Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027497 (nausea)
 23,468 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The therapeutic application of high-dose interleukin (IL) 2 in human malignancy is limited by severe multiorgan toxicities that are mediated, in part, by tumor necrosis factor (TNF) and IL-1. CT1501R (lisofylline; LSF) is one of several methyl xanthine congeners that inhibit the effects of TNF by the interruption of specific signal transduction pathways. This randomized, placebo-controlled trial was designed to assess the activity of LSF in reducing the toxicities of high-dose IL-2 therapy. Fifty-three patients with metastatic renal cancer or malignant melanoma were treated with i.v. bolus IL-2, 600, 000 IU/kg every 8 h for 5 days (14 doses), followed by 9 days of rest and another 5-day course of IL-2. Patients were randomly assigned to LSF, 1.5 mg/kg i.v. bolus, or placebo every 6 h during IL-2 therapy. All patients were to be treated to individual maximum tolerance of IL-2 at the intensive care unit level of support. The end points for statistical analysis were the number of IL-2 doses administered during the first cycle of treatment (maximum, 28) and the toxicities experienced by each group after the first 8 planned IL-2 doses. There was no difference between the LSF and placebo groups in the mean number of IL-2 doses tolerated in the entire first cycle of therapy (19.6 +/- 5.4 versus 19.5 +/- 5.8, P = 0.86) or in the first or second 5-day course of IL-2. The only significant difference in toxicities occurring through the eighth dose of IL-2 was in the maximum elevation of serum creatinine (mean, 1.7 +/- 0.8 for placebo versus 1.5 +/- 0.6 mg/dl for LSF, P = 0.013). A Monte Carlo analysis of major toxicities over the first 14-dose course of therapy showed a statistically significant difference favoring the LSF-treated group (P = 0.025). LSF was well tolerated, associated only with mildly increased nausea (P = 0.006 after eight IL-2 doses, but not significant for the entire first cycle). The antitumor activity was comparable in both groups (objective responses, 2 of 28 with LSF versus 4 of 24 with placebo). The mean peak plasma concentrations of LSF on days 1, 5, and 19 were 6.24, 3.83, and 5.04 micromol/liter, respectively. In conclusion, with this dose and schedule, LSF did not alter the toxicities of high-dose i.v. IL-2 sufficiently to impact the overall dose intensity of IL-2. Successful IL-2 toxicity modulation may require the use of higher doses of LSF, the development of agents with more potent anti-TNF activity, and/or combined modulating agents that function via distinct mechanisms to interrupt cytokine-mediated signaling.
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PMID:Prospective randomized trial of lisofylline for the prevention of toxicities of high-dose interleukin 2 therapy in advanced renal cancer and malignant melanoma. 981 21

Interleukin (IL) 2 plays an important role in enhancing the immune response, whereas IL-4 has pluripotent activities which include affecting immune function. Preclinical data suggest that the combination might have enhanced immunomodulatory activity. In this Phase I trial in patients with advanced solid tumors, both IL-2 and IL-4 were given by separate s.c. injections simultaneously daily, 5 days in a row, Monday through Friday, for 3 consecutive weeks, followed by a 1-week break from treatment. Cycles could be repeated. The dose of IL-2 was kept constant at 9 x 10(6) IU/m2/injection while the dose of IL-4 was escalated beginning at 100 microgram/m2/injection and increasing by 100-microgram/m2 increments to a planned level of 400 microgram/m2/injection. Sixteen patients were entered in this study, with one patient being ineligible because of the presence of brain metastases. Of the 15 eligible patients, there were 14 males and 1 female, with a median age of 54 (range, 38-67) years and initial performance status of 0 in 5 patients and 1 in 10 patients. Patients were treated at levels of up to 300 microgram/m2/injection of IL-4 before the study was closed due to withdrawal of the drug by the manufacturer. The most commonly observed toxicities were fatigue, fever and chills, local reaction, nausea/vomiting and anorexia, headache and nasal stuffiness, and coughing, sometimes with the production of clear white sputum, more common in smokers. Duodenal ulcers occurred in one patient and one patient had grade 4 cardiac toxicity consisting of an asymptomatic minimal elevation of the creatinine phosphokinase MB isoenzyme (CPK-MB). Grade 3 hyponatremia occurred in two patients, and elevated liver function tests and creatinine occurred but were not dose limiting. Eosinophilia of unknown significance occurred in all patients. There were statistically significant elevations in absolute numbers of most T-cell subsets examined, without changes in circulating B cells. No antibodies to the IL-4 were found after one cycle. One patient with renal cell carcinoma showed a significant decrease in tumor burden after one cycle of treatment. Because of the IL-4 withdrawal, the maximum tolerated dose for this combination of drugs given by the route and schedule used here was not determined and will require additional testing. Subcutaneous IL-2 and IL-4 given simultaneously show important immunomodulatory and antitumor effects and should be tested further in cancer patients.
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PMID:Phase I trial of simultaneous administration of interleukin 2 and interleukin 4 subcutaneously. 981 6

