Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0001418 (adenocarcinoma)
 68,496 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The metastatic non-small cell lung cancer (NSCLC) still remains an untreatable disease, and the role played by chemotherapy has yet to be defined. The new immunotherapeutic strategies, such as interferon and IL-2, seem to be also less effective, since they generally determine only a stabilisation of disease. On the basis of previous experimental results suggesting a synergistic action between IL-2 and the pineal neurohormone melatonin (MLT), a study was started to evaluate the clinical efficacy and toxicity of a neuroimmunotherapeutic combination consisting of IL-2 plus MLT as a first line therapy in metastatic NSCLC. The study included 20 patients (adenocarcinoma: 10; epidermoid cell carcinoma: 7; large cell carcinoma: 3). MLT was given orally at a dose of 10 mg day-1 at 8.00 pm every day, starting 7 days before the onset of IL-2 administration. IL-2 was given subcutaneously at a dose of 3 x 10(6) IU m-2 every 12 h for 5 days/week for 4 weeks, corresponding to one cycle of immunotherapy. In responder patients or in those with stable disease, a second cycle was given after a rest-period of 21 days. A partial response was achieved in 4/20 (20%) patients. Ten other patients had a stable disease (50%), whereas the last six patients progressed. Toxicity was low in all cases. This study shows that the neuroimmunotherapeutic therapy with IL-2 and the pineal hormone MLT may represent a new effective and well tolerated treatment in metastatic NSCLC, with results comparable to those obtained with chemotherapy, but with an apparent lower biological toxicity.
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PMID:Biological and clinical results of a neuroimmunotherapy with interleukin-2 and the pineal hormone melatonin as a first line treatment in advanced non-small cell lung cancer. 132 55

TS/A is a spontaneous adenocarcinoma, apparently not immunogenic in BALB/cnAnCr mice. TS/A cells are unable to stimulate a syngeneic antitumor response either in vitro or in vivo. To evaluate the immunogenic potential of IL-2-releasing neoplastic cells, we used an expression vector to introduce the cDNA coding for murine IL-2 into TS/A cells. Six clones releasing between 30 and 6800 U of IL-2/10(5) cells/ml/48 h have been isolated. Both low (30 U, B1.30) and high (6000 U, B4.6000) IL-2-releasing clone are capable of stimulating a proliferative and cytotoxic response in syngeneic cultures. While the B1.30 clone grows in 60% of syngeneic mice with a delayed pattern, the five clones that release higher levels of IL-2 are promptly rejected. Rejection is associated with neutrophil infiltration, the intensity of which is directly proportional to the amount of IL-2 released. NK cells and CD4+ lymphocytes are uninfluential, whereas CD8+ lymphocytes play only a minor role. This neutrophil-dominated rejection leaves a long-lasting, tumor-specific, T lymphocyte-mediated immune memory. For its induction, CD4+ lymphocytes are required. Their specific activation appears to depend on both the amount of IL-2 released and the granulocyte-mediated reaction that may lead to a more efficient presentation of tumor-associated Ag. These data support the notion that, after transduction of IL-2 gene, cancer cells may elicit an immune antitumor response, and stress the potential use of IL-2 as a component of new tumor vaccines.
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PMID:Role of neutrophils and CD4+ T lymphocytes in the primary and memory response to nonimmunogenic murine mammary adenocarcinoma made immunogenic by IL-2 gene. 135 74

