Recombinant Human Interferon-alpha Research Articles

Circadian Dependence of Interferon Antitumor Activity in Mice

Chronobiological studies with anticancer drugs have shown that their effectiveness and/or toxicity is significantly influenced by the time of their administration in the circadian cycle. Previous studies also have shown that the myelotoxicity of interferons is similarly influenced. This study was undertaken to evaluate the antitumor activity of interferons as a function of their administration to animals at defined points in the circadian cycle with equal light and dark periods. A murine tumor model was employed. Following adaptation to alternating cycles of 12 hours of light and 12 hours of dark for a period of 2-3 weeks, C57BL/6 mice were inoculated with B16 melanoma cells intraperitoneally at different hours after light onset. Exactly 24 hours after inoculation, each group received intraperitoneal injections of either recombinant human interferon alpha (rHuIFN-alpha A/D), recombinant murine IFN-gamma (rMuIFN-gamma), or interferon-carrier solution as control (once a day for 5 days) and were monitored for the length of their survival. The antitumor activity (calculated as percent increased life span) of both rHuIFN-alpha A/D and rMuIFN-gamma varied with the points at which they were administered in the circadian cycle. However, the points showing minimum and maximum activity for rHuIFN-alpha A/D (12-16 and 0-4 hours after light onset, respectively) did not correspond with the points for the rMuIFN-gamma (0-8 and 16 hours after light onset, respectively). To generate maximum antitumor activity, approximately fivefold higher amounts of rHuIFN-alpha A/D were required at 12 than at 4 hours after light onset (dose range, 3333-90,000 IU/d) (P < .0001). Similarly, for rMuIFN-gamma at least 8.5-fold greater amounts were required at 8 than at 16 hours after light onset (dose range, 667-6000 IU/d) (P < .01). In the murine tumor model, administration of rHuIFN-alpha A/D at 4 hours after light onset and rMuIFN-gamma at 16 hours after light onset may produce maximum antitumor activity.

Studies on silica-bonded monoclonal antibody packing material for separation of recombinant interferon by high performance immunoaffinity chromatography.

A method for the preparation of a new packing material for high performance liquid chromatography by bonding an anti-interferon monoclonal antibody to the surface of silica gel is described. The high coupling efficiency and activity of the interferon-alpha A-monoclonal antibody (IFN-alpha A-McAb) column were obtained by activated diol-silica gel with an activating agent. After purification with this packing material, the specific activity of recombinant human interferon-alpha A rose by up to 1.03 x 10(7)IU/mg protein and the purification efficiency was increased by approximately 100 times.

Hypothalamic modulation of splenic natural killer cell activity in rats.

1. The cytotoxic activity of splenic natural killer cells measured by a standard chromium release assay in urethane and alpha-chloralose-anaesthetized rats was significantly suppressed 20 min after bilateral ablation of the medial part of the preoptic hypothalamus (MPO). The suppression was completely blocked by prior splenic denervation. The splenic natural killer cell activity of MPO sham-lesioned rats or thalamus-lesioned rats, both having an intact splenic innervation, were not different from that of a non-treated control group. 2. Electrical stimulation of the bilateral MPO (0.1 ms, 0.1-0.3 mA, 5-100 Hz) suppressed the efferent activity of the splenic nerve in all six rats examined. The reduction of the nerve activity was accompanied by a transient fall in blood pressure. An I.V. injection of phenylephrine (3 micrograms/0.3 ml) also evoked a suppression of the nerve activity, which was accompanied by transient hypertension, suggesting that the suppressive effect of the MPO stimulation was independent of changes in blood pressure. On the other hand, a bilateral lesion of the MPO resulted in a sustained increase in the electrical activity of the splenic sympathetic nerve filaments which lasted for more than 2 h. 3. Microinjection of monosodium-L-glutamate (0.1 and 0.01 M in 0.1 microliters saline) unilaterally into the MPO evoked a transient suppression of the efferent discharge rate of the splenic nerve activity within 1 min, which was also accompanied by a decrease in blood pressure. The injection of saline (0.1 microliter) into the MPO had no effect. The microinjection of recombinant human interferon-alpha (200 and 2000 U in 0.1 microliter saline) into the MPO dose dependently increased the splenic nerve activity without any change in blood pressure. 4. In contrast, microinjection of interferon-alpha into the paraventricular nucleus of the hypothalamus (PVN) had no effect on splenic nerve activity, although an injection of glutamate increased the nerve activity. 5. The present results, taken together with previous reports, suggest that the neuronal networks between the MPO and the splenic sympathetic nerve, which may be activated by centrally administered interferon-alpha, are important in the suppression of the splenic cellular immunity.

