Dose Of IFN-alpha Research Articles

Long-term use of bevacizumab with interferon-alfa as a first-line targeted therapy of advanced kidney cancer

This article presents the results of our observations of the treatment of patients with metastatic kidney cancer. Bevacizumab is used in combination with interferon-alpha (IFN-a) as a first-line treatment. The medicament belongs to the new generation group of drugs that block angiogenesis. Aim: to determine the effectiveness and possible adverse effects of the treatment of renal cell carcinoma with the combination of bevacizumab and interferon-alpha. Materials and methods: treatment was performed in 22 patients with distant metastases of renal cell carcinoma. Patients received therapy in the mode of bevacizumab 10 mg/kg intravenously every 14 days, and IFN-a-2A 3 million units subcutaneously 3 times a week. Blood test, serum biochemistry, coagulogram and analysis of urine were monitored every 2 weeks. Computed tomography of the chest, abdomen and pelvis was performed every 3 months. Results: progression-free survival was 12 months, overall survival was 21 months (12-24 months). We identified adverse events during the treatment, in relation to which some patients had either temporarily cancel current treatment or to modify the dose (grade 3 (G3) was detected in 18% of patients). Conclusion: after 24 months of treatment 14 patients (63%) had disease progression, 5 (22%) patients had stabilization of the disease and 3 patients (15%) had partial response to treatment. Our results (overall survival, progression-free survival, rate of side effects) are consistent with results of the treatment described in world literature. Side effects of the treatment are associated primarily with the use of low doses of IFN-alpha and there were practically no side effects of high severity, requiring special treatment or cancel of treatment. It allows to recommend bevacizumab and interferon-alpha in low doses as first-line combination therapy. Prevention of adverse effects of treatment allows to continue the ongoing targeted therapy.

Combination Treatment with RG7112 and Pegylated Interferon α 2a Specifically Targets JAK2V617F Positive Progenitor Cells From Patients with Myeloproliferative Neoplasms.

Abstract 2865▪▪This icon denotes a clinically relevant abstractWe have recently reported that MDM2 levels are increased in PV CD34+ cells as a consequence of JAK2617F, while the p53 levels are reduced in CD34+ cells from both patients with PV and PMF. These observations led us to explore therapeutic approaches by which to up-regulate p53 as a strategy to treat MPN patients. We previously reported that combination treatment with low doses of Peg IFNα 2a and Nutlin-3, an antagonist of MDM2, induced PV CD34+ apoptosis and inhibited PV colony formation significantly. The combination of these agents also decreased the proportion of JAK2V617F-positive HPCs. We demonstrated that these two drugs affect p53 through different pathways with Peg IFNα 2a activating p38 MAP kinase and STAT1 leading to increased p53 transcription while nutlin-3 prevents the degradation of p53 (Lu et al, Blood, 2012; In Press).RG7112 is an orally bioactivity small molecule inhibitor of p53-MDM2 binding which activates the p53 pathway. RG7112 is currently being evaluated in several phase 1 cancer trials. Based on our previous data, we hypothesized that RG7112 would be an effective drug to combine with low doses of IFN alpha to treat MPN patients. In order to evaluate the therapeutic effects of RG7112 alone or in combination with Peg IFNα 2a on hematopoietic progenitor cells from MPN patients, CD34+ cells were isolated from patients with PV and PMF patients and were treated with varying of doses of RG7112 alone or/and in combination with a low dose of Peg IFNα 2a and its effects on PV CD34+ cell proliferation, apoptosis and colony formation was evaluated. The effects of this drug on MPN CD34+ cells was compared to its effects on cord blood CD34+ cells After treatment with RG7112 at doses ranging from 100 nM to 5000 nM for 4 days, the numbers of PV CD34+ cells were reduced to a far greater degree (about 60%) than that observed with cord blood CD34+ cells (90% and 80%) at the doses between 200 and 500 nM indicating that low doses of RG7112 selectively affects MPN HPCs. 200nM of RG7112 and 200 U/ml of Peg-IFNα 2a alone induced cell cycle arrest of PV CD34+ cells, and combination treatment significantly promoted apoptosis of MPN CD34+ cells (2.5 folds). This observation leads us to examine the possibility that low doses of RG7112 might be used in combination with Peg-IFNα 2a to treat MPN patients. Treatment with 200 nM of RG7112 alone decreased PV CFU-GM and BFU-E-derived colony formation by 20% while combination treatment with 200 U/ml of Peg-IFNα 2a decreased PV CFU-GM and BFU-E-derived colony formation by 60% and 70%, respectively. Similarly, treatment with 200 nM of RG7112 alone decreased PMF CFU-GM and BFU-E-derived colony formation by 20% and 40%, respectively, while combination treatment with 200 U/ml of Peg-IFNα 2a decreased PMF CFU-GM and BFU-E-derived colony formation by 60% and 80%, respectively. We also found that treatment with both agents in combination also decreased the size of the hematopoietic colonies. By contrast, treatment with the same low doses of RG7112 and Peg-IFNα 2a alone or in combination did not significantly affect the ability of normal CD34+ cells to generate CFU-GM and BFU-E-derived colonies. Combined treatment with low doses of RG7112 and Peg-IFNα 2a decreased the total number of JAKV617F-positive PV HPC by 9% - 25% (p=0.014) leading to an increased proportion of colonies with wild type JAK2. In conclusion, these data demonstrate that IFNα plus RG7112 specifically target malignant MPN HPC by activating p53 in vitro, which we propose can be exploited therapeutically to eliminate JAK2V617F positive HPC in both PV and PMF patients. These results strongly suggest that combinations of low doses of IFNα and RG7112 might serve as a novel therapeutic strategy for the long term treatment of MPN patients. Disclosures:No relevant conflicts of interest to declare.