We have derived a TNF-alpha-resistant clone (RA-I) from the parental TNF-sensitive human breast-adenocarcinoma cell line (MCF-7). The acquisition of TNF-resistance was not associated with endogenous TNF production or with differential levels of TNF receptors since both MCF-7 and RA-I display comparable TNF-receptor expression. We have investigated the relationship between acquisition of resistance to TNF and susceptibility to lysis by cytokine-activated effectors. Experiments were performed using human peripheral-blood monocytes stimulated with IL-2, IFN or GM-CSF, and lymphokine-activated killer cells as effector cytotoxic cells. Our data indicate that both TNF-resistant (RA-I) and TNF-sensitive (MCF-7) cells were killed by IL-2-activated monocytes. Incubation of monocytes with IFN also resulted in the activation of their tumoricidal activity against MCF-7 and RA-I. When stimulated monocytes were pre-incubated in the presence of a TNF-specific neutralizing monoclonal antibody, prior to co-culture with target cells, no effect on their lytic capacity was observed. Thus, the monocyte killing does not appear to involve the membrane form of TNF. These observations suggest that, in our experimental system, IL-2 and IFN are able to induce non-TNF-mediated mechanisms of cytotoxicity by monocytes. Experiments performed using GM-CSF and LPS for monocyte stimulation indicate that, although both reagents were efficient in inducing the membrane form of TNF on monocytes, they did not enhance the cell-killing capacity towards MCF-7 and RA-I targets. Furthermore, using IL-2-stimulated LGL as effector cells, we show in this study that the TNF-resistant clone RA-I was as sensitive as MCF-7 to human LAK cells.
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PMID:The development of human tumor-cell resistance to TNF-alpha does not confer resistance to cytokine-induced cellular cytotoxic mechanisms. 145 36

Conventional therapy of pancreatic exocrine cancer is disappointing. The poor prognosis of the disease challenges development of novel therapeutic strategies. We report the results of clinical trials of the monoclonal antibody (Mab) 17-1A in patients with histologically verified unresectable pancreatic exocrine cancer. No antitumor response was seen in 18 patients treated with Mab 17-1A (500 mg) admixed with 10(9) autologous mononuclear cells, and 81% of the patients developed antimouse antibody response. Combination of recombinant gamma interferon and Mab 17-1A mixed with autologous mononuclear white cells resulted in complete response of 4-mo duration in 1 out of 25 evaluable patients and unusually stable disease from 4 to 48+ mo in another 6 patients. High intermittent doses of infused Mab 17-1A did not show any objective antitumor response and caused serious anaphylaxis in two of the patients in the trial. Because examination of six pancreatic adenocarcinoma cell lines with different doses of Mab 17-1A and IL-2 failed to augment lytic activity of mononuclear effector cells against all cancer cell lines tested, there seemed to be no rationale for pursuing clinical studies with IL-2 and Mab 17-1A in either the murine or chimeric form. Attractive therapeutic approaches include active immunotherapy with immunization using idiotypic antibodies or targeted toxicity with the use of radioimmunoconjugates, particularly 125I-labeled chimeric Mab 17-1A.
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PMID:Immunotherapy with monoclonal antibody (Mab) in pancreatic adenocarcinoma. 174 38

The effect of RGD-sequence-containing pentapeptides and monoclonal antibodies (MAbs) against the adhesion molecules CD11a-c/CD18, ICAM-1 (CD54) and CD2 on the binding and cytotoxicity of endogenous (freshly purified) and IL-2-stimulated CD3-negative NK cells has been studied. Antibody to CD18 exerted the most significant inhibition of adhesion and cytotoxicity of endogenous NK cells to MOLT-4 lymphoma cells, followed by antibodies to CD2 and CD54. Antibodies to either CD11a, CD11b or CD11c did not inhibit adhesion when used separately, whereas as a mixture their inhibitory capacity was as strong as that of anti-CD18. Antibodies against CD18, CD54 and CD2 exerted an additive effect on the inhibition of adhesion. Their combination eradicated the binding of endogenous NK cells. The RGD-containing peptide did not inhibit the binding or cytotoxicity of freshly purified NK cells to MOLT-4, whereas some inhibition was detected against the adenocarcinoma cell line COLO-205. According to FACS analysis, IL-2 increases the expression of CD2 and CD54 on NK cells. However, the relative contribution of the adhesion molecules to the NK cell binding did not change as a result of the stimulation with IL-2. The RGD-peptide substantially inhibited the binding of IL-2-stimulated killer cells to COLO, and the combination of this peptide with MAbs to CD18, CD54 and CD2 practically blocked the adhesion. Our results indicate that both CD11a-c/CD18- (involving the 3 heterodimers) and CD2-dependent adhesion pathways are used by LGL in endogenous and IL-2 stimulated natural killing. In addition, RGD-binding receptors are involved in adhesion to some target cells.
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PMID:Participation of CD11a-c/CD18, CD2 and RGD-binding receptors in endogenous and interleukin-2-stimulated NK activity of CD3-negative large granular lymphocytes. 197 68

