Serum levels of interleukin-2 in cancer patients: Preliminary considerations

1989 ◽  
Vol 4 (4) ◽  
pp. 203-206 ◽  
Author(s):  
P. Lissoni ◽  
S. Viviani ◽  
A. Santoro ◽  
S. Barni ◽  
G. Tancini
Keyword(s):  
Cancer Patients ◽  
Solid Tumors ◽  
Healthy Subjects ◽  
Interleukin 2 ◽  
Serum Levels ◽  
Low Concentrations ◽  
Preliminary Study ◽  
Low Levels

In order to investigate the production of interleukin-2 (IL-2) in human neoplasms, we determined IL-2 and soluble IL-2 receptors (sIL-2R) in serum from 18 patients with lymphoma and 28 patients with solid tumors, with (15 cases) or without (13 cases) metastases. As controls, 58 healthy subjects were evaluated. Low levels of IL-2 were not observed in patients with lymphoma or limited solid tumor but abnormally low concentrations of IL-2 were seen in 4/15 metastatic solid tumors, associated with abnormally high values of sIL-2R. This preliminary study confirms in vivo the reduced IL-2 production in metastatic solid neoplasms, previously documented in vitro

Increased Level of Soluble Interleukin-2 Receptor in Advanced Solid Tumors: A Preliminary Study

1988 ◽  
Vol 74 (6) ◽  
pp. 633-637 ◽  
Author(s):  
Franco Rovelli ◽  
Paolo Lissoni ◽  
Sergio Crispino ◽  
Sandro Barni ◽  
Gabriele Fumagalli ◽  
...  
Keyword(s):  
Cancer Patients ◽  
Solid Tumors ◽  
Interleukin 2 ◽  
Normal Subjects ◽  
Serum Levels ◽  
High Serum ◽  
Human Solid Tumors ◽  
Soluble Interleukin 2 Receptor ◽  
Preliminary Study

Both activated normal and transformed lymphocytes produce not only cell-associated but also cell-free IL-2R. Evidence of high serum concentrations of IL-2R appears to serve as a tumor marker in patients with lymphomas On the contrary, the role of soluble IL-2R in solid neoplasms has still to be defined. This investigation was carried out to analyze soluble IL-2R production in human solid tumors. The study included 35 patients with solid tumors (12 without and 23 with metastases), 58 healthy subjects and 6 lymphoma patients. Among cancer patients, lung and breast carcinoma were the two most frequent neoplasms. In each subject or patient, serum levels of IL-2R were measured by using an enzyme immunoassay. Moreover, in 14/23 patients with metastatic solid tumors, lymphocyte subpopulations were also evaluated. Serum levels of IL-2R were significantly higher in the cancer patients than in the normal subjects. The patients with metastatic solid tumors showed significantly higher mean levels than those without metastases, and similar to those observed in the lymphoma patients. Finally, there was no correlation between serum levels of IL-2R and the T4/T8 ratio, which was reduced in 5/14 cancer patients. Further studies will be needed to establish if elevated concentrations of IL-2R in the serum can contribute to the immunoincompetence of patients with disseminated solid neoplasms.

Immunologic Reactivity in Patients Bearing Solid Tumors

1980 ◽  
Vol 66 (3) ◽  
pp. 311-318 ◽  
Author(s):  
Emma Menconi ◽  
Anna Barzi ◽  
Massimo Greco
Keyword(s):  
Cancer Patients ◽  
Solid Tumors ◽  
Peripheral Lymphocyte ◽  
Immune Reactivity ◽  
Immune Competence ◽  
Tumor Type ◽  
Healthy Controls ◽  
In Vivo Tests

The immune reactivity of 50 patients with solid tumors before therapeutic treatment and 26 healthy controls was assessed by both in vitro and in vivo tests. No significant differences between controls and patients were found in peripheral lymphocyte counts or in delayed hypersensitivity to recall antigens. However, impairment of lymphocyte stimulation with phytohemagglutinin (PHA) and a decrease in the number of E-rosette forming cells (E-RFC) were detected in cancer-bearing patients irrespective of tumor type. The results of the present study further confirm the usefulness of the PHA and E-RFC tests in monitoring the immune competence of cancer patients.