Ascorbic acid has superior antiviral and antiproliferative effects over IFN-alpha in HAM/TSP PBMC ex vivo

IFN-alpha and high dose ascorbic acid (AA) have a modest clinical benefit in HAM/TSP (Nakagawa, 1996). We investigated the effect of ex vivo and in vitro AA and IFN-alpha treatment on HAM/TSP PBMC and HTLV-1-infected cell lines, respectively. We treated cells for 48-72h ex vivo and in vitro with low-high (10-100µg/ml) dose of AA and 1000U/ml of IFN-alpha and quantified lymphoproliferation by [3H]thymidine incorporation, tetraploid DNA content and PCNA expression (flow cytometry). Viral expression was measured at the RNA (tax, LTR) and protein (Tax, p19) level by RT-PCR, Western blot and ELISA, respectively. Apoptosis was quantified by subdiploid DNA content (flow cytometry). Th1/Th2/Th17 cytokines were quantified by cytometric bead array. AA induced a dramatic 95% decrease (control 3689±755 cpm vs. AA 121±52 cpm, p=0.001) in spontaneous, virus-driven lymphoproliferation and a decrease in tax and LTR transcription in HAM/TSP PBMC. In addition, AA decreased the exacerbated ex vivo IFN-gamma production in HAM/TSP PBMC. In HTLV-1 infected cell lines (MT-2 and MT-4), AA induced a dose-dependent increase in DNA fragmentation (p=0.02, p=0.005), paralleled by a decrease in PCNA (p=0.003), as well as p19 (p<0.001) and Tax levels. These effects appear virus-specific, since high-dose (100µg/ml) AA did not exert a significant antiproliferative or pro-apoptotic effect on PBMC of normal donors. On top, AA displayed a superior antiproliferative, antiviral and immunomodulatory effect over IFN-alpha in both cell lines and HAM/TSP PBMC. Considering the selective antiproliferative and antiviral effects of AA ex vivo and in vitro, the therapeutic potential of combination therapy with high dose AA in HAM/TSP should be further explored.

Interferon Alpha Adjuvant Therapy in Patients With High-Risk Melanoma: A Systematic Review and Meta-analysis

Based on previous meta-analyses of randomized controlled trials (RCTs), the use of interferon alpha (IFN-alpha) in the adjuvant setting improves disease-free survival (DFS) in patients with high-risk cutaneous melanoma. However, RCTs have yielded conflicting data on the effect of IFN-alpha on overall survival (OS). We conducted a systematic review and meta-analysis to examine the effect of IFN-alpha on DFS and OS in patients with high-risk cutaneous melanoma. The systematic review was performed by searching MEDLINE, EMBASE, Cancerlit, Cochrane, ISI Web of Science, and ASCO databases. The meta-analysis was performed using time-to-event data from which hazard ratios (HRs) and 95% confidence intervals (CIs) of DFS and OS were estimated. Subgroup and meta-regression analyses to investigate the effect of dose and treatment duration were also performed. Statistical tests were two-sided. The meta-analysis included 14 RCTs, published between 1990 and 2008, and involved 8122 patients, of which 4362 patients were allocated to the IFN-alpha arm. IFN-alpha alone was compared with observation in 12 of the 14 trials, and 17 comparisons (IFN-alpha vs comparator) were generated in total. IFN-alpha treatment was associated with a statistically significant improvement in DFS in 10 of the 17 comparisons (HR for disease recurrence = 0.82, 95% CI = 0.77 to 0.87; P < .001) and improved OS in four of the 14 comparisons (HR for death = 0.89, 95% CI = 0.83 to 0.96; P = .002). No between-study heterogeneity in either DFS or OS was observed. No optimal IFN-alpha dose and/or treatment duration or a subset of patients more responsive to adjuvant therapy was identified using subgroup analysis and meta-regression. In patients with high-risk cutaneous melanoma, IFN-alpha adjuvant treatment showed statistically significant improvement in both DFS and OS.