LAK activity could be induced by IL-2 from human PBL. After co-culture of LAK cells with Anip973 human lung adenocarcinoma cells, LAK-tumor conjugates were microscopically observed. Formation of the conjugates paralleled well with the expression of LAK activity (P less than 0.001), suggesting that LAK cells' killing of Anip973 cells depended on their close contact. Under electron microscope, LAK cells had various shapes and certain degrees of motility. Ten minutes after co-culture, close binding between microvilli of LAK cells and tumor cells could be seen. Four hours after co-culture, Anip973 cells bound with LAK cells developed numerous membrane blebs with cytoplasm and nucleus very condensed, which was followed by destruction of cell structure and appearance of cell debris. These features are consistent with apoptosis rather than a cytolytic mechanism of cell death. These findings suggest that LAK cells share certain common features with CTL and NK cells on killing tumor cells.
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PMID:[Morphological observation of human LAK cell killing activity on lung adenocarcinoma cells]. 207 37

Soluble interleukin-2 receptor (sIL-2R) levels in cigarette smokers and in patients with lung cancer were measured using an enzyme immunoassay. The rationale for our study was based on the fact that activation of T-cells is dependent upon the T-cell growth factor, interleukin-2, which may be regulated by its receptor, IL-2R. Measurements of circulating sIL-2R might be useful in the immune assessment of certain conditions. This study assessed elevated concentrations of circulating sIL-2R in smokers and in patients with lung cancer. The data show that healthy smokers, as a group, have an elevated level of sIL-2R compared with that in nonsmokers. Significantly higher than normal levels were found among light, moderate, and heavy smokers. Patients with lung cancer (squamous cell carcinoma [SSC] or adenocarcinoma [AC]) also have abnormally high sIL-2R levels. In the SCC group, the highest level of sIL-2R was among asymptomatic patients with well-differentiated tumors. Similarly, patients with SCC whose tumors were less than 3 cm in diameter had a significantly higher mean level of sIL-2R than did patients whose tumors exceeded 3 cm. The sIL-2R level in the SCC group also correlated with the tumor stage, with the highest level found among Stage I patients. In patients with SCC, but not in those with AC, the sIL-2R level was indicative of the extent of malignancy. These data support the concept that sIL-2R may be important in the pathogenesis of immune alterations associated with smoking and lung cancer.
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PMID:Elevated concentration of soluble interleukin-2 receptors in serum of smokers and patients with lung cancer. Correlation with clinical activity. 220 Mar 17

Autologous lymphokine-activated killer (LAK) cells and recombinant human interleukin-2 (rIL-2) were administered intraperitoneally (IP) to 24 patients with malignancies limited to the peritoneal space. Ten patients had ovarian cancer, 12 had colorectal cancer, and one patient each had endometrial carcinoma and primary small-bowel adenocarcinoma. All ovarian cancer patients, three of twelve colorectal cancer patients, and one patient with endometrial carcinoma had received prior therapy. Patients received IL-2 100,000 U/kg every 8 hours intravenously (IV) for 3 days, and 2 days later underwent daily leukapheresis for 5 days. LAK cells were generated in vitro by incubating the peripheral blood mononuclear cells in IL-2 for 7 days and were then administered IP daily for 5 days through a Tenckhoff catheter (Davol, Inc, Cranston, RI) together with IL-2 25,000 U/kg IP every 8 hours. All but one patient completed at least one cycle of therapy. Toxic side effects included minor to moderate hypotension, fever, chills, rash, nausea, vomiting, abdominal pain and distension, diarrhea, oliguria, fluid retention, thrombocytopenia, and minor elevations of liver function tests; all of these rapidly improved after discontinuation of IL-2. One patient had a grand mal seizure, and one suffered a colonic perforation; these were felt to be treatment-related. IP fibrosis developed in 14 patients and limited repeated cyclic administration of this therapy in five patients. Two of 10 (20%) ovarian cancer patients and five of 12 (42%) colorectal cancer patients had laparoscopy- or laparotomy-documented partial responses. We conclude that LAK cells and rIL-2 can be administered IP to cancer patients, resulting in moderate to severe short-term toxicity and modest therapeutic efficacy. Further investigation of this form of adoptive immunotherapy modified to address the problem of IP fibrosis and with lower IP IL-2 doses is justified by these initial results.
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PMID:Intraperitoneal lymphokine-activated killer-cell and interleukin-2 therapy for malignancies limited to the peritoneal cavity. 221 99