Ex vivo blood stimulation assay as a translational research tool in the development of the ticilimumab (CP-675,206)

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 2542-2542 ◽  
Author(s):  
R. Millham ◽  
D. Pavlov ◽  
P. Canniff ◽  
D. Guyot ◽  
D. Hanson ◽  
...  
Keyword(s):  
Cancer Patients ◽  
T Lymphocyte ◽  
Whole Blood ◽  
Ex Vivo ◽  
Interleukin 2 ◽  
Screening Experiments ◽  
Batch Release ◽  
Ctla4 Blockade

2542 Background: Cytotoxic T Lymphocyte-associated Antigen 4 (CTLA4) is an activation-induced T lymphocyte negative costimulatory receptor which down-regulates cellular immune responses. CTLA4 blockade may break peripheral immunological tolerance, leading to an effective immune response to cancer. Tools for assessing the effects of such a blockade are limited, as CTLA4 is not constitutively expressed on circulating T cells, and because activated lymphocytes are difficult to access in vivo. Therefore, we have employed ex vivo blood stimulation assays to define pharmacodynamic properties of the anti-CTLA4 antibody, ticilimumab. Methods: Ex vivo blood stimulation assays employed staphylococcal enterotoxin A (SEA) to stimulate isolated peripheral blood mononuclear cells (PBMC) or whole blood. Stimulation was monitored by production of interleukin 2 (IL-2). This assay was used preclinically to predict in vivo responses in animal models and in samples from cancer patients, as a batch release assay for production runs of ticilimumab, and clinically as a pharmacodynamic measurement in clinical trials of ticilimumab. Results: Screening experiments using the SEA assay allowed us to identify the lead candidate mAb with optimal CTLA4 blockade activity, ticilimumab. Dose-dependent increases in IL-2 production were observed in PBMC and whole blood samples up to an in vitro concentration of 100 ug/mL of ticilimumab, with 10 ug/mL identified as the minimum predicted efficacious concentration (Ceff). This functional potency assay was adapted for qualification of production lots of ticilimumab. Whole blood taken from cynomolgus monkeys dosed with ticilimumab demonstrated significant enhancement of IL-2 production at the same magnitude observed in in vitro experiments. Additionally, longitudinal samples taken from healthy volunteers and cancer patients suggested that an enhancement of 2.8 fold would be indicative of a pharmacodynamic effect of ticilimumab. Conclusions: The SEA assay provides a functional assessment of ticilimumab activity and can be used to guide the clinical development of this agent. Our data suggest that T cell reactivity is enhanced in the presence of ticilimumab in vitro, in primate models and in humans. [Table: see text]

Clinical Study of Melatonin in Untreatable Advanced Cancer Patients

1987 ◽  
Vol 73 (5) ◽  
pp. 475-480 ◽  
Author(s):  
Paolo Lissoni ◽  
Sandro Barni ◽  
Gabriele Tancini ◽  
Sergio Crispino ◽  
Franco Paolorossi ◽  
...  
Keyword(s):  
Cancer Patients ◽  
Performance Status ◽  
The Other ◽  
Advanced Cancer Patients ◽  
Cancer Of The Pancreas ◽  
Preliminary Study ◽  
Study Performance

It is known that the pineal gland has some antitumor activity. Melatonin, its most important hormone, has been shown to inhibit tumor growth in vivo and in vitro. Moreover, some investigations have demonstrated an altered melatonin secretion in cancer patients. Despite these interesting data, clinical trials have never been carried out to evaluate the effects of melatonin on human neoplasms. The aim of this study was to draw some preliminary conclusions on melatonin therapy in advanced human neoplasms. Nineteen patients suffering from advanced solid tumors, which did not respond to standard therapies, entered the study. Performance status (PS) was 20 or less in 9 cases, and more than 20 in the other 10. Melatonin was given intramuscularly at a daily dose of 20 mg at 3.00 p.m., followed by a maintenance period with lower doses in patients who had a remission, a stabilization of disease or an improvement in PS. Among patients with a PS higher than 20, a partial response was achieved in one case with cancer of the pancreas; moreover, 5 of 10 had stable disease, but the other 4 cases had a progression; an evident improvement of PS was obtained in 6 of the 10 cases. In contrast, among patients with a very poor PS, 7 of 9 died within the first 2 months of therapy. This preliminary study would suggest that melatonin may be of some value in treating cancer patients in whom standard antitumor therapies have failed, particularly in improving their PS and quality of life.