Strategies to Enhance the Therapeutic Activity of Cancer Vaccines: Using Melanoma as a Model

Although there has been initial success with some types of immunotherapy, such as adoptive cellular therapy and monoclonal antibody therapy for cancer, the experience with therapeutic cancer vaccines has been much less encouraging. Almost all randomized phase III trials testing therapeutic cancer vaccines have failed to meet their end points. There are several potential explanations for this, ranging from factors related to the clinical trial design and the vaccine itself. Perhaps the most important are host-related factors. Specifically, progression and metastases of many cancers are associated with induction of multiple cancer-specific immune-inhibitory pathways. These inhibitory pathways include induction of T-cell anergy through dendritic cell dysfunction, release of immunosuppressive cytokines, T-cell exhaustion through inhibitory T-cell signaling and T regulatory cell-mediated tumor-specific immune suppression. All of these pathways have been shown to be operational in patients with melanoma. To enhance the activity of therapeutic cancer vaccines, these immunosupressive pathways need to be addressed and reversed. A number of new immunomodulatory reagents that are able to interfere with some of these pathways are now being assessed in the clinic. Sanofi Pasteur designed a clinical trial in patients with advanced or metastatic melanoma that is intended to both induce tumor-specific T-cell responses and modulate or reverse some of the immune suppression pathways that the melanoma has induced. To accomplish this, the recently optimized ALVAC melanoma multi-antigen vaccine is administered with high doses of IFN-alpha. Clinical trial parameters have also been optimized to enhance the likelihood of inducing and documenting antitumor activity. Success with other therapeutic cancer vaccine approaches will likely require similar approaches in which promising immunogenic vaccines are integrated with biologically and clinically active immunomodulatory reagents.

Efficacy of Adjuvant Interferon-alpha Therapy Following Curative Resection in Renal Cell Carcinoma: Before the Molecular Targeting Therapy Era

Although present treatment programs for renal cell carcinoma (RCC) typically involve molecular-targeting drugs, interferon-alpha (IFN-alpha) remains an important therapeutic drug for this cancer. We evaluated the effect of adjuvant therapy in 508 patients with RCC following curative surgery. Patients were classified into one of the two categories based on the duration and the total dose of IFN-alpha treatment. Median follow-up time was 65.5 months. Overall survival rates at 5, 10, 15 and 20 years were 88.8%, 80.5%, 69.6% and 54.1%, respectively. Cause-specific survival rates at 5, 10, 15 and 20 years were 95.0%, 89.1%, 83.0% and 83.0%, respectively. Cox's proportional hazard model revealed that C-reactive protein, T classification, histological grade and age were significantly independent factors indicative of a poor prognosis. Our examination of the 253 patients diagnosed as pT1-2N0M0 who underwent adjuvant IFN-alpha therapy following surgery found that the therapy was not significantly associated with either cause-specific or disease-free survival. With regard to effects of duration of therapy and total dose of IFN-alpha, patients with a total IFN-alpha exposure of > or = 180 x 10(6) international units (IU) had a better prognosis than those exposed to <180 x 10(6) IU. Adjuvant therapy using large doses of IFN-alpha may improve the prognosis of patients with RCC following curative resection, and the new possibility of IFN-alpha therapy merits further investigation.

The antitumor and immunoadjuvant effects of IFN-alpha in combination with recombinant poxvirus vaccines.

