Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Polyethylene glycolated (pegylated) interleukin-2 (PEG IL-2) was administered as a weekly i.v. bolus to patients with metastatic cancer in a phase-I trial. Efficacy, toxicity and pharmacokinetics have been described previously. To explore mechanism of IL-2 action and discover predictors of efficacy, the levels of several lymphokines were measured in pharmacokinetic serum samples. IL-1 beta and IL-6 were elevated in many patients before PEG IL-2 administration, forming a continuous, log-normal distribution among patients. The levels of the two lymphokines were strongly correlated. However, no significant correlation could be found between these levels, clinical chemistry, or tumor regression seen after PEG IL-2 administration. Three hours after PEG IL-2 administration, IL-1 beta and IL-6 levels, if elevated, fell to normal. In all patients, independent of initial levels, IL-6 and IFN-gamma, but not IL-1 beta, increased 4 to 6 h after the injection and then fell rapidly, even though PEG IL-2 levels were high and often changed only slightly during this period. This suggests an active shut down of lymphokine synthesis, or an increase in elimination rate. After the fourth administration of PEG IL-2, the peak level of IFN-gamma was 2 to 20 times higher than after the first, while the peak level of IL-6 did not change in a consistent direction. Responding patients had typical peak levels of IL-6 and IFN-gamma. Low levels of TNF and IL-4 were occasionally seen before and after PEG IL-2 administration, but no consistent pattern was evident.
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PMID:Suppression and transient induction of lymphokines in cancer patients after administration of polyethylene glycolated interleukin-2. 154 19

Interleukin-7 (IL-7) is a 25-kDa cytokine that was initially described as a pre-B cell growth factor and more recently has been shown to cause T cell proliferation. We have investigated the in vitro effects of IL-7 on mature T cells to include the generation and further expansion of allospecific and antitumor CTL. B6 anti-DBA allospecific CTL were generated in the presence of IL-7, IL-2, the combination IL-7 plus IL-2, or no cytokine. IL-7 alone or when combined with IL-2 enhanced the generation of allospecific CTL. To evaluate the proliferative effects of IL-7, 4-day B6 anti-DBA cultures were cultured in IL-7, IL-2, or no cytokine. Cell proliferation and duration of growth of cells cultured in IL-7 were significantly greater than cells cultured in IL-2 or in the absence of cytokine. Allospecific cytolytic activity was maintained during proliferation in IL-7 to a maximum of 60 days. In contrast with the ability of IL-2 to generate LAK cells, murine splenocytes cultured at varying doses of IL-7 (1 to 10,000 ng/ml), resulted in minimal LAK cell activity. The effect of IL-7 in the generation of CTL with antitumor activity was also studied. Seven days after footpad injection of MCA 203 or 205 sarcoma, draining lymph nodes (DLN) were harvested and restimulated in vitro with MCA 203 or 205, respectively, and maintained in culture with either IL-7, IL-2, the combination of IL-7 plus IL-2, or no cytokine. After 10 days in culture, cells generated in IL-7 or IL-2 exhibited similar cytotoxicity against the syngeneic autologous MCA tumor. IL-7 generated cells, however, showed specificity when tested by 51Cr release which was not seen with IL-2-generated cells. Cells generated in IL-7 plus IL-2 were more cytolytic than cells cultured with either cytokine alone. To further define the mechanism of action of IL-7 in antitumor CTL cultures, a monoclonal antibody, S4B6.1, capable of blocking murine-specific IL-2 was employed. The partial inhibition by this mAb of the generation of antitumor CTL demonstrated that IL-7 acted, in part, by an IL-2-dependent mechanism. Finally, IL-7 cultures restimulated at Day 11 with autologous MCA 203 showed greater proliferation than IL-2 cultures and remained lytic at Day 21 of culture.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Interleukin-7 mediates the generation and expansion of murine allosensitized and antitumor CTL. 155 57

