Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0178874 (tumor progression)
 40,807 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

There is, at present, considerable interest in the possible role for the proinflammatory cytokines, tumor necrosis factor-alpha, interleukin-1, interleukin-6, and interferon-gamma in the pathogenesis of cancer cachexia. Indirect evidence for such a role is based on the observation that chronic administration of many of these cytokines, either alone or in combination, can reproduce the myriad of host responses seen in experimental and human cancer cachexia. Elevated plasma levels of tumor necrosis factor-alpha, interleukin-2, and interferon-gamma have rarely been detected in patients or experimental animals with cancer, although interleukin-6 levels appear to correlate with tumor progression in animal models. The strongest evidence for a causal role for cytokines has come from rodent studies in which tumor-bearing animals have been passively immunized with antibodies directed against individual cytokines. Several groups have shown modest but significant improvements in food intake and lean tissue retention with antibodies directed against tumor necrosis factor-alpha, interleukin-1, interleukin-6, and interferon-gamma. However, there has been no consistent finding that one cytokine is universally involved in cancer cachexia in histologically distinct tumor models. One ominous finding in several tumor models has been that the endogenous production of cytokines appears to support tumor growth. Such findings raise the intriguing possibility that these cytokines, although contributors to tissue wasting and anorexia, may also serve the tumor as either direct or indirect cell growth factors.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The role of cytokines in cancer cachexia. 128 23

Brain tumors are highly resistant to therapy. Their diffuse infiltrative nature and the relative inaccessibility of brain tissue to blood and lymph are barriers to surgical and cytotoxic treatments alike. The purpose of this study was to produce immune cells specifically reactive with an anaplastic rat glioma (RT2) and determine whether those cells could affect tumor progression in the brain. RT2-specific cytotoxic cells were prepared by priming rats in vivo with RT2 tumor cells and Corynebacterium parvum and stimulating the primed lymphocytes in vitro with irradiated RT2 tumor cells and interleukin-2 (IL-2). Cultured cells exhibited a high level of cytotoxicity against RT2, but not C6 (an allogeneic glioma), 3M2N (a syngeneic mammary tumor), or CSE (a syngeneic fibrosarcoma) tumor cells. To generate a model for therapy, rats were injected intracerebrally with RT2, generating progressing brain tumors, which killed untreated rats in approximately 2 weeks. To test the therapeutic potential of the effector cells, tumor-bearing rats were treated by intravenous injection of lymphocytes on Day 5 of tumor growth. Treated rats also received a 5-day course of systemic IL-2 beginning on Day 5. Treatment with IL-2 alone, RT2-primed spleen cells, or RT2-primed spleen cells stimulated in vitro with C6 did not affect rat survival. However, tumor-bearing rats treated with RT2-stimulated lymphocytes exhibited increased survival or were cured. Systemic IL-2 was an essential adjunct, because survival was not affected by treatment with effector cells alone. Therapy initiated on Day 8 of tumor progression lacked effect on survival.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Successful treatment of a malignant rat glioma with cytotoxic T lymphocytes. 140 33

Thirty-one patients with disseminated melanoma or renal cell cancer (RCC) who had a limited relapse or persistent disease after a partial or complete response to interleukin-2 (IL-2)-based immunotherapy underwent resection of progressing tumors or residual sites of disease. There were no surgery-related deaths. The median time to disease progression after resection for patients with RCC (n = 16) and melanoma (n = 15) was 11 and 5 months, respectively. All patients with melanoma had tumor progression within 10 months of surgery. Seven of 16 patients with RCC were free of tumor progression 4 to 44 months after surgery. Three of 12 patients with RCC rendered disease-free by surgery remain disease-free after 2 years. These data suggest that surgical resection is a reasonable option in selected patients who have a relapse after responding to IL-2-based immunotherapy. Although this retrospective study could not determine the relative survival benefits of surgery and immunotherapy, it showed that resection of metastatic disease after a response to immunotherapy can result in significant disease-free survival in patients with RCC but not melanoma.
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PMID:Surgical resection of metastatic renal cell carcinoma and melanoma after response to interleukin-2-based immunotherapy. 155 Oct 67