We previously demonstrated findings suggestive of autologous GVHD in patients receiving IL-2-activated peripheral blood stem cells (PBSC) with IL-2 after transplantation. A pilot study was designed to test tolerability, feasibility and frequency of autologous GVHD and engraftment using IL-2 and alpha-IFN post-transplantation. After cyclophosphamide (6 g/m2) and carboplatin (1800 mg/m2), patients with high-risk stage II or III breast cancer received chemotherapy and rhG-CSF mobilized autologous PBSC that had been cultured in IL-2 for 24 h. Subcutaneous administration of IL-2 began on day 0 at 6 x 10(5) IU/m2/day for 5 of 7 days each week and continued for 4 weeks. Once engraftment occurred, alpha-IFN was initiated at a dose of 1 x 10(6)/m2/day subcutaneously for 30 days. Thirty-four consecutive patients with stage II (n=20), IIIA (n=6) and IIIB (n=8) disease were treated. All patients were without evidence of disease at the time of transplantation. The average time required for the ANC to reach 500/mm3 was 10 days (range: 8-11 days) and for platelets to reach 20000/mm3 was 10.7 days (range: 6-21 days). Forty-seven percent of patients (n=16) completed the full course of immunotherapy; the remaining patients received attenuated doses due to patient's request (n=6), development of temperature >38 degrees C (n=3), development of neutropenia (n=3), serious infection (n=1) and miscellaneous reasons (n=5). Four patients experienced transient moderate toxicities (level 3) including elevated liver function tests, nausea, rash and capillary leak syndrome. Pathological findings suggestive of skin GVHD developed in 43% of patients (12/28 patients) when skin biopsies were evaluated in a blinded fashion. At 13 months post-transplant (median; range: 5-24 months), 28 patients (82%) remain disease-free. These results demonstrate the feasibility and toxicity of this regimen along with pathological findings compatible with autologous GVHD of the skin.
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PMID:Immunotherapy with interleukin-2 and alpha-interferon after IL-2-activated hematopoietic stem cell transplantation for breast cancer. 1021 42

To minimize interleukin-2-related toxicity while retaining its efficacy, a treatment schedule utilizing subcutaneous IL-2 was evaluated in a phase II setting. Eighty unselected, consecutive patients with metastatic or recurrent renal cell carcinoma (RCC), mean age 58 years (range, 21 to 76), received IL-2 on an outpatient basis, 5 days per week for 4 or 6 consecutive weeks. During the first 5-day cycle, a dose of 18 million IU IL-2 was administered once a day; during subsequent cycles the dose in the first two days was reduced to 9 million IU. Two 6-week or three 4-week courses were given maximally. Patients who had completed at least one full course were considered evaluable. To circumvent flu-like symptoms, all patients received a maximum oral dose of 3 g acetaminophen daily. Seventy-seven patients were assessable for response. Three (4%) complete responses (CR) and 6 (8%) partial responses (PR) were observed, and 44 (57%) patients had stable disease (SD). Response durations were 64, 29, 29+ months for the CR and 2, 6, 8, 11, 32, 47 months for the PR. The median length of survival of all patients was 12 months, whereas the median survival of responders and non-responders was 35+ and 10+ months, respectively (P < 0.001). Side effects included fever, chills, nausea, vomiting, and transient inflammation and induration at the injection sites. These complications were acceptable, even in the patients with concomitant disease, and completely disappeared after cessation of IL-2. Subcutaneous IL-2 mediates antitumor responses, has limited side effects and is also suitable for elderly RCC patients with concomitant disease.
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PMID:Outpatient-based subcutaneous interleukin-2 monotherapy in advanced renal cell carcinoma: an update. 1085 6

