IFN-alpha2b and thalidomide synergistically inhibit tumor-induced angiogenesis.

Angiogenesis is an absolute requirement for tumor growth and metastasis. The purpose of this study was to evaluate the antiangiogenic activity of interferon-alpha2b (IFN-alpha2b) and thalidomide, as single agents and in combination. The murine dermis model was used to assess tumor-induced angiogenesis in nude mice. Human ACHN (renal), NIH-OVCAR-3 (ovarian), LNCaP (prostate), and SK-Mel-1 (melanoma) tumor cells were inoculated intradermally into the flanks of nude mice. IFN-alpha2b and thalidomide, administered daily, were effective inhibitors of angiogenesis induced by all four tumor types. The combination of IFN-alpha2b and thalidomide caused a synergistic decrease in mean vessel count in tumors that were resistant to the antiproliferative effects of IFN-alpha2b and thalidomide in vitro. This enhanced suppression of angiogenesis translated into synergistic antitumor activity in a xenograft model. Pegylated IFN-alpha (PEG-IFN-alpha2b) (10(6) U) administered once in 10 days was as effective as daily IFN-alpha2b treatment (10(6) U x 10 days). IFN-alpha2b and thalidomide have potentiated antiangiogenic activity when used in combination. A single dose of PEG-IFN-alpha2b (10(6) U) was as effective at suppressing vessel growth as an equivalent dose of IFN-alpha2b given daily for 10 days.     

比较α-干扰素不同联合治疗方案对儿童HBeAg阳性慢性乙型肝炎的疗效

目的评估两种不同的α-干扰素联合治疗对儿童HBeAg阳性慢性乙型肝炎的临床疗效。方法选择HBeAg阳性慢性乙型肝炎儿童120例,随机分为3组,每组各40例:第1组(A组)为α-干扰素(IFN-α)组;第2组(B组)为IFN-α 拉米夫定(LAM)组。第3组(C组)为α-干扰素(IFN-α) 乙肝疫苗组。其中干扰素疗程6个月,拉米夫定疗程6个月,所有病例均观察至12个月。结果治疗结束时丙氨酸转氨酶(ALT)复常率3组无差异。治疗6个月和12个月时B组HBeAg阴转率和HBV DNA的阴转率明显高于A组和B组,差异有统计学意义(P<0.05)。结论α-干扰素与拉米夫定联合治疗对HBeAg阳性慢性乙型肝炎儿童的病毒学应答(VR)疗效明显优于单用α-干扰素组和α-干扰素 乙肝疫苗组。     

Short communication: the efficacy of fixed dose rate infusion of gemcitabine combined with IFN-alpha2a in patients with advanced refractory renal cell carcinoma.

The fixed dose rate (FDR) infusion of gemcitabine is based on pharmacokinetic studies demonstrating an increased peak concentration of gemcitabine-active metabolites inside the cell. In this prospective study, for the first time we investigated gemcitabine FDR infusion together with interferon-alpha2a (IFN-alpha) in pretreated patients with advanced renal cell carcinoma (RCC). Twelve patients received 800 mg/m2 gemcitabine (i.v. infusion of 10 mg/m2/min) on days 1 and 8 every 3 weeks, combined with 3.0 x 10(6) U s.c. IFN-alpha on days 1, 3, and 5 of each week. Median age of patients was 64 years, and the Eastern Cooperative Oncology Group performance status (ECOG PS) was 0-1 in 10 patients. All patients were pretreated, 5 with > or =2 lines of chemoimmunotherapy. A median number of five cycles of gemcitabine per patient were given, with a mean weekly dose intensity of 72% of that planned. Among 11 evaluable patients, 2 (18%) partial responses and 5 (46%) stable diseases (median duration of 9.3 months) were observed. Median time to progression (TTP) and overall survival were 7.1 months and 13.0 months, respectively. The most frequently occurring grade 3 or 4 adverse events were leukoneutropenia (25%), thrombocytopenia (17%), and diffuse edema (25%). One patient developed a cerebrovascular accident potentially related to treatment. These promising results with the combination of gemcitabine infused at FDR and IFN-alpha deserve further investigation.     

Immunoregulatory effects of interferon-alpha. I. Interferon-alpha inhibits in vitro antibody synthesis by normal human lymphocytes.