Primary polycythaemia: diagnosis by non-conventional positive criteria.

Patients with polycythaemia and normal controls have been studied to establish and subsequently test non-conventional criteria for the diagnosis of primary polycythaemia (primary proliferative polycythaemia, polycythaemia vera) as compared with conventional Polycythaemia Vera Study Group (PVSG) assessment. One criterion was erythroid colony formation from peripheral blood in a serum-free system, assayed alone and with the addition of recombinant human erythropoietin (Epo), interleukin 3 (IL3), or alpha interferon (alpha-IFN) (Dudley et al. 1990). The remaining criteria were non-culture associated and comprised platelet distribution width (PDW), platelet nucleotide ratio (ATP:ADP), serum erythropoietin and clinical evidence of ischaemic vascular disease. The combination of culture associated and non-culture associated variables, by use of a simple additive scoring system, gave no false positive and only 6% false negative results in distinguishing primary polycythaemia from other polycythaemias and normal controls in those (34 patients Group A) used in its derivation. Testing the scoring system in a newly presenting group (25 patients Group B) was highly satisfactory with no false positives and only a few false negative results (14%). Use of these non-conventional criteria should allow more confident diagnosis of primary polycythaemia, where conventional clinical and laboratory assessment is inconclusive.

Impairment of natural killer cell activity in Indian kala-azar: restoration of activity by interleukin 2 but not by alpha or gamma interferon.

Indian kala-azar patients have normal numbers of peripheral blood NK cells but impaired functional activity due to decreased binding and lysis of target cells. This impairment of NK activity could not be corrected by exogenous recombinant human alpha or gamma interferon. However, recombinant human interleukin 2 was able to restore this activity by augmenting conjugate formation and lysis of target cells.

Restoration of interferon alpha potentiation of a recombinant ricin A chain immunotoxin following cytoreduction of xenografts of advanced ovarian tumors.

We have demonstrated that, in the human ovarian carcinoma cell line (OVCAR-3), recombinant human interferon alpha (rHuIFN-alpha) potentiated in vitro inhibition of protein synthesis by immunotoxins. The antitumor activity of intracavitary immunotoxin administered to nude mice 5 days after tumor cell injection was enhanced by a nontherapeutic dose of rHuIFN-alpha, as evidenced by increased survival time. Our purpose was to determine the outcome of treatment with immunotoxin and rHuIFN-alpha in xenografts of more advanced tumors. At 10 or 15 days after tumor cell injection, nude mice with peritoneal OVCAR-3 xenografts were treated intraperitoneally with immunotoxin or with 454A12 monoclonal antibody (MAb) recombinant ricin A chain (rRA), alone or combined with a nontherapeutic dose of rHuIFN-alpha. The immunotoxin was composed of rRA covalently bound to an anti-CD71 (transferrin receptor) MAb. In other experiments, mice were treated intraperitoneally with cyclophosphamide and cisplatin to reduce tumor size on days 20 and 27 after tumor cell inoculation and then, beginning on day 40, with immunotoxin alone or combined with rHuIFN-alpha. Initiation of treatment 10 days after OVCAR-3 transplantation significantly increased median survival from 41 to 89 days (10% survivors on day 120) with 454A12 MAb rRA alone and to more than 120 days (70% survivors) with 454A12 MAb rRA combined with rHuIFN-alpha (P < .0001). The increase in survival time between tumor-bearing mice treated with immunotoxin combined with rHuIFN-alpha and those treated with immunotoxin alone was statistically significant (P = .017). In contrast, the 15-day transplant tumors were not curable with immunotoxin therapy (survival, 72 days; 0% survivors) and were refractory to rHuIFN-alpha potentiation (survival, 75 days; 0% survivors). After the second course of chemotherapy to reduce the size of the advanced tumors (day 40), during the ascites cell count nadir, initiation of treatment with 454A12 MAb rRA alone or combined with rHuIFN-alpha resulted in significantly different survival times of 129 and 162 days, respectively (P = .0037). Pathologic examination of surviving mice treated with chemotherapy and 454A12 MAb rRA alone or in combination with rHuIFN-alpha revealed that one (17%) of six mice and 11 (65%) of 17 were tumor free, respectively. The synergy between immunotoxins and IFN-alpha is dependent on tumor burden. These agents are less effective against large tumor burdens (i.e., advanced stage disease), but their beneficial effects re-emerge after cytoreduction by combination chemotherapy. The ideal setting for testing the efficacy of intracavitary immunotoxin combined with rHuIFN-alpha after front-line chemotherapy is in patients with residual tumor refractory to additional chemotherapy or in those with toxic effects that prevent delivery of effective doses.