The purpose of this study was to evaluate the potential efficacy of alternating two outpatient regimens for the treatment of metastatic renal cell cancer. These regimens consisted of 4 weeks of recombinant interleukin 2 (rIL-2) plus IFN-alpha2B followed by 4 weeks of 5-fluorouracil plus IFN-alpha2B. Fifty patients meeting eligibility criteria of previous Cytokine Working Group studies were treated on an outpatient basis. Patients received s.c. rIL-2 (Proleukin; Chiron, Emeryville, CA) during weeks 1-4 of the 8-week regimen. During weeks 1 and 4, the dosage for rIL-2 was 10 MIU/m2 twice daily on days 3-5, and the dosage for IFN-alpha2B (Intron; Schering Plough, Kenilworth, NJ) was 6 MIU/m2 on day 1. During weeks 2 and 3, the dosage for rIL-2 was 5 MIU/m2 on days 1, 3, and 5, and the dosage for IFN-alpha2B was 6 MIU/m2 on days 1, 3, 5. During weeks 5-8, 5-fluorouracil (750 mg/m2) was administered once weekly by i.v. infusion, and IFN-alpha2B (9 MIU/mZ) was administered as a s.c. injection three times weekly. Throughout the treatment, an assessment of quality of life was made and a symptom-distress scale was evaluated. There were two patients with complete responses (CRs) and seven with partial responses (PRs) for an objective response rate of 18% (95% confidence interval, 10-25). The median response duration was 8 months (range, 3-51+ months). The CRs lasted 5 months and 51+ months and the PRs ranged from 3+ to 18 months. After completing at least one course of treatment, eight patients (three with PR, one with minor response, four with stable disease) became CRs after surgery for remaining metastatic disease. Six remain alive at 43+ to 53+ months, and 5 remain disease-free since surgery. The median survival of the study group is 17.5 months, with a maximal follow-up of 53+ months. The range in survival is 1-53+ months. Toxicity was primarily constitutional. and treatment modifications were designed to maintain toxicity at grade 2/3. The most common toxicities during treatment with IL-2/IFN were fatigue, nausea/vomiting, anorexia, skin reaction, diarrhea, fever, and liver enzyme elevations. One-third had central nervous system toxicity (headache, depression, insomnia). During 5FU/IFN treatment, 49 of 50 patients experienced grade 2/3 myelosuppression during course 1. Eight patients experienced grade 4 toxicities. In conclusion, the activity of this alternating regimen is similar to that of IL-2/IFN alone, given in 4-week cycles. The addition of 5FU/IFN failed to increase the efficacy and added new toxicity (myelosuppression). This report does not confirm the results previously reported for either alternating or simultaneous administration of these three agents. Because 5FU does not appear to add to the antitumor activity of IL-2-based therapy for renal cancer, current efforts are directed toward a Phase III randomized comparison of high-dose i.v. bolus inpatient IL-2 treatment versus treatment with outpatient s.c. injection of IL-2 plus IFN.
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PMID:Phase II trial of interleukin 2, interferon alpha, and 5-fluorouracil in metastatic renal cell cancer: a cytokine working group study. 1099 27