The effects of human interferon-alpha (IFN-alpha) on in vitro synthesis of specific anti-influenza virus antibody were measured in cultures of peripheral blood lymphocytes from normal donors. IFN-alpha suppressed antibody synthesis in a time and dose related manner. This suppression was also produced by monoclonal antibody purified IFN-alpha and was blocked by anti-IFN-alpha antibody. However antibody induced by a combination of antigen and 'B cell helper supernatant' was not suppressed indicating that IFN-alpha inhibits the initial events in antibody synthesis but does not affect cells committed to antibody production.     

Pharmacokinetics and pharmacodynamics of pegylated interferon lambda-1 in cynomolgus monkeys

Type III lambda interferons (IFNs) have activity similar to type I IFNs, but a more restricted receptor distribution. A pegylated human IFN lambda-1 (pegIFNλ) is under development for chronic hepatitis C. Induction of receptor signaling (STAT1 phosphorylation) and expression of interferon-stimulated genes (ISGs) by pegIFNλ were assessed in, respectively, cynomolgus monkey leukocyte subsets and hepatocytes stimulated in vitro. ISG induction by pegIFNλ or IFNα was also assessed in peripheral leukocytes and liver biopsies after single and repeat (x3) dosing of pegIFNλ (0.03, 0.3, 3.0 mg/kg) or unpegylated IFNα-2b (10(7) IU/kg). Single-dose pharmacokinetics of pegIFNλ were evaluated. Strong ISG induction occurred in cultured hepatocytes and liver biopsies with both pegIFNλ and IFNα. However, STAT1 phosphorylation, MHC class 1 upregulation, and ISG induction in leukocytes only occurred with IFNα. Serum neopterin was unaffected by pegIFNλ; however, β-2-microglobulin was elevated at all doses. The terminal half-life of pegIFNλ was 23 h with a 59 mL/kg volume of distribution, consistent with other pegylated IFNs. Serum exposure was dose-proportional across the dosing range. These data demonstrate the suitability of cynomolgus monkeys for the preclinical evaluation of pegIFNλ. Additionally, the absence of pegIFNλ pharmacologic activity in leukocytes is consistent with its low receptor expression in blood.     

Efficacy of low-dose interferon with antiretroviral therapy in Kaposi's sarcoma: a randomized phase II AIDS clinical trials group study.

We wished to evaluate the efficacy and safety of a low and an intermediate daily dose of interferon-alpha2b (IFN-alpha2b) with didanosine in patients with acquired immunodeficiency syndrome (AIDS)-associated Kaposi's sarcoma (KS). HIV-seropositive subjects with biopsy-confirmed cutaneous KS were randomized to receive either a low (1 million IU) or an intermediate (10 million IU) dose of IFN-alpha2b once daily with twice daily doses of didanosine. Treatment assignment was stratified by CD4 count. Response, toxicity, changes in CD4 counts, and survival were evaluated. Sixty-eight eligible subjects were accrued, 35 to low-dose and 33 to intermediate-dose IFN-alpha2b. The response rate was 40% in the low-dose group (95% CI, 24-58) and 55% in the intermediate-dose group (95% CI, 36-72) (p = 0.338). The median response duration was approximately 110 weeks in both groups. Intermediate-dose IFN induced grade 3/4 neutropenia more often (21% vs. 3%, p = 0.048) and grade 3/4 toxicity faster (p = 0.0231) and necessitated treatment discontinuation earlier for drug-related toxicities (p = 0.0416) than low-dose IFN. There were no significant differences in survival between the treatment groups. Baseline CD4 count was the only significant factor predicting response. Once-daily low-dose and intermediate-dose IFN-alpha2b induced similar response rates, which were achieved without optimal antiretroviral therapy. The slightly higher response rate in the intermediate-dose group was offset by its significantly poorer tolerance. These findings justify the use of lower, well-tolerated IFN doses for treatment of KS with currently used antiretroviral regimens.     

IFN-alpha as induction and maintenance treatment of patients newly diagnosed with Waldenstr?m's macroglobulinemia.

