Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0598934 (tumor growth)
 58,965 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recent evidence has shown that endocrine tumors are under an endocrine and an immune regulation, and that biotherapies with interferon or the long-acting somatostatin analog octreotide may be effective in the control of tumor growth and clinical symptomatology. Within the biotherapies of tumors, interleukin-2(IL-2) has appeared to play an essential role in the antitumor immune response. Despite its important antitumor role, very few studies have been carried out to investigate the possible use of IL-2 in the treatment of advanced endocrine tumors. Its potential toxicity would represent the main limiting factor for the clinical experiments with IL-2. Our previous studies have shown that the pineal hormone melatonin (MLT) may amplify the antitumor activity of IL-2, either through immunomodulating mechanisms or through a direct cytostatic activity by inhibiting tumor growth factor production. On this basis, we have performed a phase II pilot study with low-dose IL-2 plus MLT in 14 patients with untreatable endocrine tumors because of disseminated disease, lack of response to previous standard biotherapies or chemotherapies, or tumors for whom no effective therapy is available. Thyroid cancers, carcinoid and endodrine pancreatic tumors were the most frequent neoplasms. IL-2 was given at 3 million IU/day s.c. at 8 p.m. for 6 days/week for 4 weeks, corresponding to one cycle. MLT was given orally at 40 mg/day at 8 p.m. every day. In nonprogressed patients, a second cycle was given after a 21-day rest period. Patients were considered as evaluable when they received at least one complete cycle, and 12 patients were fully evaluable. According to WHO criteria, a partial response was achieved in 3/12 (25%) patients (carcinoid tumor: 1; neuroendocrine lung tumor: 1; pancreatic islet cell tumor: 1). Another patient with gastrinoma had a more than 50% reduction of tumor markers. Toxicity was low in all patients. This preliminary study suggests that low-dose IL-2 immunotherapy in association with the pineal hormone MLT may constitute a new well-tolerated and potentially active therapy of untreatable advanced endocrine tumors.
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PMID:Immunoendocrine therapy with low-dose subcutaneous interleukin-2 plus melatonin of locally advanced or metastatic endocrine tumors. 785 78

Interleukin-12 (IL-12) is a cytokine with a wide variety of immunoregulatory activities. These include stimulation of interferon-gamma production, cytolytic activity of natural killer (NK) cells and T-cell subsets, the development of cellular immunity, and induction of maturation of Th1 cells. IL-12 also has potent anti-tumor activity in vivo. In the present study the possibility of enhanced anti-tumor activity was examined using a combination of local IL-12 by cytokine gene therapy at the tumor site, combined with systemic or local IL-2 delivery. NIH 3T3 fibroblasts transfected with the genes for both subunits of IL-12, p35 and p40, were used as the source of IL-12 therapy producing 240 HLRU/10(6) cells/48 hr. In the first part of the study the effect of different regimens of systemic IL-2 delivery with local IL-12 administration on the size and growth rate of subcutaneous MCA-105 murine sarcoma was examined. Local IL-12 alone reduced the sizes of tumors after 32 days from 163 to 26.8 mm2 (P < 0.002). Adding the longer-acting polyethylene-glycol-modified IL-2 (PEG IL-2; 30,000 IU) for 5 days prevented the development of tumors in all treated mice compared to 1/3 mice treated with PEG IL-2 alone and 3/6 mice with IL-12, but this was a highly toxic therapy and most of the animals died. Administration of 60,000 IU of IL-2 on Days 1-5 postinoculation of tumor, delivered with IL-12 gene therapy, reduced the tumor growth rate compared to animals treated with IL-2 alone (P < 0.02) or IL-12 (0.1).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Administration of systemic or local interleukin-2 enhances the anti-tumor effects of interleukin-12 gene therapy. 786 76