During the past 5 years publications from the NIH (Rosenberg et al.) and other centers have reported encouraging results in the treatment of metastatic renal cell carcinoma. Adoptive immunotherapy was applied, using lymphocytes activated by interleukin-2 (LAK cells) plus high doses of interleukin (IL-2) systemically. The mean clinical response rate was 20-35%. Severe lifethreatening adverse reactions to high doses of IL-2 were noted, although they were all of short duration. Laboratory findings of Novogrodsky et al. from Beilinson Medical Center, Israel showed that oxidizing mitogens can induce lymphocyte activation (PLAK cells). Further studies suggested that a combination of such activated cells with low doses of IL-2 could produce effective toxicity to tumor cells without the need for high doses of IL-2 which could be very toxic for the patient. In the past year we treated 7 patients with PLAK cells and IL-2. 4 completed the treatment, of whom 1 responded partially (regression of more than 50% of lung metastases), 1 is stable and in 1 liver metastases regressed but metastases in lumbar vertebrae and in the pelvis progressed. 1 patient died a month after discharge from hospital, probably due to rapid progression of the disease. Our protocol follows that of the Phase II clinical study of 40 patients treated at the Rogosin Institute, New York Hospital--Cornell Medical Center. The mean clinical response rate was 23.6%. Toxicity of IL-2 is dose-dependent. In this protocol, the low doses of IL-2 gave significantly fewer adverse reactions.
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PMID:[Immunotherapy for metastatic renal cell carcinoma: treatment with PLAK cells and low-dose interleukin-2]. 157 61

A murine model of minimal residual disease (MRD) was established utilizing the murine B-cell leukemia (BCL1). BALB/c mice inoculated with up to 10(4) BCL1 were cured (greater than 1 year disease-free survival) following administration of intraperitoneal injections of recombinant human IL-2 (10(5) Cetus units x 3/day intraperitoneally x 5 days). Lethally irradiated BALB/c or (BALB/c x C57BL/6)F1 recipients were reconstituted with syngeneic bone marrow cells or T-cell-depleted C57BL/6 bone marrow cells contaminated with 10(4), 10(5), or 10(6) BCL1 to simulate quantitative MRD. Untreated mice died of typical leukemia without exception, whereas a substantial anti-leukemia effect was noted in mice treated by allogeneic spleen cells, IL-2, or particularly a combination of allogeneic spleen cells and IL-2 given concomitantly. Increments of donor-type spleen cells (10(6), 10(7), and 5 x 10(7)) or IL-2 (10(4) U x 2/day x 3 days) were given alone or in combination on days +1, +5, and +9 following Thy 1.2-depleted allogeneic BMT. All adoptive recipients of 10(5) spleen cells obtained from mice inoculated with 10(4) and 10(5) BCL1 treated by a combination of allogeneic spleen cells and IL-2 showed no evidence of disease greater than 100 days. The antitumor effects of allogeneic spleen cells alone and IL-2 alone were also highly significant, although not totally curative in all mice. Allogeneic spleen cells seemed more effective as compared with low dose IL-2 (3 courses of 2 x 10(4) U x 2/day x 3 days). None of the recipients of 10(6) BCL1 could be completely cured under the experimental conditions described without additional chemotherapy, although significant antitumor effects could again be documented following concomitant administration of allogeneic spleen cells and IL-2. Using an experimental model of autologous BMT, recipients of 10(3) tumor cells could also be cured following transplantation of syngeneic spleen cells by high-dose IL-2 (10(5) U x 3/day x 5 days) given at the time lymphocytes were present, optimally at 3 weeks following BMT. Based on encouraging results from experiments using our animal model of MRD, in conjunction with autologous and allogeneic BMT, pilot clinical trials are currently underway, investigating the effect of cytokine-mediated immunotherapy (CMI) in MRD following conventional and high-dose cytoreductive anticancer therapy in conjunction with ABMT. In addition, we are attempting induction of cell-mediated cytokine-activated immunotherapy (CCI) in conjunction with autologous and allogeneic BMT. Prospective randomized clinical trials and longer observation periods are required to assess the full efficacy of these new therapeutic modalities.
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PMID:Immunotherapy of minimal residual disease by immunocompetent lymphocytes and their activation by cytokines. 158 31