Waldenstr?m's macroglobulinemia is a rare malignant disorder of B lymphocytes. There are no studies on the use of interferon-alpha (IFN-alpha) as frontline therapy in this disease. Between April 1991 and September 2000, we treated 21 newly diagnosed patients using 8 mg/m(2) chlorambucil and 40 mg/m(2) prednisone p.o. daily for 10 days and 3 megaU/m(2) IFN-alpha three times a week. Patients who responded after induction continued receiving IFN until relapse or death. We found a high frequency of peripheral neuropathy (43%) and grade 3 diffuse marrow fibrosis (43%). Objective response was achieved in 12 (57%) patients, including 4 (19%) complete responders. Median time from treatment to response was 8 months (range 3-18). Median progression-free survival was 70 months (95% CI 47-93), and overall survival was 91 months (95% CI 50-132). Patients who achieved objective response lived longer (91 vs. 33 months, p < 0.03), as did patients who had lactic dehydrogenase (LDH) < 180 U/L (89 vs. 54 months, p < 0.01). Grade 3 hematologic toxicity was observed during induction in 5 patients. IFN-alpha is an effective agent for the induction and maintenance treatment of Waldenstr?m's macroglobulinemia patients. LDH > 180 U/L and failure to respond are adverse prognostic factors.     

Antidepressant reversal of interferon-alpha-induced anhedonia

Interferon-alpha(IFN-alpha) is used clinically in the treatment of several pathologies such as hepatitis C and various cancers. The positive therapeutic potential is however often limited by negative secondary effects which include major depression, one of the cardinal symptoms of which is anhedonia which has been operationalized as a decreased sensitivity to rewards (inability to experience pleasure). Previous studies have demonstrated the existence of anhedonia in rats following an acute injection of IFN-alpha at doses corresponding to those used in clinical applications. If this previously demonstrated anhedonia is indeed part of a depression syndrome in rats, this behavioural symptom should be reversible by the administration of antidepressants. The objective of the present experiment was to determine whether two commonly used antidepressants (desipramine and fluoxetine) were effective in ameliorating IFN-alpha-induced anhedonia in rats. The experiment consisted of two phases. In the first, the effects of daily systemic injections of 104 units/kg of IFN-alpha (or vehicle) were evaluated with the three-bottle (1%, 8%, and 32%) sucrose-consumption test. In the second phase of the experiment, in addition to continued injections of IFN-, different groups received daily injections of desipramine (7.5 mg/kg ip), fluoxetine (7.5 mg/kg ip), or vehicle. The IFN-alpha injections during Phase 1 resulted in clear anhedonia, as expressed by increased consumption of the 32% solution and decreased consumption of 1% over the 33 days of this phase. After 15 days of antidepressant treatments, 32% sucrose consumption returned to baseline values. We have therefore confirmed that IFN-alpha-induced anhedonia is susceptible to reversal following chronic antidepressant treatment and thus it may appear timely to consider the prophylactic use of such in particular patients prescribed IFN in the clinic.     

Development of fetal and placental innate immune responses during establishment of persistent infection with bovine viral diarrhea virus

Transplacental viral infections are dependent upon complex interactions between feto-placental and maternal immune responses and the stage of fetal development at which the infection occurs. Bovine viral diarrhea virus (BVDV) has the ability to cross the placenta and infect the fetus. Infection early in gestation with non-cytopathic (ncp) BVDV leads to persistent infection. Establishment of fetal persistent infection results in life-long viremia, virus-specific immunotolerance, and may have detrimental developmental consequences. We have previously shown that heifers infected experimentally with ncp BVDV type 2 on d. 75 of gestation had transient robust up-regulation of the type I interferon (IFN) stimulated genes (ISGs) 3-15 days after viral inoculation. Blood from persistently infected (PI) fetuses, collected 115 days post maternal infection, demonstrated moderate chronic up-regulation of ISGs. This infection model was used to delineate timing of the development of innate immune responses in the fetus and placenta during establishment of persistent infection. It was hypothesized that: (i) chronic stimulation of innate immune responses occurs following infection of the fetus and (ii) placental production of the type I IFN contributes to up-regulation of ISGs in PI fetuses. PI fetuses, generated by intranasal inoculation of pregnant heifers with ncp BVDV, and control fetuses from uninfected heifers, were collected via Cesarean sections on d. 82, 89, 97, 192, and 245 of gestation. Fetal viremia was confirmed starting on d. 89. Significant up-regulation of mRNA encoding cytosolic dsRNA sensors -RIG-I and MDA5 - was detected on d. 82-192. Detection of viral dsRNA by cytosolic sensors leads to the stimulation of ISGs, which was reflected in significant up-regulation of ISG15 mRNA in fetal blood on d. 89, 97, and 192. No difference in IFN-α and IFN-β mRNA concentration was found in fetal blood or caruncular tissue, while a significant increase in both IFN-α and IFN-β mRNA was seen in cotyledons from PI fetuses on d. 192. It is concluded that fetuses respond to early gestational ncp BVDV infection by induction of the type I IFN pathway, resulting in chronic up-regulation of ISGs. Cotyledonary tissue contributes to up-regulation of ISGs by increased production of IFNs. The innate immune response might partially curtail viral replication in PI fetuses, but is not able to eliminate the virus in the absence of a virus-specific adaptive immune response.     