A 40-year-old HIV-infected woman developed nausea, vomiting, and epigastric pain and died following her third dose (per study protocol) of interleukin (IL)-2. Her HIV infection was diagnosed in 1996. Her last CD4 cell count was 390/microL, and her viral load was negligible (as of November 28, 1998). She had no known general risk factors for thrombosis other than HIV infection, injection drug abuse, and antiretroviral therapy with indinavir. Abdominal films showed no sign of mechanical obstruction but a generalized gas distention of the bowel, which was suggestive of paralytic ileus. Autopsy revealed dilation of the small bowel with extensive necrosis and hemorrhage involving all the segments. The superior and inferior mesenteric arteries revealed severe atherosclerosis. The stenotic celiac artery was occluded by a recent thrombus at the aortic ostium. Clinicians need to be aware of the potential for thrombosis and accelerated atherosclerosis in HIV-infected patients. Both injection drug abuse and protease inhibitors, such as indinavir, have been shown to be risk factors for thrombosis. However, it is likely IL-2 contributed to the severe thrombosis in this patient, although definitive proof is lacking. An acute awareness of intestinal infarction in HIV-infected patients is warranted.
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PMID:Case report. Intestinal infarction due to vascular catastrophe in an HIV-infected patient. 1118 43

Granulocyte/macrophage-colony-stimulating factor (GM-CSF) plays a central role in the differentiation and function of dendritic cells, which are crucial for the elicitation of MHC-restricted T cell responses. Preclinical and the first clinical data provide a rationale for the application of GM-CSF in immunotherapy of cancer. Ten patients with renal cell carcinoma stage IV (Holland/ Robson) were treated in this pilot study. Therapy was started with GM-CSF alone (2 weeks). Interleukin (IL-2) and interferon alpha (IFNalpha) were added sequentially (3 weeks GM-CSF plus IL-2 or IFNalpha, 3 weeks GM-CSF plus IL-2 plus IFNalpha). Therapy was performed on an outpatient basis. The cytokine regimen was evaluated for toxicity, clinical response and immunomodulatory effects [fluorescence-activated cell sorting analysis of peripheral blood mononuclear cells (PBMC), mixed-lymphocyte reaction and cytotoxicity of PBMC]. GM-CSF treatment caused a significant increase in the number of PBMC expressing costimulatory molecules. Addition of IL-2 and IFNalpha led to an increase in CD3 , CD4+, CD8+ and CD56+ PBMC in week 9. In an autologous mixed-lymphocyte reaction a 2.1-fold increase in T cell proliferation was observed after 2 weeks of GM-CSF treatment, and cytotoxicity assays showed changes in natural-killer-(NK)- and non-NK-mediated cytotoxicity in some patients. Two patients achieved partial remission, one patient had a mixed response. The toxicity of the regimen was mild to moderate with fever, flu-like symptoms and nausea being observed in most patients. Severe organ toxicity was not observed. We conclude that GM-CSF might be useful for immunotherapy of renal cell carcinoma, especially in combination with T-cell-active cytokines. Further studies are warranted.
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PMID:Granulocyte/macrophage-colony-stimulating-factor plus interleukin-2 plus interferon alpha in the treatment of metastatic renal cell carcinoma: a pilot study. 1122 92

Some clinicians are claiming that IL-2 (interleukin-2) can quadruple T-cells, and is effective in rebuilding HIV-impaired immune systems. However, IL-2 also increases HIV replication. The increase can potentially be offset by combination therapy with protease inhibitors, but other concerns linger over IL-2's use in HIV treatment. It has minimal or detrimental effects on patients with T-cell counts below 200, the group most in need of an immune system boost. Insurance companies will generally not cover the treatment, and there are several cases of physicians charging exorbitant prices for the treatment. Patients taking IL-2 also suffer severe side effects, including nausea, aches, and flu-like symptoms. Drug trials are currently underway to test the effectiveness of IL-2.
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PMID:Cells for sale. 1136 58