Spleen cells from BALB/c mice bearing a syngeneic tumor (CSA1 M) 2 to 3 wk after inoculation with CSA1 M cells produced IL-2, IFN-gamma, and TNF upon in vitro cultures. This was previously demonstrated to be a result of collaboration between tumor-primed CD4+ T cells and APCs binding CSA1 M tumor Ags in vivo. The IL-2- and IFN-gamma-producing capacities decreased with the progress of tumor-bearing stages. This was parallel to the levels of IL-2 and IFN-gamma mRNAs expressed by cultured spleen cells. In contrast, comparable levels of TNF mRNA were expressed by all groups of cultured cells. However, large amounts of TNF were secreted by the cells from early but not from late tumor-bearing mice. TNF was produced mainly by the non-T cell fraction upon stimulation with CD4+ T cell-derived IFN-gamma. Therefore, the reduced TNF production by whole spleen cells from late tumor-bearing mice was restored by addition of rIFN-gamma to their cultures. Reciprocally to the progressive decrease in the production of IFN-gamma/TNF, the capacities of tumor-bearing mice to produce TGF-beta and IL-6 increased along with tumor growth. TGF-beta suppressed production of IL-2, IFN-gamma, and TNF, but not of IL-6. Moreover, IFN-gamma/TNF production was negatively regulated by IL-6. Taken together with the fact that the growth of CSA1 M cells is completely inhibited by the combination of TNF and IFN-gamma, these results demonstrate that the tumor-bearing state induces an abnormal cytokine network under which the production of antitumor cytokines is negatively regulated.
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PMID:Regulatory mechanisms for production of IFN-gamma and TNF by antitumor T cells or macrophages in the tumor-bearing state. 786

A number of studies have demonstrated that potent anti-tumor immunity can be induced using cytokine gene transfer, a strategy termed transgenic immunotherapy. Our aim is to express cytokine genes in the vicinity of tumor cells, either by transducing tumor cells themselves, or by delivering cytokine-expressing endothelial cells to tumor sites. We compared the ability of cytokine-expressing tumor cells or endothelial cells to inhibit the tumorigenesis of MDA-MB-435 breast cancer cells in athymic nude mice. Retroviral vectors containing either human interleukin 2 (hIL-2) or interleukin 1 (hIL-1 alpha) were used to transduce MDA-MB-435 cells or human umbilical vein endothelial cells (HUVEC). Using a modified MTT bioassay and an ELISA specific for hIL-2, 43 of 70 MDA-MB-435 clones transduced with IL-2 were found to secrete between 100-800 units of IL-2/10(6) cells/24 hr. hIL-2 and hIL-1 alpha-transduced HUVEC secreted 40 ng/IL-2/10(6)/24 hr and 1.8 ng/10(6)/24 hr, respectively. To facilitate in vivo tracking of tumor cells, both nontransduced and IL-2-expressing MDA-MB-435 cells were genetically-marked with the E. coli lacZ gene and selected using flow cytometry. To study in vivo tumorigenicity, cells were injected into the mammary fat pad of athymic nude mice: (1) lacZ/MDA-MB-435 cells injected alone formed tumors in all animals; (2) IL-2-expressing lacZ/MDA-MB-435 cells did not form any tumors; (3) co-inoculation of MDA-MB-435/IL-2, or HUVEC/IL-2, or HUVEC/IL-1 alpha with lacZ/MDA-MB-435 cells prevented or delayed tumor growth.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Breast cancer gene therapy: transgenic immunotherapy. 788 Nov 11

To investigate critical factors influencing the localization and antitumor effects of monoclonal antibodies (MAb) or toxic conjugates, we have adapted a single rat sarcoma, HSN, for preferential growth in the lungs, liver, and lymph nodes (the major sites of metastasis in humans) and have raised a panel of syngeneic rat MAbs to a stably-expressed cell surface antigen. Using this model we have shown that localization in tumors is significantly influenced by their anatomical location and vascularization, and the degree of MAb interaction with host cells. Uptake in small hepatic tumors was excellent, but access to lung tumors was limited by the poor permeability of pulmonary vessels. HSN cells transfected with th human IL-2 gene and coinjected in low numbers with parental tumors secreted sufficient cytokine to enhance the local permeability of vessels and doubled MAb localization in tumors without any systemic toxicity, suggesting that regional delivery of IL-2 may be used to enhance MAb localization in this situation. In order to extent the applicability of the model to studies of MAbs raised against human tumor targets, we have transfected the human c-erb B-2 gene (homolog of the rat neu) into the highly metastatic HSN.LV subline. MAbs raised against the external domain of the p185 product can now be screened for their ability to localize in metastases, and for various conjugates to inhibit tumor growth either independently of, or in association with, a fully functional immune system.
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PMID:Monoclonal antibodies for the treatment of metastases. Evaluation of strategies using a syngeneic rat model. 788 38