The effect of immunotherapy with stimulated autologous lymphocytes (SAL) in malignant gliomas is documented and discussed in a bioptical and autoptical case study. A five-year-old child with a recurrently operated and radiated right hemispheric anaplastic astrocytoma died six weeks after immunotherapy with mitogen-activated killer cells and recombinant Interleukin-2. The autopsy revealed a large butterfly glioma with partially necrotic gelatinous tissue at the site of the SAL reservoir. The tumor cell density on the right was less than on the left hemisphere, and T-lymphocyte content was higher on the right hemisphere. These results demonstrate a local effect of SAL therapy in vivo, although the tumor progression as a whole could not be stopped. They also demonstrate the need of a detailed neuropathological examination in all cases of immunotherapy of malignant gliomas.
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PMID:Immunotherapy with stimulated autologous lymphocytes in a case of a juvenile anaplastic glioma. 164 Oct 79

Alteration in interactions between tumor-infiltrating lymphocytes (TILs) and tumor cells after chemotherapy or immunotherapy was studied in metastatic melanoma patients. Tumors were harvested from surgical specimens 17 days after the end of chemotherapy with cisplatin, vinblastine, and dacarbazine (CVD). Tumors of nonlymph-node metastases from two responders yielded neither TILs nor tumor cells, whereas those from all four nonresponders had both TILs [(1.1-13.8) x 10(6) cells/g tumor] and tumor cells [(2.8-30.8) x 10(6) cells/g tumor). Tumors of lymph node metastases from nine patients yielded substantial numbers both of TILs and tumor cells, regardless of different clinical responses, except with one complete responder, whose tumor did not contain tumor cells. The mean increase of TILs from these tumors (n = 14) 3-4 weeks after incubation with 200 U/ml recombinant interleukin-2 (rIL-2) was 2.5-fold, whereas there was a 56-fold increase in TILs from untreated tumors (n = 3). CD3+ T cells predominated in TILs before and after expansion with IL-2. IL-2-activated TILs from five of six tumors tested displayed higher cytotoxicity against autologous tumor cells than against cells from any of three allogeneic tumors. Mean tumor cell numbers (10(6) cells/trial) obtained by serial needle biopsies for the same tumor in five patients decreased from 1.2 before therapy to 0.25 at day 4 of therapy (interferon alpha alone), and to 0.02 at day 8 (interferon alpha and IL-2). This decrease did not correlate with clinical responses. Yields (x 10(6) cells/g tumor) of TILs and tumor cells in subcutaneous melanomas obtained by excisional biopsies in one nonresponder under IL-2 therapy were respectively 0.2 and 1.1 before therapy (day 0), 0.1 and less than 0.01 during (day 7), 0.2 and less than 0.01 at the end of therapy (day 21), and 0.5 and 0.5 at the time of tumor progression (day 66). Yields of TILs and tumor cells in the other nonresponder were respectively 3 and 26 before (day 0), 16 and 3 during (day 7), and 0.4 and less than 0.01 at the end of IL-2 therapy (day 17), and 2.5 and 6 at the time of progression (day 62). TILs in these two patients before therapy proliferated well in culture with IL-2 (570- and 720-fold, respectively), and showed higher cytotoxicity against autologous tumor cells, whereas none of those from the five tumors biopsied during or at the end of IL-2 therapy proliferated. TILs at the time of progression showed modest proliferation (54- and 76-fold, respectively) and showed major-histocompatibility-complex-nonrestricted cytotoxicity. In summary, a decrease in the number of live tumor cells did not always correlate with clinical response in either therapy. CVD chemotherapy may simply impair IL-2-induced proliferation of TILs. IL-2 therapy may induce transient unresponsiveness of TILs to IL-2.
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PMID:Alteration in interactions between tumor-infiltrating lymphocytes and tumor cells in human melanomas after chemotherapy or immunotherapy. 205 68