The adoptive transfer of tumor-infiltrating lymphocytes (TIL) with the concomitant administration of IL-2 has been shown to mediate the regression of established 6- and 14-d murine hepatic and pulmonary metastases. For successful immunotherapy with TIL, however, pretreatment with either cyclophosphamide (CP) or whole body irradiation (WBX) was required. The exact mechanism of CP and WBX augmentation of TIL antitumor activity remains unknown, but the elimination of Ts cells has been frequently invoked as an explanation. To address this possibility and to determine if local tumor irradiation (LTX) could synergize with TIL as well as WBX, we investigated the effect of LTX on the therapeutic efficacy of TIL and IL-2 in the treatment of multiple 7-d murine hepatic metastases. Experiments studying the treatment of a weakly immunogenic murine adenocarcinoma, MC-38, showed prolonged survival of mice treated with the combination of IL-2, TIL, and either LTX or WBX, compared with treatment with radiation alone or radiation plus IL-2 controls (p less than 0.0001). In addition, therapy with LTX and IL-2 prolonged survival, compared with LTX administration alone, whereas therapy with WBX combined with IL-2 did not alter survival. This augmentation of TIL-mediated antitumor activity was dependent on the dose of radiation used. To assess the possibility that tumor-associated Ts cells inhibit the function of adoptively transferred TIL in animals with 7-d metastatic tumor and are eliminated by WBX and LTX, we repeated the above experiments leaving some tumor unirradiated. Mice underwent either LTX or limited LTX, which included only the right side of the liver (LTX1/2). The number of right- and left-sided metastases were then individually counted. These studies showed that the reduction in the number of right-sided metastases was identical between the two groups and that the presence of left-sided tumor in the LTX1/2 group did not suppress the observed antitumor activity of TIL against irradiated tumor. Additional evidence against the elimination of suppressor cells as an important mechanism in radiation-induced augmentation of TIL antitumor activity was provided by experiments studying the effectiveness of TIL in thymectomized, lethally irradiated, and reconstituted B mice. Unless CP was administered before the adoptive transfer of TIL, therapy with IL-2 and TIL in these B mice was ineffective in the absence of demonstrable T lymphocytes.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Synergistic antitumor activity of tumor-infiltrating lymphocytes, interleukin 2, and local tumor irradiation. Studies on the mechanism of action. 229 78

Soluble interleukin-2 receptor (IL-2R) level and IL-2R positive (IL-2R+) cells were studied in twenty patients with carcinomatous pleural effusions. The mean value of soluble IL-2R level in carcinomatous pleural effusions was 2930 +/- 1722 U/ml and that in sera was 965 +/- 610 U/ml. Soluble IL-2R level in carcinomatous pleural effusions was found to be significantly higher (p less than 0.001) than that in sera of patients with carcinomatous pleural effusions and that in transudates. Serum soluble IL-2R level in patients with carcinomatous pleural effusions was found, to be significantly higher (p less than 0.001) than that in normal controls (264 +/- 70 U/ml). We also studied IL-2R+ cells in pleural fluids and peripheral blood of patients with carcinomatous pleural effusions. The mean percentage of IL-2R+ cells in carcinomatous pleural fluid lymphocytes was 22.8 +/- 17.8%, as compared with 3.0 +/- 2.2% in peripheral blood lymphocytes of normal controls (p less than 0.001). No significant differences were observed among the cell types of lung cancer examined (adenocarcinoma, squamous, small cell and large cell carcinoma) and no correlation among levels of soluble IL-2R and IL-2R+ cell in either pleural fluid or blood. Our results suggest that in patients with carcinomatous pleural effusions, T cell-mediated active immune mechanisms (IL-2/IL-2R system) against cancer cells are more active in pleural fluid than in peripheral blood.
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PMID:[Elevated soluble interleukin-2 receptor and interleukin-2 receptor positive cells in carcinomatous pleural effusions]. 235 70


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