Twenty patients with either melanoma ( 7) or kidney cancer ( 13) were treated with outpatient bolus interleukin (IL)-2 18-22 MIU/m2 IVPB for 3 consecutive days for 6 consecutive weeks followed by a 2-week rest break (on an 8-week cycle). Patient characteristics included 16 males/4 females, eleven patients had received no prior systemic therapy, median ECOG performance status = 1, and most common disease sites being lung, lymph node, subcutaneous, bone, and liver. Two patients with melanoma (29% response rate) (95% CI: 8-64%) and two with kidney cancer (15%) (95% CI: 3-43%) have achieved partial responses. Two minor responses in kidney cancer were also seen. The most common toxicities were nausea, fatigue, rigors, fever, and myalgias/arthralgias. No cardiac events occurred, and no patients required hospitalization due to toxicity. IL-2 at this outpatient dose and schedule is well tolerated and displays some evidence of activity in melanoma and kidney cancer. Larger patient numbers are required to corroborate these response rates and to determine whether complete responses are possible.
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PMID:Outpatient experience with moderate dose bolus interleukin-2 in metastatic malignant melanoma and kidney cancer. 1280 82

The prognosis for patients with metastatic renal cell carcinoma (RCC) remains unsatisfactory to date. Combined immunochemotherapy (ICT) strives for a synergistic effect avoiding a substantial increase of therapy-related adverse events. The combination therapy regimes consisting of either interferon-alpha-2a/vinblastine (IFN-alpha2a/VBL) or interferon-alpha-2a/interleukin-2/5-fluorouracil (IFN-alpha2a/IL-2/5-FU) demonstrated objective remission rates, surpassing the results obtained with the administration of single immunotherapeutic agents. Despite the data from a recently published study, the role of these two therapy combinations did not seem clearly defined. Therefore, we compared the impact of IFN-alpha2a/VBL and IFN-alpha2a/IL-2/5-FU on remission and survival as well as the safety profile in a retrospective study in patients with metastatic RCC. In a retrospective single-center study, 105 patients with metastatic RCC having received treatment between 1992 and 2002 with either s.c. IFN-alpha2a/ i.v. VBL ( n=70, group 1) or s.c. IFN-alpha2a/ s.c. IL-2/ i.v. 5-FU ( n=35, group 2) were evaluated. At a median follow-up of 17 months, remission and survival rates as well as the toxicity profiles of the respective groups were documented and compared. The median age throughout the entire patient population was 61 years. Patients in the IFN-alpha2a/VBL group reached a median overall survival of 20 months compared to 17 months for the patients in the IFN-alpha2a/IL-2/5-FU population ( p=0.850). The objective response rate in the first patient group reached 25.7%, whereas the tumor remission rate of group 2 amounted to 22.9% ( p=0.680). Patients showing an objective response reached a significantly higher survival rate than patients without response reaction (median survival was 36 vs 10 months, p=0.0001). The incidence of each therapy-induced adverse event was higher throughout the second treatment group. These differences were significant with respect to flu-like symptoms (85.7 vs 57.1%, p=0.003), grade 3/4 elevations of liver enzymes (14.3 vs 1.4%, p=0.007), nausea/vomiting (74.3 vs 50%, p=0.017), the severity of erythemas (74.3 vs 10%, p<0.001), and patients with lung edema (17.1 vs 2.9%, p=0.009). Eight patients discontinued the ICT, two of whom died of a myocardial infarction.Despite an overall limited prognosis, patients showing a tumor remission seem to benefit from ICT in terms of overall survival. While both treatment options offer comparable remission and survival rates, the IFN-alpha2a/VBL regimen induces fewer adverse events than the treatment with IFN-alpha2a/IL-2/5-FU.
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PMID:[Impact of immunochemotherapy on survival of patients with metastatic renal cell carcinoma. A retrospective study comparing interferon-alpha-2a/vinblastine versus interferon-alpha-2a/interleukin-2/5-fluorouracil]. 1523 86


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