Modulation of Soluble Interleukin 2 Receptor (sIL-2R) Levels in Patients with HIVWaldenstrom Macroglobulinemia (HIV-WM) Treated with Biaxin-Pentoxifylline-Dexamethasone Followed by Prednisolone (BPD-Pred)

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 5214-5214
Author(s):  
Eugene McPherson ◽  
P. Tassy
Keyword(s):  
Interleukin 2 ◽  
Tumor Infiltrating Lymphocytes ◽  
Serum Levels ◽  
Disease Stage ◽  
Independent Effect ◽  
C Reactive Protein ◽  
Necrosis Factor Alpha ◽  
Reactive Protein

Abstract Serum levels of sIL-2R represents the total amount of activated T-lymphocytes in tumor infiltrating lymphocytes of cancer tissues and metastatic organ sites. Most malignant diseases overexpress sIL-2R in comparison to non-malignant controls. Immunomodulatory effect of IL-2 therapy on interferon (IFN), tumor necrosis factor alpha (TNF-a) production, nuclear factor kappa–b (NFkb) in vivo and in vitro and on the expression of sIL-2R in Human Immunodeficiency Virus – Waldenstrom Macroglobulinemia (HIV-WM) patients with IgM is not well defined. We present a 42 year old female with HIV, CD4-343/cu mm, viral load (VL) of >100K (persistently elevated VL), hypercoagulable state, serum viscosity >3 centpoises, IgM level of >1 gram with serum free light chain kappa/lambda ratio elevated as well as IgG and IgA on immunofixation studies. She was treated initially with BPD (Biaxin, Pentoxifylline, Dexamethasone) with partial response and with poor paraprotein parameter response. Her HAART regimen consisted of ritonavir base therapy. When dexamethasone was weaned off and prednisolone therapy started, greater than 50% reduction of paraprotein (IgM) occurred over 4–6 weeks. We measued serum sIL-2R, C-reactive protein (CRP), throughout treatment over 12 weeks. The serum sIL-2R level significantly decreased from 21,513.274 pg/ml to 5,424.779 pg/ml (normal 3,592.9 – 9,734.5 pg/ml). The C-reactive protein normalized and IgM was now 0.211 gram and within normal limits as well as serum viscosity. CONCLUSIONS: The suppression and modulation therapy of CRP gene transcription with manipulation of NFkb/IKKb with ritonavir based HAART and BPD-Pred with normalization of sIL-2R, CRP, and IgM paraprotein in HIV-WM patients may have an independent effect on prognosis and maintenance therapy. Serum sIL-2R levels may serve as a useful marker in evaluating HIV-WM disease, stage for stage and monitoring disease progression.

scholarly journals Reduced Th1, but Not Th2, Cytokine Production by Lymphocytes after In Vivo Exposure of Healthy Subjects to Endotoxin

2000 ◽  
Vol 68 (3) ◽  
pp. 1014-1018 ◽  
Author(s):  
Fanny N. Lauw ◽  
Tessa ten Hove ◽  
Pascale E. P. Dekkers ◽  
Evert de Jonge ◽  
Sander J. H. van Deventer ◽  
...  
Keyword(s):  
Whole Blood ◽  
Healthy Subjects ◽  
Cytokine Production ◽  
Interleukin 2 ◽  
Normal Serum ◽  
T Helper 1 ◽  
Th2 Cytokine ◽  
Ifn Γ

ABSTRACT Endotoxin (lipopolysaccharide [LPS]) tolerance is characterized by a reduced capacity of monocytes to produce proinflammatory cytokines upon restimulation in vitro. To determine whether LPS exposure induces a change in lymphocyte cytokine production and whether this results in a shift in the T-helper 1 (Th1)/Th2 balance, whole blood obtained from seven healthy subjects before and after an intravenous injection of LPS (4 ng/kg) was stimulated in vitro with the T-cell stimulus anti-CD3/CD28 or staphylococcal enterotoxin B. Whole-blood production of the Th1 cytokines gamma interferon (IFN-γ) and interleukin-2 (IL-2) was markedly reduced at 3 and 6 h, while the production of the Th2 cytokines IL-4 and IL-5 was not influenced or was slightly increased. The IFN-γ/IL-4 ratio was strongly decreased at 6 h. Serum obtained after LPS exposure could slightly inhibit the release of IFN-γ but increased IL-4 production during stimulation of blood drawn from subjects not previously exposed to LPS. Normal serum also inhibited IFN-γ production, albeit to a lesser extent. LPS exposure influences lymphocyte cytokine production, resulting in a shift toward a Th2 cytokine response, an effect that may be mediated in part by soluble factors present in serum after LPS administration in vivo.