Regression of infancy hemangiomas with recombinant IFN-alpha 2b.

Interferon-alpha (IFN-alpha) has antitumor and antiangiogenic effects. The purpose of this work was to evaluate its efficacy and safety in the treatment of infancy hemangioma and to monitor the appearance of anti-IFN antibodies in these patients. Thirty-nine children (29 girls) aged 1.5-158 months, with 19 younger than 1 year and 9 older than 5, were treated with 3 x 10(6) IU/m(2) IFN-alpha 2b, subcutaneously (s.c.) daily. Inclusion criteria were life-threatening or life-limiting hemangioma and parents' informed consent. Regression was considered if tumor size diminished by 50% or more. Of the 38 patients who completed 6 months of treatment, 27 (71.1%) had regression and 11 (28.9%) had stable disease. No patient experienced progression. Regression was more frequent (100%) among patients between 1 and 5 years old, but it was particularly important (68%) among those under 1 year old, when spontaneous regression is rare. The main side effects were the IFN-related flulike syndrome (79%), increase in serum alanine aminotransferase (ALT) (28%), anorexia (19%), and mild inflammation at the injection site (19%). There was no effect on psychomotor or physical development. On the contrary, 1 patient with neurologic symptoms improved remarkably, including seizure disappearance. Eight patients developed anti-IFN-alpha 2 neutralizing antibodies, and 7 of them responded to IFN treatment. IFN-alpha 2b is a safe and efficacious treatment of infancy hemangioma. Further work should look for other treatment schedules and ways of administration and carefully monitor anti-IFN neutralizing antibodies, which does not seem to interfere with response.     

α干扰素中和抗体对慢性病毒性肝炎病毒的影响

目的 探讨慢性病毒性肝炎患者中α－干扰素（αＩＦＮ）中和抗体（ＮＡ）的产生及其对干扰素疗效的影响。方法 采用抗病毒中和生物测定法检测了３０名健康人及１１６例经三种亚型αＩＦＮ治疗的慢性病毒性肝炎患者血清中的ＮＡ。结果 健康人及ＩＦＮ治疗前的患者中检出ＮＡ,治疗后共２０例（１７．２％）ＮＡ阳性。ＮＡ在ＩＦＮ治疗后２个月 可出现,６个月达高峰（２０例全部阳性）,至９个月后则有所下降。     

Therapy with interferon alfa and ribavirin in patients with chronic hepatitis C and normal levels of alanine aminotransferase

The aim of the study was to evaluate the efficacy of combination therapy with interferon-alpha (IFN-alpha) and ribavirin in patients with chronic hepatitis C and normal alanine aminotransferase (ALT) values. In this retrospective study, 12 HCV-RNA positive patients (7 males and 5 females, mean age 38.1 years), treated between 1998 and 2001, with normal or near normal ALT values on three consecutive occasions and histologically mild disease were identified. During the induction period of four weeks they received 56 MU IFN-alpha 2b and ribavirin 1000 mg daily. During the next 44 weeks they received 3 MU IFN-alpha 2b three times a week with ribavirin 1000 mg daily. Seven out of 12 (58%) patients were HCV-RNA negative at the end of the therapy (end-of-treatment-response) and 5 of 12 (42%) showed sustained virologic response at 6 months. No significant elevation of aminotransferase values was recorded during therapy. Patients with mild chronic hepatitis C and normal ALT levels respond well to combination therapy with interferon and ribavirin, similar to those with elevated ALT levels. As long as the natural history and long-term outcome of these patients are not completely known, this might be a beneficial treatment option.