Roles of sympathetic nervous system in the suppression of cytotoxicity of splenic natural killer cells in the rat.

1. We previously demonstrated that a central injection of interferon-alpha in rats induced a suppression of cytotoxicity of splenic natural killer cells which depended upon intact splenic sympathetic innervation, suggesting the important role of the splenic nerve in immunosuppression. To further study the mechanisms of this phenomenon, we investigated: (1) the effects of a central injection of recombinant human interferon-alpha on the electrical activity of the splenic nerve, and (2) the responses of splenic natural killer cytotoxicity on the electrical stimulation of the splenic nerve in urethane with alpha-chloralose anaesthetized rats. 2. An injection of recombinant human interferon-alpha (1.5 x 10(3) and 6.0 x 10(3) units (u) per rat) into the third cerebral ventricle produced a sustained and long lasting (at least for more than 60 min) increase in the electrical activity of splenic sympathetic nerve filaments in a dose-dependent manner. Following an intra-third-ventricular injection of recombinant human interferon-alpha at a dose of 6.0 x 10(3) u, the efferent discharges were elevated 2-6 times that of the pre-injection level with a mean onset latency of 12 min (8-16 min). No changes in the arterial blood pressure and body temperature were observed after injections of recombinant human interferon-alpha. 3. The excitation of the nerve activity induced by intra-ventricular recombinant human interferon-alpha was reversibly suppressed by an intravenous injection of an opioid antagonist, naloxone (1 mg/kg in 0.1 ml saline), whereas the injection of naloxone alone did not affect either the baseline level of the nerve activity or the systemic blood pressure. 4. The cytotoxicity of natural killer cells in the spleen measured by a standard chromium release assay was reduced 20 min after the laparotomy alone in anaesthetized rats. The reduced natural killer activity then recovered significantly when the splenic nerve was cut immediately after the laparotomy. When the peripheral cut end of the splenic nerve was subsequently stimulated (0.5 mA, 0.5 ms, 20 Hz for 20 min), a further suppression of natural killer cytotoxicity was observed. 5. The reduction of natural killer cytotoxicity produced by the stimulation of the splenic nerve was completely blocked by an intravenous injection of nadolol (a peripherally acting beta-adrenergic receptor antagonist), but not by that of prazosin (an alpha-antagonist). 6. These results indicate that a central injection of recombinant human interferon-alpha activates the splenic sympathetic nerve through brain opioid receptors and thereby suppresses the natural killer cytotoxicity by beta-adrenergic mechanisms.(ABSTRACT TRUNCATED AT 400 WORDS)

Optimal Circadian Timing Reduces the Myelosuppressive Activity of Recombinant Murine Interferon-γ Administered to Mice

There is a marked, reproducible circadian variation in the toxicity of a number of antineoplastic drugs. A recent study has employed a murine model to show that recombinant human interferon-alpha A/D (rHuIFN-alpha A/D) exhibited a differential potency in its peripheral white blood cell (WBC)-suppressive and bone marrow-suppressive activities according to the time in the circadian cycle at which it was administered. It was of interest to determine whether another biological response modifier such as IFN-gamma would also exhibit a differential potency during the circadian cycle. A mouse model was used to study peripheral WBC suppression, a toxicity associated with IFN-gamma therapy. Recombinant murine (rMu)IFN-gamma was employed to induce peripheral WBC suppression and was evaluated for its ability to induce peripheral WBC suppression as a function of the time of rMuIFN-gamma administration. Mice were maintained on cycles of 12 h of light and 12 h of darkness. The rMuIFN-gamma was administered at various hours after light onset (HALO). The rMuIFN-gamma-induced peripheral WBC-suppressive effect varied in its intensity in a cyclical manner. Administration of rMuIFN-gamma at 4 HALO caused the greatest suppressive effect, whereas administration of rMuIFN-gamma at 14 HALO caused the least suppressive effect. Mice treated at 14 HALO were found to be about 20-fold less sensitive to the peripheral WBC-suppressive effects of rMuIFN-gamma than mice treated at 4 HALO. This differential sensitivity to the peripheral WBC-suppressive effects of rMuIFN-gamma was examined at six different times in the circadian cycle and was found to be a general effect, occurring throughout the circadian cycle.(ABSTRACT TRUNCATED AT 250 WORDS)