Murine interleukin 9 (mIL-9) is a novel T-cell-derived lymphokine previously described as a T-cell growth factor (P40/TCGFIII) and as a mast cell growth-enhancing activity (MEA). In the present study we examined the potency of recombinant (r)mIL-9 to exhibit hemopoietic growth factor activity in the human system. In semisolid cultures of normal human bone marrow-derived mononuclear cells, rmIL-9 alone at a concentration range from 25 to 200 U/ml did not reveal any colony-stimulating activity on human granulocyte-macrophage colony-forming cells (GM-CFC), erythroid colony-forming units (CFU-E), and erythroid burst-forming units (BFU-E). Furthermore, we did not observe synergistic effects of rmIL-9 on the number, size, and morphological composition of human granulocyte-macrophage colonies in cultures stimulated with giant cell tumor-conditioned medium. However, a synergistic effect of rmIL-9 in the human erythropoietic culture system was clearly demonstrated in the presence of recombinant human erythropoietin (rhEpo). Recombinant murine IL-9 at a concentration of 200 U/ml enhanced the number of BFU-E-derived day-14 colonies about 3.6-fold as compared to control cultures stimulated with Epo alone. The formation of CFU-E-derived day-7 colonies was not significantly altered under the same conditions. Our results demonstrate that in the presence of rhEpo, rmIL-9 is synergistically active in human bone marrow cultures as an erythroid burst-promoting factor. The development of granulocyte-macrophage colonies obviously is not affected. This finding strongly suggests that mIL-9 can mediate signals via human IL-9 receptors and further extends the range of biological activities hitherto ascribed to mIL-9.
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PMID:Recombinant murine interleukin 9 enhances the erythropoietin-dependent colony formation of human BFU-E. 158 1

Patients with classical European Kaposi's sarcoma were treated by intra- and peritumoral injections of human alpha leukocyte interferon (IFN) (12 cases) or, alternatively, with IFN and naturally synthesized IL-2 (8 cases). All the patients were HIV negative with tumors which had been present for at least six months. In each patient, one tumor received 1 ml (50,000 IU) IFN alone or alternatively associated with 1 ml IL-2 twice a week for 4-6 weeks; another nodule situated 10-12 cm away was considered as a control and remained uninjected. The clinical follow-up revealed that, in the same patient in the same anatomical area, the treated nodule was cured in all the investigated cases; the untreated one was not. These data strongly suggest that IFN is the factor responsible for the involution and final cure of these Kaposi tumors treated by perilesional inoculations. Association with IL-2 (and certainly also other interleukins) increases the beneficial clinical activation of the tumor involution. Histological examination showed that important histopathological changes occur in the treated nodules: complete disappearance of the Kaposi's aspect, fibrosclerous modifications progressively replacing the fibroblasts characteristic of Kaposi's sarcoma, abundant infiltrations of leukocytes, especially lymphocytes and necrotic patches, often with hemorrhagic centers. IL-2 association seems to especially induce this last type of histological phenomenon.
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PMID:Intralesional human leukocyte interferon treatment alone or associated with IL-2 in non-AIDS related Kaposi's sarcoma. 159 18

Owing to improved systemic control of widespread malignancy, neurological complications have become a major outcome factor and determinant of life quality in oncological patients. While solitary cerebrospinal metastases are often amenable to surgical and radiological treatment, the management of diffuse leptomeningeal neoplasia, mostly using combined radiochemotherapy, is still very difficult. Immunomodulative approaches represent a therapeutic alternative with increasing potential. We have analysed the natural immune response to leptomeningeal tumor invasion in 43 Patients by assessing cerebrospinal fluid (CSF) levels of albumin, IgG, IgM, interleukins (IL) 1, 2, 4 and 6, soluble IL-2 receptor (sIL-2R), interferon gamma (IFN gamma), tumor necrosis factor alpha (TNF alpha), and the tumor markers, carcinoembryonic antigen (CEA) and alphafetoprotein (AFP). In most patients, either elevated IgG index, IgM index, CSF IL-6, or detection of CSF oligoclonal immunoglobulin bands indicated a host reaction against tumor cells. IL-1, IL-2, and IL-4 were never detected in CSF or serum. sIL-2R and IFN gamma were rarely detected and were not associated with specific malignancies. CSF TNF alpha was only detected in melanoma patients and may be a specific indicator of that neoplasm. No correlation was found between levels of the tumor markers, CEA and AFP, and parameters of the immune response such as IgG, IgM or IL-6. The demonstration of intrathecal immune activation in a majority of patients with leptomeningeal neoplasia may offer a new option for immunomodulative oncological therapy.
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PMID:[Intrathecal immune response in meningeosis neoplastica: IgG, IgM, oligoclonal bands and cytokines]. 159 86