Injection of anti-CD3 antibodies causes prompt expression of interleukin (IL)-4, IL-2, and interferon gamma (IFN-gamma) mRNA among spleen cells. The optimal dose of anti-CD3 for such induction was 1.33 microgram/animal; lymphokine mRNA was first observed at 30 min, peaked at 90 min, and was undetectable (for IL-4) or had declined markedly by 4 h. Cells harvested from spleens of mice injected with anti-CD3 90 min earlier secreted IL-4, IL-2, and IFN-gamma without further stimulation. By contrast, in vitro stimulation with anti-CD3 of spleen cell suspensions or splenic fragments from noninjected donors failed to cause prompt production of IL-4 and, even after 24 h of stimulation, the amount of IL-4 produced in such cells was substantially less than that secreted within 1 h by spleen cell suspensions or splenic fragments from mice injected with anti-CD3 90 min earlier. Production of IL-4 by spleen cells from anti-CD3-injected mice was not inhibited by pretreatment with anti-IL-4 antibody or with IFN-gamma or tumor growth factor beta nor enhanced by treatment with IL-4. By contrast, CTLA-4 immunoglobulin (Ig) treatment clearly diminished IL-4 production in response to in vivo anti-CD3, indicating that cellular interactions involving CD28 (or related molecules) were important in stimulation. Cell sorting analysis indicated that the cells that produced IL-4 in response to in vivo injection of anti-CD3 were highly enriched in CD4pos cells with the phenotype leukocyte cell adhesion molecule-1 (LECAM-1)dull, CD44bright, CD45RBdull, NK1.1pos. Indeed, the small population of CD4pos, NK1.1pos cells had the great majority of the IL-4-producing activity of this population. Injection with Staphylococcal enterotoxin B also caused prompt induction of IL-4 mRNA; the cells that were principally responsible for production also had the phenotype of CD4pos, NK1.1pos. These results suggest that possibility that this rare population of T cells may be capable of secreting IL-4 at the outset of immune responses and thus may act to regulate the pattern of priming of naive T cells, by providing a source of IL-4 to favor the development of T cell helper 2-like IL-4-producing cells.
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PMID:CD4pos, NK1.1pos T cells promptly produce interleukin 4 in response to in vivo challenge with anti-CD3. 790 23

T alpha 1, a 28-amino-acid peptide, is derived from PT alpha, which is an intracellular, nonsecretory protein of unknown function. Both T alpha 1 and PT alpha are found in the blood of normal individuals. Subcutaneous and intramuscular injections of T alpha 1 in doses up to 9.6 mg/m2 are tolerated without side effects, and 0.9 mg/m2 injections raise the serum level approximately 30-fold after 1 hr of administration, which slowly returns to baseline within 24 hr. In vitro, and perhaps in vivo, T alpha 1 restores normal T-cell function. It increases IL-2 production and IL-2 receptors in normal mitogen-stimulated T cells and stimulates IL-3 production in immunocompromised mice. The dose-response relationship for these effects is not linear and may be bimodal. T alpha 1 binds to VIP receptors and inhibits in vitro and xenograft growth of non-SCLC cell lines. In patients with nonbulky carcinomas who have received standard therapy, T alpha 1 is possibly effective in prolonging the time to relapse and in improving survival. At present there is a great need to clearly define the clinical role of T alpha 1 in cancer patients. A major problem encountered in studies with T alpha 1 will, however, be the present lack of knowledge with regard to its mechanism in effecting tumor growth. It is not at all clear whether its immunomodulatory functions, its interaction with VIP receptors, or none of these mechanisms are related to its antineoplastic activities. In addition, the apparent nonlinear dose-response relationship will make it difficult to choose a reasonable dosing schedule for clinical trials. This is particularly apparent in light of the experimental animal data summarized above where a tumor response was seen at doses of 4 micrograms/kg and 400 micrograms/kg but not at 0.4 microgram/kg and 40 micrograms/kg. This dose range could conceivably be given to humans since 9.6 mg/m2, the maximum dose given to humans without major side effects to date, is roughly equivalent to 250 micrograms/kg. At this time a reasonable clinical approach would be a well-designed risk factor stratified phase III clinical trial using 0.9 mg/m2 T alpha 1 subcutaneously twice a week compared to a control group to substantiate the data reported by Schulof et al. Before such data are available, T alpha 1 should not be used in clinical oncology.
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PMID:Thymosin alpha-1 as adjunct for conventional therapy of malignant tumors: a review. 792 12