Inositol lipid-mediated intranuclear signalling: A comparative analysis of in vivo labelling in interferon alpha-sensitive and -resistant daudi lymphoma cells

Changes in inositol lipid and diacylglycerol metabolism have been analysed in Daudi lymphoma cells treated up to 24 h with human Dna recombinant interferon alpha. Results showing a different response of nuclear phosphoinositides and diacylglycerol, compared to whole cells, suggest that the intranuclear signalling system activated by interferon in Daudi cells involves nuclear inositol lipid metabolism. A well-characterized clone of Daudi cells selected for resistence to the antiproliferative action of interferon provided controls for the specificity of results.

A 4-week subcutaneous toxicity study of recombinant human interferon alpha A (LBD-007) in Sprague-Dawley rats.

Recombinant human interferon alpha A (code name: LBD-007) was subcutaneously administered to both sexes of Sprague-Dawley rats at the doses of 0, 6, 12 and 24 x 10(6) IU/kg of body weight five days per week for 4 weeks to evaluate the subchronic toxicity. 20 to 50% of rats except the male control group showed minimal to mild, focal to multifocal renal mineralization. Whether renal mineralization is related to the test substance is not elucidated. Male rats dosed at 24 x 10(6) IU/kg showed the decrease of the absolute kidney weights and the increase of the brain relative weights. Female rats dosed at 24 x 10(6) IU/kg showed the increase of the absolute and relative ovary weights, and the decreases of specific gravity, bilirubin and urobilinogen in urine. However, no drug-related changes were noted in clinical findings, body weights, food consumption, water consumption, hematology, blood clinical chemistry and necropsy findings. Based on the results it is concluded that the estimated subcutaneous non-toxic dose of the recombinant human interferon alpha A (LBD-007) in rats is (6 approximately 12) x 10(6) IU/kg.

Administration Route Dependent Bioavailability of Interferon-α and Effect of Bile Salts on the Nasal Absorption

Administration route dependent bioavailability of recombinant human interferon alpha (IFN-α) and effect of seven bile salts and polyoxyethylene-9-lauryl ether (BL-9) on nasal absorption of IFN-a were studied in rats. IFN-a (1.5 × 10 7 IU/kg) was administered through iv, pv, po and ip routes and AUC of the routes were compared. As a result, it was found that IFN-α is extracted almost completely during its passage through the GI lumen, and is not absorbed from the GI lumen. Moreover, IFN-α sparingly transported through the GI lumen suffers additional extraction by the GI mucosa (57%) and the liver (8%) consecutively and only about 40% of it can reach the systemic circulation. Therefore, a high bioavailability of IFN-a cannot be expected through the oral route even with the aid of absorption enhancers. On the other hand, significant absorption of IFN-α could be attained through the nasal route with some absorption enhancers (1% w/v). Among the enhancers examined, sodium cholate (CH), sodium glycocholate (GC), sodium taurocholate (TC), sodium glycodeoxycholate (GDC), sodium taurodeoxycholate (TDC) and BL-9 increased the nasal bioavailability of IFN-a. However, sodium dehydrocholate (DHC) and sodium deoxycholate (DOC) did not show such effect. Nasal bioavailability of IFN-a was increased up to 32.3 (± 15.5)% by 1% TC. The enhancing effect of TC was significantly (p<0.05) greater than those of CH, DOC, DHC and BL-9. TC and GC seemed to be potential candidates for the nasal absorption enhancers of IFN-α, considering that they are reportedly less toxic than GDC and TDC.

An acute toxicity study of recombinant human interferon alpha A (LBD-007) in Sprague-Dawley rats.

The acute toxicity of a recombinant human interferon alpha A (code name: LBD-007) was evaluated in both sexes of Sprague-Dawley rats, 5 weeks old, by the oral, subcutaneous and intravenous routes of administration. Based on the results, LBD-007 was not considered to induce any toxicological effect on the rats in mortalities, clinical findings, body weights and gross findings. It is suggested that LD50 values in rats would be > 48 x 10(8) IU/kg in the study of oral administration and > 24 x 10(8) IU/kg in the study of subcutaneous or intravenous administration.