IFN-alpha is a pleiotropic cytokine possessing immunomodulatory properties that may improve the efficacy of therapeutic cancer vaccines. The aim of this study was to evaluate the effectiveness and compatibility of combining recombinant IFN-alpha with poxvirus vaccines targeting the human carcinoembryonic antigen (CEA) in murine models of colorectal and pancreatic adenocarcinomas, where CEA is a self-antigen. The phenotypic and functional effects of IFN-alpha were evaluated in the draining inguinal lymph nodes of tumor-free mice. We studied the effect of the site of IFN-alpha administration (local versus distal) on antigen-specific immune responses to poxvirus vaccination. Mechanistic studies were conducted to assess the efficacy of IFN-alpha and CEA-directed poxvirus vaccines in tumor-bearing CEA transgenic mice. We identified a dose and schedule of IFN-alpha that induced a locoregional expansion of the draining inguinal lymph nodes and improved cellular cytotoxicity (natural killer and CD8(+)) and antigen presentation. Suppression of the vaccinia virus was avoided by administering IFN-alpha distal to the site of vaccination. The combination of IFN-alpha and vaccine inhibited tumor growth, improved survival, and elicited CEA-specific CTL responses in mice with CEA(+) adenocarcinomas. In mice with pancreatic tumors, IFN-alpha slowed tumor growth, induced CTL activity, and increased CD8(+) tumor-infiltrating lymphocytes. These data suggest that IFN-alpha can be used as a biological response modifier with antigen-directed poxvirus vaccines to yield significant therapeutic antitumor immune responses. This study provides the rationale and mechanistic insights to support a clinical trial of this immunotherapeutic strategy in patients with CEA-expressing carcinomas.

Combined chemo- and immunotherapy of tumors induced in mice by bcr-abl-transformed cells

For our experiments we selected two oncogenic, bcr-abl-transformed mouse cell lines, viz. B210 and 12B1. Both cell types are capable of inducing leukemia-like disease in syngeneic BALB/c mice after intravenous inoculation. 12B1 cells can moreover form solid tumors after subcutaneous injection. Since immunotherapy would expectedly be most effective in animals in which the tumor mass had been reduced by other therapeutic means, we attempted to develop a combined therapeutic system for suppressing tumor growth. In the present study, mice inoculated with the aggressive 12B1 cells were treated with imatinib mesylate (IM), mouse interferon alpha (IFNalpha) and cyclophosphamide (Cy) in combination with genetically modified tumor cells engineered to produce various cytokines. These cell vaccines had been derived from B210 cells. Therapy with IM or IFNalpha alone or cell immunotherapy alone resulted in partial suppression of tumor growth. Of the different therapeutic regimens tested, a combination of repeated doses of IM, IFNalpha and cell vaccines with one relatively high dose of Cy (200 mg/kg) was the most effective, resulting in tumor-free survival of a large portion of mice. The spleens, livers and bone marrows of the successfully treated animals were tested for the presence of bcr-abl-positive cells by means of RT-PCR technique. Results were negative, this suggesting that the animals had been cleared of residual disease.

Effect of Type I Interferon(s) on Cell Viability and Apoptosis in Primary Human Thyrocyte Cultures

Interferon (IFN) therapy may induce a generalized activation of the immune system, hence triggering or exacerbating autoimmune disease. Apoptosis contributes to the development of hypothyroidism in autoimmune thyroiditis. IFN can affect all phases of the cell cycle and may induce apoptosis in several cell lines from varied histologies. To date, no data exist on the possible effect of type I IFN(s) on FAS/FASL system and cell apoptosis of human thyroid follicles. Therefore, we evaluated the effect of both IFN-alpha and -beta on apoptosis in primary human thyrocyte cultures and the potential role of the FAS/FASL pathway. Thyrocytes were cultured in monolayers and FAS, FASL, and Bcl-2 mRNA expression was determined by reverse transcriptase polymerase chain reaction after exposure to 10 mIU/mL bovine thyroid-stimulating hormone alone or in combination with increasing doses of IFN-alpha or -beta for 24, 48, and 72 hours. The percentage of apoptotic hypodiploid cells was evaluated by flow cytometry. Thyroid-stimulating hormone significantly decreased FAS and increased Bcl-2 mRNA expression while reducing the percentage of hypodiploid cells. The concomitant addition of either IFN-alpha or -beta reduced cell viability and increased the number of hypodiloid cells, but only IFN-beta modulated the expression of FAS and Bcl-2 mRNA expression in a proapoptotic sense. Both type I IFN(s) increase apoptosis in primary thyrocyte cultures, but only IFN-beta modulates FAS and Bcl-2 gene expression toward a proapoptotic pathway. Because apoptosis plays an important role in thyroid homeostasis and disease, this mechanism may contribute to the development and progression of type I IFN(s) therapy-associated thyroid disease.