scholarly journals Immunogenicity of Eight Dormancy Regulon-Encoded Proteins of Mycobacterium tuberculosis in DNA-Vaccinated and Tuberculosis-Infected Mice

2006 ◽  
Vol 75 (2) ◽  
pp. 941-949 ◽  
Author(s):  
Virginie Roupie ◽  
Marta Romano ◽  
Lei Zhang ◽  
Hannelie Korf ◽  
May Young Lin ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Immune Responses ◽  
Interleukin 2 ◽  
Cell Epitope ◽  
Dna Encoding ◽  
Histocompatibility Complex ◽  
Low Concentrations ◽  
Dosr Regulon

ABSTRACT Hypoxia and low concentrations of nitric oxide have been reported to upregulate in vitro gene expression of 48 proteins of the dormancy (DosR) regulon of Mycobacterium tuberculosis. These proteins are thought to be essential for the survival of bacteria during persistence in vivo and are targeted by the immune system during latent infection in humans. Here we have analyzed the immunogenicity of eight DosR regulon-encoded antigens by plasmid DNA vaccination of BALB/c and C57BL/6 mice, i.e., Rv1733c, Rv1738, Rv2029c (pfkB), Rv2031c/hspX (acr), Rv2032 (acg), Rv2626c, Rv2627c, and Rv2628. Strong humoral and/or cellular Th1-type (interleukin-2 and gamma interferon) immune responses could be induced against all but one (Rv1738) of these antigens. The strongest Th1 responses were measured following vaccination with DNA encoding Rv2031c and Rv2626c. Using synthetic 20-mer overlapping peptides, 11 immunodominant, predicted major histocompatibility complex class II-restricted epitopes and one Kd-restricted T-cell epitope could be identified. BALB/c and (B6D2)F1 mice persistently infected with M. tuberculosis developed immune responses against Rv1733c, Rv2031c, and Rv2626c. These findings have implications for proof-of-concept studies in mice mimicking tuberculosis (TB) latency models and their extrapolation to humans for potential new vaccination strategies against TB.

Kinetics of Various 99mTc-Sn-Pyrophosphate Compounds in the Rat

1977 ◽  
Vol 16 (04) ◽  
pp. 157-162 ◽  
Author(s):  
C. Schümichen ◽  
B. Mackenbrock ◽  
G. Hoffmann
Keyword(s):  
Normal Saline ◽  
Half Life ◽  
Compound A ◽  
Short Half Life ◽  
Low Concentrations ◽  
The Stability ◽  
Kinetics Of ◽  
In Vitro Stability

SummaryThe bone-seeking 99mTc-Sn-pyrophosphate compound (compound A) was diluted both in vitro and in vivo and proved to be unstable both in vitro and in vivo. However, stability was much better in vivo than in vitro and thus the in vitro stability of compound A after dilution in various mediums could be followed up by a consecutive evaluation of the in vivo distribution in the rat. After dilution in neutral normal saline compound A is metastable and after a short half-life it is transformed into the other 99mTc-Sn-pyrophosphate compound A is metastable and after a short half-life in bone but in the kidneys. After dilution in normal saline of low pH and in buffering solutions the stability of compound A is increased. In human plasma compound A is relatively stable but not in plasma water. When compound B is formed in a buffering solution, uptake in the kidneys and excretion in urine is lowered and blood concentration increased.It is assumed that the association of protons to compound A will increase its stability at low concentrations while that to compound B will lead to a strong protein bond in plasma. It is concluded that compound A will not be stable in vivo because of a lack of stability in the extravascular space, and that the protein bond in plasma will be a measure of its in vivo stability.

Enhanced Increases in Cytosolic Ca2+ in ADP-Stimulated Platelets from Patients with Delta-Storage Pool Deficiency – A Possible Indicator of Interactions between Granule-Bound ADP and the Membrane ADP Receptor

1997 ◽  
Vol 77 (02) ◽  
pp. 376-382 ◽  
Author(s):  
Bruce Lages ◽  
Harvey J Weiss
Keyword(s):  
Platelet Rich Plasma ◽  
Limited Range ◽  
Dense Granule ◽  
Receptor Desensitization ◽  
Fura 2 ◽  
Storage Pool ◽  
Low Levels ◽  
The Right