Twenty-six patients with metastatic cancer were entered into a phase I trial of concurrent recombinant interleukin-2 (IL-2) and recombinant interferon-gamma (IFN-gamma). IL-2 was administered as a continuous intravenous infusion for 5 days. IFN-gamma was administered by a daily intramuscular (IM) injection during the 5 days of IL-2 administration. Treatment was repeated twice after 9-day rest periods. After a 2-week rest, patients without evidence of tumor progression were retreated. Natural killer (NK)- and lymphokine-activated killer (LAK)-cell activity were assayed in each patient before treatment, on day 1, and on day 5 of each cycle. Constitutional symptoms occurred in most patients but were not dose-limiting. Other toxicities included hypotension responsive to fluids, transient elevations in liver function tests, erythema/pruritus, eosinophilia, and transient leukopenia/thrombocytopenia. The maximum-tolerated dose (MTD) of the combination was 1 x 10(6) U/m2/d of IL-2 combined with 0.50 mg/m2/d of IFN-gamma. The dose-limiting toxicity was pulmonary manifesting as rales and shortness of breath. The dose of the combination that resulted in the optimal generation of in vivo LAK-cell activity was a dose of at least 0.25 mg/m2/d of IFN-gamma combined with 1 x 10(6) U/m2/d of IL-2. Objective clinical responses were seen in five of 26 patients. These included a partial response of 2 months duration in a patient with non-Hodgkin's lymphoma (NHL), mixed responses in a patient with NHL and two patients with renal cell carcinoma (RCC), and an ongoing assessable response in a patient with bone metastases from RCC. The recommended dose for phase II trials of this combination is 0.50 mg/m2 of IFN-gamma and 1 x 10(6) U of IL-2.
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PMID:A phase I trial of recombinant interleukin-2 combined with recombinant interferon-gamma in patients with cancer. 211 71

Peripheral blood lymphocytes of 63 patients with gastric cancer were studied by using different monoclonal antibodies and flow cytometry. Used monoclonal antibodies were OKT3 (total T cell), OKT4 (helper/inducer), OKT8 (suppressor/cytotoxic), Leu 7 and Leu 11 (NK/K cell). Interleukin-2 was measured by tritium-labelled thymidine CTLL assay on the supernatant of peripheral blood lymphocytes after 24 hours stimulation with phytohemagglutinin. Interleukin-2 receptor was also studied by using monoclonal antibody (for Tac antigen) and flow cytometry. The results were as follows: among peripheral blood lymphocytes; 1. the number of OKT3, OKT4 cells and the percentage of OKT4 cells decreased significantly with more advanced stage of cancer. 2. production of interleukin-2 also decreased with the progression of the cancer. 3. decreases in the OKT4/OKT8 ratio were found with cancer progression. 4. the percentage and the number of OKT8 cells increased. 5. the percentage and the number of Leu 11 cells and the number of Leu 7 cells were increased significantly in the stage III (moderately advanced cancer). These results suggested that the activated helper T cells decreased, the induction capability of cytotoxic T cells decreased and the suppressor T cells increased with the progression of cancer. Quantitative and qualitative change in T-cell subsets in advanced stage may be one factor responsible for immunosuppression.
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PMID:[A clinical study of immunological status in patients with gastric cancer: with special reference to T-cell subsets, interleukin-2 in the lymphocytes of peripheral blood]. 213 44

With the exception of testis cancer, the variety of genitourinary cancers have not been found to be consistently responsive to chemotherapeutic agents or regimens for other than anecdotal short duration. This has generated keen interest in the possibility that biologic response modifiers might either directly or through manipulation of immune response mechanisms successfully prevent tumor progression in these systems. In recent years, those substances that have attracted the greatest attention have included interferon (and, more recently, recombinant gamma interferon), bacillus Calmette-Guerin (BCG), tumor necrosis factor, prostaglandin synthetase inhibitors, and interleukin-2. Results with each of these agents in the variety of genitourinary cancers have been both promising and disappointing. A number of mechanisms have been suggested to underlie the actions of each of these substances, and the successful or unsuccessful recruitment of these mechanisms, in the context of the particular intrinsic behavior of the cancers being treated, have been suggested as reasons for the treatment results that have been seen. Therapeutic efficacy has been described in the treatment of renal cell cancer by both systemic interferon and interleukin-2. Successful treatments have been reported in approximately 20% of patients treated with each substance, but generally, these results have been of short duration. Topical BCG has been used with great success to treat superficial transitional cell bladder cancer. In these instances, the generation of tumor necrosis factor has been suggested as possibly accounting for the 70% success rate both in therapy and prophylaxis that has been seen. Leukocyte-derived interferon and, more recently, recombinant gamma interferon, were found in initial trials to generate a 20% response rate in renal cell carcinoma patients. Enthusiasm for these agents, however, has been tempered more recently both by a failure to reproduce these results with any substantial duration as well as by the significant side effects that have been seen. Clearly, these agents continue to be intriguing both because of their intellectual appeal through the mechanisms by which they may be effective, as well as by the absence of any definitive therapy for the cancers they are being used to treat. An understanding of the complex host/tumor cell interaction that may ultimately determine therapeutic efficacy for each of these agents is undoubtedly critical if the role of these substances in the treatment of genitourinary cancer is to be successfully implemented, either alone or in combination with other treatment modalities.
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PMID:Biologic response modifiers in genitourinary neoplasia. 243 87