Long‐term follow‐up of interferon‐alpha induction and low‐dose maintenance therapy in hairy cell leukemia

Interferon-alpha (IFNalpha) was the first effective pharmacologic treatment of hairy cell leukemia (HCL). Since 1990 purine analogs replaced IFNalpha because of higher rates of complete remission and an invariable disease recurrence after cessation of IFNalpha. However, there are only limited data about long-term maintenance treatment with IFNalpha and none about dose finding in this phase. Fifty-two consecutive patients treated at our institution for HCL are included in this retrospective analysis. Forty (77%) patients received IFNalpha and 35 patients continue on long-term IFNalpha maintenance therapy. The initial dose of IFNalpha was 3 Mio IU three times per week and was tapered 6 months after initiation to doses as low as 3 Mio IU/12 wk. Dose adaptation was performed by repeated measurement of soluble Interleukin 2 receptor (sIL2R) together with peripheral blood values. The median follow-up of patients in the long-term IFNalpha group was 13.6 +/- 7.5 yr. Long-term IFNalpha was in general well tolerated and only in six (17%) patients the treatment had to be changed to purine analogs in the long-term IFNalpha group because of side effects. There are no deaths directly related to HCL. IFNalpha is still an effective and well tolerated therapeutic option. By repeated measurements of sIL2R together with the peripheral blood values, IFNalpha doses can be tapered to the minimal effective dose. The advantages and disadvantage of IFNalpha in regards to the standard treatment in HCL patients are discussed.

Phase I analysis of BCNU-impregnated biodegradable polymer wafers followed by systemic interferon alfa-2b in adults with recurrent glioblastoma multiforme

Carmustine (BCNU)-impregnated biodegradable polymer wafers have been shown to prolong survival in patients with recurrent malignant glioma. Interferon alfa-2b (IFNalpha(2b)) has demonstrated antitumor activity against a number of cancers, but its use in glioma has been limited. The use of these agents in combination is appealing because the mode of antitumor activity likely differs. This is a report of a phase I dose-finding study for IFNalpha(2b) in combination with surgery and BCNU wafers in patients with recurrent glioblastoma. Patients with progressive malignant glioma that was confirmed intraoperatively to be glioblastoma were treated with surgical resection and implantation of 8 BCNU wafers. A week later, IFNalpha(2b) was initiated three times a week at a dose of 3 MU/m(2), which was escalated in increments of 3 MU/m(2). The treatment cycle encompassed 8 weeks. Toxicity was monitored by clinical and laboratory testing. Correlative studies of methylguanine methyltransferase (MGMT) expression and gene expression array analysis were carried out. Ten patients were enrolled, and 9 patients had evaluable data. Dose-limiting toxicity in the form of fatigue occurred at 9 MU/m(2). Two complete imaging responses were observed at the 3 MU/m(2) dose. MGMT expression and gene expression arrays did not correlate with toxicity or response. Multimodal therapy with surgery, BCNU wafers, and IFNalpha(2b) appears to be a feasible and safe treatment strategy. The maximum tolerated dose of IFNalpha(2b) was determined to be 6 MU/m(2). Analysis of MGMT expression and gene expression was feasible.

Cytokine and sex hormone effects on zidovudine- and lamivudine-triphosphate concentrations in vitro

Elevated zidovudine- and lamivudine-triphosphates have been observed in peripheral blood mononuclear cells (PBMCs) from females versus males and in patients with high inflammatory states versus lower inflammatory states. Consistent with high triphosphate exposures, these same patient groups also experience elevated rates of toxicity, including lipoatrophy. The purpose of this study was to evaluate the effects of oestradiol, progesterone and testosterone as well as tumour necrosis factor (TNF)-alpha and interferon (IFN)-alpha on zidovudine- and lamivudine-triphosphates in PBMCs and, for the cytokines, in 3T3-L1 adipocytes. Multiple replicates of adipocytes and human PBMCs were incubated with experimental versus control conditions using several cytokine and sex hormone doses. Zidovudine- and lamivudine-triphosphate concentrations were determined with validated LC-MS-MS assays. A mixed effects, cell means model that accounted for experiment number was used to evaluate the effects of experimental conditions relative to control. In adipocytes, TNF-alpha doses below 2 ng/mL increased zidovudine-triphosphate by 18% (5-31%). Lamivudine-triphosphate was not detectable in adipocytes. In PBMCs, pooled IFN-alpha doses (0.1-10 U/mL) decreased zidovudine-triphosphate 26% (10-42%); 100 and 1000 ng/mL of progesterone decreased lamivudine-triphosphate by 22% (1-43%) and 47% (25-68%), respectively. Pooled testosterone doses (10-1000 ng/mL) decreased lamivudine-triphosphate by 24% (7-41%). No other statistically significant effects were observed. We found evidence that sex hormones and cytokines influence zidovudine-triphosphate and lamivudine-triphosphate slightly in PBMCs and adipocytes in vitro. These findings provide insight and scientific direction to address inflammation-dependent and sex-dependent phosphorylation and responses in patients.