Enhanced cytotoxicity of 5-fluorouracil combined with [6RS]leucovorin and recombinant human interferon-alpha 2a in colon carcinoma cells.

We had proposed previously that one mechanism of intrinsic resistance to 5-fluorouracil (FUra) in colon adenocarcinomas was suboptimal concentrations of intracellular 5,10-methylenetetrahydrofolate (CH2-H4PteGlun).1 Whereas the concentration of this reduced folate may not be rate limiting for thymidylate synthesis de novo, it may be suboptimal to allow maximal interaction between the FUra metabolite, 5-fluorodeoxyuridylate (FdUMP), and thymidylate synthase.1–5 Supplementation with a reduced folate, therefore, elevates intracellular levels of CH2-H4PteGlun and enhances the rate of formation or stabilization of the ternary complex. In human colon tumor xenografts, pools of CH2-H4PteGlun and H4PteGlun expanded by 2- to 5-fold in response to 24 hr infusions of [6RS]leucovorin ([6RS]LV), elevating species containing from 2 to 5 glutamate residues.6’7 KeywordsThymidine KinaseColon AdenocarcinomaHuman Colon AdenocarcinomaHuman Colon Cancer Cell LineThymidylate SynthetaseThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Time-resolved fluorescence study of human recombinant interferon alpha 2. Association state of the protein, spatial proximity of the two tryptophan residues.

Human recombinant interferon alpha 2 belongs a to family of proteins active against a wide range of viruses. It contains two tryptophan residues located at positions 77 and 141 in the peptide sequence. The fluorescence emission spectrum of these tryptophan residues displays a maximum at 335 nm. The fluorescence intensity decay is described by one broad excited-state-lifetime population centered around a value of 1.7 ns (full width at half maximum, 1.5 ns). These observations suggest that in the native protein, both tryptophan residues emit from similar environments, not directly exposed to the surrounding solvent. The anisotropy decay is essentially biexponential. The correlation-time value characterizing the Brownian rotation of the protein varies linearly with the viscosity/temperature ratio. The calculated hydrodynamic volumes are compatible with the existence of a dimer and a tetramer, at pH 5.5 and 9.4, respectively. Addition of urea at pH 5.5 disrupts the dimer and modifies to some extent the excited-state-lifetime distribution which becomes more heterogeneous. Disulfide-bond reduction also dissociates the dimer and leads to a highly heterogeneous fluorescence-intensity decay with four excited-state-lifetime populations. An opening of the local structure in the Trp region of the protein is likely to occur in these conditions. The fast-anisotropy-decay components can be due to either fast rotation or energy transfer between the indoles. Close proximity of the two Trp residues (less than 1 nm) is suggested from steady-state and time-resolved fluorescence-anisotropy measurements in vitrified medium [95% (by mass) glycerol at -38 degrees C]. This suggestion is in agreement with the recently published three-dimensional structure of the homologous protein murine interferon beta [Senda, T., Shimazu, T., Matsuda, S. Kawano, G., Shimizu, H., Nakamura, K. T. & Mitsui, Y. (1992) EMBO J. 11, 3193-3201].

Interferon-alpha prevents endotoxin-induced mortality in mice.

Endotoxins, the lipopolysaccharide (LPS) moieties on the bacterial cell wall, cause many of the pathological features of Gram-negative septicemia. Tumor necrosis factor (TNF), primarily a product of monocyte/macrophages, has been shown to mediate many of the pathophysiological effects of endotoxin. Kupffer cells, the largest macrophage population in the body, release TNF when stimulated by LPS in vitro. A recombinant human hybrid interferon-alpha A/D (rIFN-alpha) markedly inhibited this LPS-elicited TNF production by Kupffer cells. The effects of rIFN-alpha were further tested in C57BL/6 mice receiving a lethal dose (400 micrograms/mouse) of LPS. All LPS-treated mice died within 2 days. Pretreatment with rIFN-alpha 1 h before LPS challenge improved the survival at 3 days to 22% (5/23, p < 0.04). In contrast, rIFN-alpha was more effective when administered 20 min after LPS injection, increasing the survival rate to 81% (13/16, p < 0.0001). TNF mRNA expression in the liver and spleen 50 min after LPS challenge, and plasma TNF 1.5 h after LPS were also reduced by either pretreatment or post-treatment with rIFN-alpha. Subsequently, experiments were carried out to test the efficacy of delayed rIFN-alpha treatment. A significant protective effect was still apparent when rIFN-alpha was administered 6, 10 and even 14 h (81%, 62% and 28% survival, respectively) after LPS challenge when serum TNF levels had already returned to near baseline. These experimental results suggest that rIFN-alpha might have a therapeutic potential for the prevention and treatment of the deleterious effects associated with endotoxemia besides mechanisms initially blocking TNF production.