Human CD3AK and LAK cells were prepared from peripheral blood mononuclear cells (PBMC) by culturing them in recombinant IL-2 (rIL-2, 30 mu/ml) and anti-CD3 monoclonal antibody, and in rIL-2 alone (300/ml), respectively. By MTT assay, it was found that the PBMC, when cultured in the presence of anti-CD3/rIL-2, proliferated more actively and persistently than PBMC cultured in the presence of rIL-2 alone. In vitro cytotoxicity assay showed that CD3AK cells had stronger killing activity against a poorly differentiated human gastric adenocarcinoma cell line MNK 45 than LAK cells did. Winn's assay at an E/T ratio of 20 carried out in nude mice also indicated that CD3AK cells were more effective than LAK cells in tumor growth inhibition. When the nude mice were inoculated with MNK 45 admixed with CD3AK, none of them developed tumor whereas those inoculated with either MNK 45 or MNK 45 admixed with LAK cells all developed tumor. The results indicate that CD3AK would be a better choice than LAK for the adoptive immunotherapy of human stomach cancer.
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PMID:[Experimental study of the anti-tumor activity of CD3AK against human gastric cancer cell line in vitro and in vivo]. 792 59

There is considerable evidence to demonstrate that immune function is abnormal in tumor-bearing mice, perhaps accounting, at least in part, for progressive tumor growth. In an attempt to generate an antitumor response, we used retroviral vectors to express IL-2 cDNA in CMS5, a murine fibrosarcoma. Mice inoculated with unmodified tumor cells suffered progressive tumor growth, whereas tumors secreting IL-2 were rejected or grew slowly. Animals bearing unmodified but not IL-2-secreting tumors also were immunosuppressed. On the basis of these observations, we were interested in how IL-2 secretion by the tumor cells prevented the onset of hyporesponsiveness. To identify biochemical differences between T cells of mice with parental vs slowly growing IL-2-secreting tumors, we examined signal transduction after activation through the CD3/TCR complex. Protein tyrosine phosphorylation was altered and calcium flux was reduced in cells of mice with parental tumors compared with animals with slowly growing IL-2-secreting tumors. In addition, levels of protein for the tyrosine kinases p56lck and p59fyn, as well as the TCR-zeta-chain, were reduced. These differences in signal transduction were observed for T cells of mice with parental and IL-2-secreting tumors of the same size, demonstrating that differences in tumor size alone could not explain our findings. Thus, IL-2 secretion by tumors seems to be able to prevent immunosuppression by maintaining normal signal transduction in T cells, facilitating the generation of antitumor responses.
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PMID:Abnormal signal transduction by T cells of mice with parental tumors is not seen in mice bearing IL-2-secreting tumors. 796 75

The therapeutic efficacy of cellular immunotherapy depends not only on the anti-tumor activity of the administered effector cells but also on their ability to gain access to the tumor by extravasation. Although interleukin-8 (IL-8) has been shown to prevent the vascular leak associated with IL-2, it also abrogates the anti-tumor effect of IL-2. We undertook these studies to determine if LHT could abrogate the anti-immunotherapeutic effect of IL-8, since IL-8 inhibits leukocyte adhesion. C57BL/6 mice were divided into four groups of six animals each after induction of MCA-105 fibrosarcoma inoculated into the right hindlimb on day 0 and were treated beginning on day 3 as follows: no therapy, IL-2 alone (1.02 x 10(6) IU ip tid on days 3-7), IL-2 + IL-8 (9.6 ng ip tid on days 3-7), and IL-2 + IL-8 + LHT (45C x 15 min on days 3, 5, and 7). Tumor growth was measured on days 10-21 and analyzed by Wilcoxon rank-sum analysis. IL-2 reduced tumor growth significantly (P < .05) compared to no therapy, and IL-8 abrogated the anti-tumor effect of IL-2, resulting in tumor growth in animals receiving IL-2 + IL-8, similar to the no therapy group (P > .05). However, addition of LHT to IL-2 + IL-8 resulted in significantly (P < .05) less tumor growth than no therapy or IL-2 + IL-8. Activity of the mice was scored as an indicator of systemic toxicity. We found that IL-8 was able to increase the activity (P = .07) of the mice when administered with IL-2. These results suggest that IL-8 may protect the tumor-bearing animal from the systemic toxicity of IL-2, while LHT abrogates the anti-immunotherapeutic effect of IL-8.
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PMID:Local hyperthermia abrogates the anti-immunotherapeutic effect of interleukin-8. 800 73


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