Different tumoricidal effects of interferon subclasses and p53 status on hepatocellular carcinoma development and neovascularization

Interferon (IFN) is known as a multifunctional cytokine. The aim of this study was to examine the different effects of IFN subclass; namely, IFN-alpha and IFN-beta, on hepatocellular carcinoma (HCC) growth especially in conjunction with angiogenesis that is known to play a pivotal role in the tumor growth. Furthermore, we also examined whether the p53 status in the tumor would alter the anti-tumoral effect of IFN against HCC growth since the p53 status reportedly affected the therapeutic effect of anti-angiogenic agents against cancer. When compared with IFN-alpha, IFN-beta exerted a more potent inhibitory effect on HCC growth, even after the tumor was established, along with suppression of neovascularization in the tumor. A single treatment with clinically comparable low doses of IFN-beta significantly inhibited HCC growth whereas the same dose of IFN-alpha did not. IFN-beta also significantly suppressed the tumor growth both in the p53-wild and p53-mutant HCC cells. Our in vitro study revealed that IFN-beta showed a more potent inhibitory effect on the endothelial cell proliferation than IFN-alpha as in the in vivo study. Collectively, IFN may be an alternative anti-angiogenic agent against HCC since it exerted a significant tumoricidal effect regardless of the host p53 status even at a low dose. A cautious approach may be also required in the clinical practice since even in a same IFN subclass (class-I), IFN-alpha and IFN-beta exert tumoricidal effects of different magnitudes on HCC.

Therapeutic efficacy of sequential and simultaneous treatments with interferon‐α and lamivudine in children with chronic hepatitis B

Interferon (IFN)-alpha and lamivudine (LAM), a nucleoside analog, are frequently used drugs for the treatment of chronic hepatitis B (CHB), and their combined therapy has been shown to be effective. The purpose of the present study was to examine the therapeutic efficacy of sequential and simultaneous combination therapies of IFN-alpha and LAM in children with CHB. A total of 45 children with CHB, whose antibody status was positive for hepatitis B surface antigen (HBsAg), hepatitis B envelope antigen (HBeAg), and HBV-DNA at least for 6 months; who had alanine aminotransferase (ALT) levels 1.5-fold higher than normal and hepatic activity index scores higher than 6, were allocated to two groups. The first group included 24 children who were given standard dose IFN-alpha (5 MU/m(2) s.c., thrice weekly) for 6 months, followed by LAM (4 mg/kg per day per oral, maximum 100 mg/day) for an additional 6 months (sequential therapy group). The second group included 21 children who were given IFN-alpha and LAM therapy simultaneously for 6 months and who continued with LAM alone for another 6 months (simultaneous therapy group). Partial response was defined as normalization of ALT and eradication of HBV-DNA. Complete response was defined as normalization of ALT, eradication of HBV-DNA and e seroconversion. Non-responders were defined as having positive HBV-DNA and abnormal ALT levels. Sustained response was defined as absence of HBsAg and presence of hepatitis B surface antibody (anti-HBs). The mean age of the sequential therapy group was 12.7 +/- 4.1 years, and 16 (66.7%) of the patients were male. The mean age of the simultaneous therapy group was 14.8 +/- 4.6 years, and 15 (71.4%) were male. In the first group, 13 patients (54.2%) were non-responders; partial response was observed in five patients (20.8%), and complete response was seen in six patients (25%). Despite the occurrence of e seroconversion, normalization of ALT was not achieved in one case. In the second group, which consisted of 21 patients, 11 subjects (52.4%) were non-responders; partial response was observed in one case (4.8%), and complete response was seen in seven (33.3%). Sustained response was found in two patients (9.5%). There were no significant differences between the groups (P > 0.05). When the therapeutic efficiency of two different treatment regimens applied for 1 year was evaluated in childhood CHB therapy, it was remarkable that there was a sustained response and a higher complete response in group 2, although there was no considerable difference between the therapy results of both groups.