SummaryThe possible involvement of secreted platelet substances in agonist- induced [Ca2+]i increases was investigated by comparing these increases in aspirin-treated, fura-2-loaded normal platelets and platelets from patients with storage pool deficiencies (SPD). In the presence and absence of extracellular calcium, the [Ca2+]i response induced by 10 µM ADP, but not those induced by 0.1 unit/ml thrombin, 3.3 µM U46619, or 20 µM serotonin, was significantly greater in SPD platelets than in normal platelets, and was increased to the greatest extent in SPD patients with Hermansky-Pudlak syndrome (HPS), in whom the dense granule deficiencies are the most severe. Pre-incubation of SPD-HPS and normal platelets with 0.005-5 µM ADP produced a dose-dependent inhibition of the [Ca2+]i response induced by 10 µ M ADP, but did not alter the [Ca2+]i increases induced by thrombin or U46619. Within a limited range of ADP concentrations, the dose-inhibition curve of the [Ca2+]i response to 10 µM ADP was significantly shifted to the right in SPD-HPS platelets, indicating that pre-incubation with greater amounts of ADP were required to achieve the same extent of inhibition as in normal platelets. These results are consistent with a hypothesis that the smaller ADP-induced [Ca2+]i increases seen in normal platelets may result from prior interactions of dense granule ADP, released via leakage or low levels of activation, with membrane ADP receptors, causing receptor desensitization. Addition of apyrase to platelet-rich plasma prior to fura-2 loading increased the ADP-induced [Ca2+]i response in both normal and SPD-HPS platelets, suggesting that some release of ADP derived from both dense granule and non-granular sources occurs during in vitro fura-2 loading and platelet washing procedures. However, this [Ca2+]i response was also greater in SPD-HPS platelets when blood was collected with minimal manipulation directly into anticoagulant containing apyrase, raising the possibility that release of dense granule ADP resulting in receptor desensitization may also occur in vivo. Thus, in addition to enhancing platelet activation, dense granule ADP could also act to limit the ADP-mediated reactivity of platelets exposed in vivo to low levels of stimulation.

scholarly journals In-vitro and in-vivo metabolism of different aspirin formulations studied by a validated liquid chromatography tandem mass spectrometry method

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Michele Dei Cas ◽  
Jessica Rizzo ◽  
Mariangela Scavone ◽  
Eti Femia ◽  
Gian Marco Podda ◽  
...  
Keyword(s):  
Oral Administration ◽  
Whole Blood ◽  
Serum Levels ◽  
Reversed Phase ◽  
Weekly Treatment ◽  
Low Dose Aspirin ◽  
Liquid Chromatography Tandem Mass ◽  
Enteric Coated

AbstractLow-dose aspirin (ASA) is used to prevent cardiovascular events. The most commonly used formulation is enteric-coated ASA (EC-ASA) that may be absorbed more slowly and less efficiently in some patients. To uncover these “non-responders” patients, the availability of proper analytical methods is pivotal in order to study the pharmacodynamics, the pharmacokinetics and the metabolic fate of ASA. We validated a high-throughput, isocratic reversed-phase, negative MRM, LC–MS/MS method useful for measuring circulating ASA and salicylic acid (SA) in blood and plasma. ASA-d4 and SA-d4 were used as internal standards. The method was applied to evaluate: (a) the "in vitro" ASA degradation by esterases in whole blood and plasma, as a function of time and concentration; (b) the "in vivo" kinetics of ASA and SA after 7 days of oral administration of EC-ASA or plain-ASA (100 mg) in healthy volunteers (three men and three women, 37–63 years). Parameters of esterases activity were Vmax 6.5 ± 1.9 and Km 147.5 ± 64.4 in plasma, and Vmax 108.1 ± 20.8 and Km 803.2 ± 170.7 in whole blood. After oral administration of the two formulations, tmax varied between 3 and 6 h for EC-ASA and between 0.5 and 1.0 h for plain-ASA. Higher between-subjects variability was seen after EC-ASA, and one subject had a delayed absorption over eight hours. Plasma AUC was 725.5 (89.8–1222) for EC-ASA, and 823.1(624–1196) ng h/mL (median, 25–75% CI) for plain ASA. After the weekly treatment, serum levels of TxB2 were very low (< 10 ng/mL at 24 h from the drug intake) in all the studied subjects, regardless of the formulation or the tmax. This method proved to be suitable for studies on aspirin responsiveness.

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