genes has been examined to enhance the antigen-presenting capacity of DCs. Viral vectors including retroviruses and adenoviruses have been reportred to be useful to obtain a sufficient transduction efficiency into DCs. TAA gene-transduced DCs could have several advantages compared with TAA peptide-pulsed DCs as follows : 1) The use of TAA gene-modified DCs are not restricted by MHC haplotypes. 2) The gene transduction with TAA genes is likely to present the unknown TAA peptides on DCs. 3) The gene-modified DCs show the prolonged presentation of TAA peptides. The transduction of DCs with cytokine genes including IL-12 and GM-CSF have also been reported to augument the antitumor effects of DCs. Although the results in the experimental systems were promising, the clinical application of gene-modified DCs includes several problems such as the standardization of methods of manipulation and gene-transduction of DCs. Approaches to solve them require further studies

ハイガン カンジャ ケッセイチュウ ニオケル ガン ヨクセイ イデンシ サンブツ pRB ニタイスル コウタイ ノ ケンシュツ

Recently, serum antibodies against the oncogene and tumor suppressor gene products have been studied in patients with various types of cancer. Antibody against p53 tumor suppressor gene product among these antibodies was suggested to be useful for early diagnosis and evaluation of prognosis of patients with some types of cancer. In this article,we review clinical significance of antibodies against product of retinoblastoma gene (pRB),one of representative tumor suppressor genes. We also describe methods of detection of antibodies in sera from patients with lung cancer by immunoblotting assays using glutathione-S-transferase (GST)-RB fusion proteins