Polymorphisms in the IFNAR1 gene in patients with chronic hepatitis C: outcome of combined IFN-alpha therapy.

Interferon-alpha (IFN-alpha) alone or in combination with ribavirin has been used for the last decade in the treatment of chronic hepatitis C, although the achievement of a sustained virological response (SVR) has not been very satisfactory. The treatment outcome depends on viral genotypes and host genetic polymorphisms in genes involved in the IFN-alpha signaling cascade. In this paper, we investigated the distribution of two variants of the IFNAR1 gene, G17470C and L168V, in two patient groups having received IFN-alpha alone or in combination with ribavirin. The analysis was performed using DNA sequencing of the relevant gene fragments. This study suggests that when combination therapy with high dose IFN-alpha and ribavirin is administered, HCV genotypes and age rather than the IFNAR1 polymorphisms are the predictors of a sustained response.

A low-dose combination therapy of interleukin-2 and interferon-α is effective for lung metastasis of renal cell carcinoma: a multicenter open study

To confirm the usefulness of a combination therapy of interleukin-2 (IL-2) and interferon-alpha (IFN-alpha) against metastatic renal cell carcinoma, the recommended dose of IFN-alpha to use in combination with low-dose IL-2 was determined (phase 1). Efficacy and safety at this dose was evaluated (phase 2). In phase 1, the dose of IL-2 was fixed at 0.7 x 10(6) Japan reference unit (JRU)/person for 5 days a week. The dose of IFN-alpha was increased from 3 x 10(6) IU for 3 days a week (level I) to 6 x 10(6) IU for 3 days a week (level II) and to 6 x 10(6) IU for 5 days a week (level III). In phase 1, 10 patients were registered, with 9 (3 at each level) able to be evaluated. Because grade 3 and grade 4 neutropenia were observed at level III in 1 patient each, level II was found to be the recommended regimen. The response rate in phase 1 was 44.4% (4/9). In phase 2, 46 patients were registered, with a response rate in 37 patients, classified as per protocol set (PPS), of 21.6% (8/37). Toxicities observed were primarily flu-like symptoms due to cytokines, and gastrointestinal symptoms. Leukocyte abnormalities were observed, but they were milder and tolerable. In the 46 patients evaluated in phase 1 and phase 2, the response rate was 26.1% (12/46), being highest in 38.7% (12/31) of those who were nephrectomized, and with only lung metastases.

Interferon-α after autologous stem cell transplantation in pediatric patients with advanced Hodgkin's lymphoma

Thirteen children with refractory or recurrent Hodgkin's lymphoma (HL) received high-dose chemotherapy and autologous hematopoietic stem cell transplant (ASCT). After hematologic recovery, 10 patients were given interferon-alpha (IFN-alpha) as adjuvant therapy, starting at a dose of 0.5 x 10(6) U/m2 subcutaneously, three times a week. The dose was escalated as tolerated. Patients were treated for a median of 12 (4-24) months. Transient myelosuppression was the most common toxicity and led to temporary treatment interruption in five patients. The IFN-alpha dose was increased in nine patients, to a median final dose of 3.5 x 10(6) U/m2/week. With a median follow-up of 67 (range 25-114) months, nine of the 10 patients are alive and in continuous remission. One patient relapsed. Three patients were not treated with IFN-alpha initially, two because of rapidly progressive disease. One patient received IFN-alpha for treatment of relapse after transplant, and is alive in remission 10 years later. IFN-alpha has activity in children with advanced HL, and prolonged, low-dose treatment given after ASCT can be tolerated. Its therapeutic effect as a post-transplant adjuvant warrants further investigation.

UVB-Mediated Induction of Cytokines and Growth Factors in Pterygium Epithelial Cells Involves Cell Surface Receptors and Intracellular Signaling