We reported recently that a novel immunomodulator, 7-thia-8-oxoguanosine (7T8OG)2 inhibited formation of pulmonary melanoma metastases (1), prevented against viral infection in mice (2) and potentiated the efficacy of a weakly immunogenic leukemia vaccine (3). Since certain tumor metastases and virus infected cells are targets to natural killer cells (NK cells), we now investigated whether 7T8OG is capable of activating NK cells in mice using NK cell sensitive YAC-1 and B16 and NK cell insensitive P815 targets. CBA/CaJ spleen cells incubated in vitro with 7T8OG at concentrations ranging from 0.005 to 0.5 mM responded with increased NK cell activity (32-62%) compared to controls (4-8%) to YAC-1 targets. Similar levels of augmentation in NK cell activity were observed when 40-168 mg/kg of 7T8OG was administered in vivo. In addition to the spleen, 7T8OG activated NK cells in the bone marrow (BM), the lungs, the liver, and in peritoneal exudate cells (PE). Although 7T8OG elicited activation of NK cells was observed as early as three hours after treatment, the maximal activity was observed after 24 h in the spleen; 12 h in the BM; 48 h in the lungs, and 72 h in PE. Administration of the drug by s.c., i.v., and i.p. routes all induced activation of NK cells in spleen, BM and PE. 7T8OG was found to activate NK cells in seven inbred and an outbred mouse strain, suggesting that the induced cytotoxicity against allogeneic and syngeneic tumor cells is not strain specific as well as independent of MHC restriction. C3H/He, CBA/CaJ and BDF/1 displayed higher levels of increased NK cell activity, whereas AKR mice were low responders. Low concentrations of IL-2 (0.25-5 U/ml) that induce little or no NK cell activity, when used in combination with 7T8OG, elicited significant enhancement of NK cell cytotoxicity. In contrast, IFN and 7T8OG showed no such synergism.
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PMID:Immunomodulatory activity of a novel nucleoside, 7-thia-8-oxoguanosine: I. Activation of natural killer cells in mice. 159 50

The effects of purified protein A from Staphylococcus aureus Cowan I stain on induction of lymphokine (IL-2) activated killer (LAK) activity were studied in normal as well as melanoma patient's lymphocyte. The coculture of peripheral blood mononuclear cells (PBMC) with various doses of protein A (0.001, 0.01 and 0.1 microgram/ml) and IL-2 (100 U/ml) for 4 days produced synergistic effect on the LAK cells mediated cytotoxicity. The potentiation of cytotoxicity and lytic ability of LAK cells against NK sensitive (K-562) and NK-resistant (M14) tumor cells were observed. Further there was potentiation of DNA synthesis in PBMC after 4 days culture. Similar results were found when PBMC from melanoma patients were cultured with PA and IL-2. The potentiation of LAK cell induction associated with its cytotoxic and lytic potential by low doses of IL-2/PA regiment may be helpful in the development of LAK immunotherapy of the cancer patients.
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PMID:Protein A potentiates lymphokine-activated killer cell induction in normal and melanoma patient lymphocytes. 159 62

Immunological evaluations were performed on 14 pediatric cancer patients who received human recombinant interleukin-2 (rIL-2) as a bolus intravenous infusion every 8 h for 5 consecutive days in a phase I trial. Three-to-four patients were treated at dose levels of 10, 30, 60, and 100 x 10(3) Cetus U/kg. Six of the patients had stage D neuroblastoma; the remainder had other solid tumors or leukemias. Infusion of rIL-2 was associated with a rapid margination of IL-2-responsive cells followed by demargination and heightened proliferative and cytotoxic activity after therapy was completed. The predominant phenotypic change in circulating peripheral blood mononuclear cells (PBMC) was an increase in CD2 expression by CD56+ natural killer (NK) cells. Appearance of CD2+ CD56+ cells in the circulation correlated with increased lymphokine-activated killer (LAK) cell activity as defined by the ability to kill NK-resistant Daudi tumor cells in vitro. Sustained LAK activity appeared to be dependent on the bioavailability of rIL-2 in vivo as well as in vitro. After rIL-2 therapy, PBMC that were highly responsive to rIL-2 (activated and "poised" LAK cells) persisted for at least 72 h. In the patients tested, increased lysis of autologous and/or allogeneic, histologically similar tumor cell lines was also observed after therapy. The immunoenhancing effects of rIL-2 occurred even at the lower doses used in this study. However, an objective tumor response was not observed in any of the patients.
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PMID:Immunological evaluation of pediatric cancer patients receiving recombinant interleukin-2 in a phase I trial. 159 13


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