Forty patients with metastatic, recurrent, or unresectable renal cell carcinoma were entered into a study of the therapeutic efficacy of adoptive immunotherapy using periodate (IO4-) and interleukin-2 (IL2)-activated autologous leukocytes and continuous infusion low-dose IL2. Patient survival was also examined. The first 15 consecutive patients were enrolled in protocol A without an IL2 priming phase and the following 25 patients were entered in protocol B where a 5-day priming phase was initiated before leukapheresis. A maintenance regimen consisted of either 3 x 10(6) units of recombinant interferon-alpha (rIFN-alpha), three times per week only or together with leukapheresis and infusion of IO4-/IL2-activated cells and 2 days of continuous infusion IL2 per month. Thirty-four patients completed the protocol treatment. Four patients were removed from the study owing to rapid tumor progression and two patients died while receiving treatment. The clinical response rate was 22%: two patients had a complete response and five patients had a partial response. Among the 25 patients who had no clinical response, 11 patients had either a mixed response or stabilization. Neither response, response duration, nor site response correlated with the total dose of IL2 administered or the number of activated killer cells infused. Patients who received maintenance therapy had longer survival times than patients who did not receive such therapy. All toxicity and side effects associated with IL2 treatment were transient and resolved after discontinuation of the drug. Patients on maintenance therapy tolerated both rIFN-alpha and monthly infusions of activated killer cells and IL2 well. This study confirms the concept of adoptive immunotherapy as a new treatment approach for advanced renal cell carcinoma and suggests that maintenance therapy may prolong survival time.
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PMID:A phase II clinical trial of adoptive immunotherapy for advanced renal cell carcinoma using mitogen-activated autologous leukocytes and continuous infusion interleukin-2. 255 51

Suppressor cells, which might be activated in patients with gastric carcinoma, were successfully enriched by the use of interleukin-2 (IL-2) prepared from human tonsils and spleens. That is, peripheral blood lymphocytes cultured for 3 or 4 weeks with IL-2 strongly inhibited the patient's own lymphocyte-proliferative responses to alloantigen or phytohemagglutinin (PHA). Quantitative fluorescence measurement for immunologic analysis of phenotypic characterization of the cells was made on FACS-IV with monoclonal antibodies anti-Leu-1 anti-Leu-2a, anti-Leu-3a, anti-Leu-4, anti Leu-5, anti-Leu-7, and anti-HLA-DR and goat anti-human immunoglobulin (Ig). Functional suppressor T-cells expanded with IL-2 showed the following phenotype: Leu-1+ Leu-2a+, Leu-3a-, Leu-4+, Leu-5+, Leu-7-, HLA-DR+, human Ig-. The IL-2-dependent suppressor T-cells could be obtained only when the cells were derived from patients with systemic metastasis of gastric carcinoma. These findings suggest that generation of IL-2-dependent suppressor T-cells is the result of large tumor burdens; this may exert negative cellular control in the immune responses, thus inducing the status of the lower cell-mediated antitumor immunity, and may promote cancer progression in gastric cancer patients.
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PMID:The generation of interleukin-2-dependent suppressor T-cells from patients with systemic metastasis of gastric carcinoma and the phenotypic characterization of the cells defined by monoclonal antibodies. 293 Nov 72


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