Pterygium is a proliferative, inflammatory, and invasive ocular surface disease associated with excessive ultraviolet (UV) exposure. This investigation was conducted to identify UV activated signaling pathways in pterygium epithelial cells (PECs) that mediate cytokine and growth factor production and to determine whether these pathways are sensitive to blockade by anti-inflammatory agents such as retinoic acid (RA) and interferon (IFN)-alpha. PECs were pretreated with or without inhibitors of the ERK1/2, JNK, and p38 (PD98059, SB202190, and SB203580, respectively) mitogen-activated protein kinases (MAPK) or with inhibitors of the tyrosine kinase activity of epidermal growth factor receptor (EGFR; PD153035) and platelet-derived growth factor (PDGF; AG1295); exposed to UVB (20 mJ/cm2); and then further treated with the same inhibitors. Media were harvested and analyzed by ELISA for interleukin (IL)-6, IL-8, and vascular endothelial growth factor (VEGF). Cytokine mRNA was assessed by reverse transcription-polymerase chain reaction (RT-PCR). Inhibitors of ERK1/2, JNK, and p38 MAPKs significantly abolished the UVB-mediated increase in IL-6, IL-8, and VEGF. PD153035 reduced IL-8, AG1295 repressed IL-6, and both inhibitors partially downregulated VEGF production in UV-exposed PECs. RA and IFN-alpha dose dependently abrogated IL-6 and IL-8 but had no effect on VEGF expression after UV exposure. The results have identified a stress-induced intracellular pathway and potential cell-surface transmitters that may be relevant to pterygium development. Moreover, two anti-inflammatory/antiangiogenic agents were identified that reduced cytokine production in the study model. Topical application of these drugs may benefit patients with pterygia, potentially reducing the necessity for surgical intervention.

Results of interferon-alfa therapy in patients with Behçet uveitis

To report on the results of interferon-alpha 2a (IFNalpha) treatment in patients with Behçet uveitis unresponsive to conventional immunosuppressive therapy. We retrospectively analyzed the medical records of 44 patients who had been treated with IFNalpha between September 2001 and May 2005. The initial dose of IFNalpha was 6 MU/day in 37 patients (84.1%) and 3 MU/day in 7 patients (15.9%), and was gradually tapered after ocular inflammation was suppressed. Immunosuppressive agents were discontinued. Oral corticosteroids were discontinued or maintained at a dosage of less than 10 mg prednisone equivalent per day. Main outcome measures were recurrence of posterior or panuveitis attacks and changes in visual acuity. Sixteen patients (36.4%) remained relapse free during treatment, whereas 28 (63.6%) patients had recurrent uveitis attacks. Four of these were considered treatment failures and were switched to other treatments. In the remaining 40 patients, the mean duration of treatment was 12.4+/-10.8 months (range 3-45 months). In 9 of 40 patients (22.5%) treatment could be discontinued 22.2+/-13.4 months after therapy, and 8 (20%) of these patients had sustained remission for up to 24 months. Three patients (7.5%) were switched to other therapies because of side effects. The frequency of uveitis attacks per 6 months was reduced from 1.6+/-1.2 to 0.8+/-0.9 in 26 patients who had a minimum follow-up of 6 months before and after IFNalpha therapy (p<0.05). There was a significant improvement in visual acuity and this was preserved throughout follow-up in 38 (95%) of 40 patients. A partial or complete response was obtained with IFNalpha therapy in 91% of Turkish patients with Behçet uveitis refractory to conventional immunosuppressive treatment. Our results suggest that there may be differences in therapeutic efficacy and side-effect profile of IFNalpha in different patient populations. Comparative studies are needed to investigate this hypothesis.

Genomic response to interferon-α in chimpanzees: Implications of rapid downregulation for hepatitis C kinetics

The mechanism of the interferon-alpha (IFN-alpha)-induced antiviral response during hepatitis C virus (HCV) therapy is n o t completely understood. In this study,we examined the transcriptional response to IFN-alpha in uninfected chimpanzees after single doses of chimpanzee, human, or human-pegylated IFN-alpha. Liver and peripheral blood mononuclear cell (PBMC) samples were used for total genome microarray analysis. Most induced genes achieved maximal response within 4 hours, began to decline by 8 hours, and were at baseline levels by 24 hours postinoculation, a time when high levels of circulating pegylated IFN-alpha were still present. The rapid downregulation of the IFN-alpha response may be involved in the transition between the observed phase I and phase II viral kinetics during IFN-alpha therapy in HCV-infected patients. The response to all three forms of IFN-alpha was similar; thus, the reasons for previous failures in antiviral treatment of chimpanzees with human IFN-alpha were not due to species specificity of IFN-alpha. The response to IFN-alpha was partially tissue-specific. A total of 1778 genes were altered in expression by twofold or more by IFN-alpha, with 538 and 950 being unique to the liver or PBMC, respectively. Analysis of the IFN-alpha and IFN-gamma responses in primary chimpanzee and human hepatocytes were compared as well. IFN-alpha and IFN-gamma induced partially overlapping sets of genes in hepatocytes. In conclusion, the response to IFN-alpha is largely tissue-specific, and the response is rapidly downregulated in vivo, which may have a significant influence on the kinetics of antiviral response.