Recombinant human tumor necrosis factor (TNF)-a increased the expression of epidermal growth factor receptor (EGFR) mRNA and protein in all of six human pancreatic carcinoma cell lines tested. In addition, TNF-a increased the expression of an EGFR ligand, tnorming growth factor (TGF)-a, at the mRNA and protein level in all cell lines. Increased expression ofEGFR protein was assodated with elevated steady-state EGFR mRNA levels. Nuclear run-on analysis showed that increase in EGFR mRNA was due to an increased rate of transcription. Induction of EGFR mRNA expression by TNF-a was abrogated by cycloheximide but occurred independently of TNF-a-induced production of TGF-a protein. Protein kinase A or Gi-type nudeotide-binding proteins were not involved in this process as assessed by using appropriate stimulators and inhibitors of these signal transduction pathways. By contrast, staurosporine, an inhibitor of protein kinase C, partially inhibited, and 4-bromophenacyl bromide, a phospholipase inhibitor, completely inhibited TNF-a-dependent EGFR mRNA expression.The phospholipase C-specific inhibitor tricyclodecan-9-yl xanthogenate did not alter TNF-a-dependent EGFR mRNA expression, suggesting that phospholipase A2 is involved in the modulation of EGFR expression by TNF-a. The simultaneous induction of a ligand/receptor system by TNF-a suggests that this cytokine modulates autocrine growth-regulatory pathways in pancreatic cancer cells.
T-cell receptor (TCR) with unique major histocompatibility complex (MHC)-unrestricted antigen-binding properties was isolated from a human T-cell clone specific for the tumor antigen MUC1. This TCR binds its epitope on the MUC1 protein without the requirement of processing and presentation. A single-chain Valpha/Vbeta/Cbeta (scTCR) was fused to a CD3 zeta (zeta) chain to allow expression on the surface of cells of the innate (granulocytes, macrophages, natural killer [NK] cells) as well as the adaptive (T and B cells) immune system. To test the ability of the cells of the innate immune system to reject a tumor when provided with a tumor antigen-specific TCR, we reconstituted severe combined immunodeficiency (SCID) mice with bone marrow cells transduced with a retroviral vector encoding this receptor and challenged them with a MUC1-positive human tumor. These mice controlled the growth of the tumor significantly better than the control mice. We performed a similar experiment in immunocompetent mice transgenic for human MUC1. Expression of the TCR on large percentages of cells did not result in infiltration or destruction of tissues expressing MUC1. Reconstituted mice controlled the outgrowth of a MUC1-transfected but not the parental control tumor. scTCR expression appears lifelong, suggesting a successful transduction of the self-renewing stem cells.
Due to improving treatment options, the number of so-called long-term cancer survivors is steadily increasing. Current studies assume that more than 60% of adults survive their cancer. These patients have a variety of problems (chemotherapy-induced neuropathy, fatigue, etc.) that require very special care. In addition to somatic and psychological side effects of the cancer or its treatment, these patients also suffer from the financial and social consequences of the disease. Thus, for a long-term survivor of working age, the question of a ‘return to work' represents a significant problem since otherwise the financial existence of the patient, and often the family, may substantially deteriorate. Studies show that cancer patients classify financial worries with regard to the quality of life as more significant than physical or psychological side effects of the cancer or its treatment. Furthermore, there are initial studies showing that the social descent due to the disease may also prove relevant for cancer prognosis. In contrast, it was shown in studies and in a Cochrane analysis that professional assistance and support services are suitable for keeping patients in their professional lives. Therefore, both patients and physicians need to be aware of this problem.
Conclusion: This study did not reveal any significant clinically relevant advantage of work-related medical rehabilitation at one year. Future studies should determine whether a second period of rehabilitation might be helpful and whether selected subjects might benefit from the assistance of case managers beyond the period of rehabilitation.
The increased expression of epidermal growth factor receptor induced by tumor necrosis factor ␣ renders pancreatic cancer cells more susceptible to antibodydependent cellular cytotoxicity by a mAb specific for this receptor. Laboratory studies with athymic mice bearing xenografts of human pancreatic cancer cells demonstrated a cytokine-induced ability of the mAb to cause significant tumor regression. In a phase I͞II clinical trial, 26 patients with unresectable pancreatic cancer were enrolled into three cohorts receiving variable amounts of the antibody together with a constant amount of tumor necrosis factor ␣. With increasing doses of antibody, the growth of the primary tumor was significantly inhibited. This was ref lected by a longer median survival, with one complete remission lasting for 3 years obtained with the highest dose of antibody employed. Thus, a combination of the cytokine, tumor necrosis factor ␣, with a mAb to the epidermal growth factor receptor offers a potentially useful approach for the treatment of pancreatic cancer.Pancreatic cancer accounts for about 25,000 deaths per year in the United States (1) and 50,000 in Europe, excluding the former USSR, and the mortality rates are increasing (2). Because symptoms are minor in early stages and often overlooked, therapy evaluation takes place at an advanced stage of the disease where available treatments are almost ineffective (3). Therefore the chances of a 5-year-survival for a patient suffering from pancreatic cancer are about 0.4% (4). Even when the diagnosis is made at an early stage (such as T 1 N 0 M 0 in the International Union Against Cancer classification), which occurs in only 2% of all pancreatic cancer patients, radical resection does not improve 5-year survival rate above 37% (5). Studies of resectable tumors, which account for less than 22% of all pancreatic cancers, revealed 5-year survival rates of 17-30% (1).Pancreatic cancer is characterized by genetic (6) and regulatory alterations including several receptor tyrosine kinases (7
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