Interferons and central regulation of feeding.

Interferons (IFNs) are immunomodulators with neuromodulatory activities. To study the effects of IFNs on the central regulation of feeding, rats were subjected to various applications. The results show the following. 1) Intracerebroventricular microinfusion of rat IFN (15-225 IU/rat) decreased short-term (2-h) food intake in rats. Computerized analysis of behavioral patterns demonstrated a reduction of meal size and meal duration, whereas meal frequency slightly increased. Nighttime and total daily food intakes were not significantly affected. 2) Short-term food intake suppression by intracerebroventricular rat IFN was accompanied by a small increase in cerebrospinal fluid and rectal temperatures. 3) Intracerebroventricular microinfusion of heat-treated rat IFN or of recombinant human interferon-alpha (rhIFN-alpha) did not affect food intake. Only one dose of rhIFN-gamma (400 ng/rat) decreased 2-h food intake. These results are consistent with the species specificity to the effects of IFNs. 4) Peripheral administration of rat IFN in doses equivalent to those administered centrally had no effect on food intake. The results suggest that IFN acts directly in the central nervous system to decrease short-term feeding.

Killing of Coccidioides immitis by human peripheral blood mononuclear cells.

The ability of human peripheral blood mononuclear cells (MNL) obtained from healthy donors to kill the fungus Coccidioides immitis was examined in vitro with an assay that uses a single fungal particle per well. MNL killed 25.0% +/- 3.5% of a coccidioidal arthroconidial target, compared with the 4.7% +/- 2.9% killed by polymorphonuclear leukocytes obtained from the same donors (P = 0.012). Arthroconidial killing by MNL was not dependent on donor delayed dermal hypersensitivity to spherulin. Killing of another fungal target, Candida glabrata, was not significantly different between MNL and polymorphonuclear leukocytes (P = 0.783). Depletion of monocytes from MNL with Sephadex G-10 resulted in a significant reduction in arthroconidial killing (21.4% +/- 13.6% versus 2.4% +/- 3.4%; P = 0.025), while enrichment of monocytes by Percoll density gradient centrifugation or plastic adherence resulted in significantly increased arthroconidial killing compared with that by MNL (P = 0.005 and 0.001, respectively). Killing of 96-h spherules by MNL was 7.3% +/- 3.1%, significantly less than the 21.4% +/- 2.8% killing of arthroconidia in the same experiments (P = 0.016). Incubation of MNL with human recombinant gamma interferon or tumor necrosis factor alpha did not result in increased MNL killing of coccidioidal arthroconidia under various conditions. These results suggest that MNL have an inherent ability to kill coccidioidal arthroconidia in vitro which is not dependent on prior host exposure to C. immitis. This activity appears to reside in peripheral blood monocytes.

Lack of effect of recombinant human interferon-alpha 2b on expression of 17-1A antigen on human colon cancer cells.

The effects of recombinant human interferon alpha (rHuIFN-alpha 2b) on cell growth, expression of antigenic receptor sites (r) and the affinity constant (Ka) of monoclonal antibody CO 17-1A IgG were studied on two human colorectal cancer cell lines, CX-1 and SW 1116. Cells were incubated with varying concentrations of rHuIFN-alpha 2b prior to exposure to 125I-labeled 17-1A IgG at 37 degrees C following which r and Ka were determined by means of Scatchard plots. Varying concentrations of rHuIFN-alpha 2b had significant growth inhibitory effects on CX-1 and SW 1116 cells, which were time and concentration dependent, but no effects on expression of r and Ka compared to controls. Our data indicate that rHuIFN-alpha 2b does not invariably increase the expression of tumor-associated antigens and that this effect may be independent of its antiproliferative activity. The in vitro response or lack thereof of neoplastic cells to rHuIFN-alpha 2b may be useful to identify those patients who potentially might gain from a clinical course of rHuIFN-alpha 2b for either therapeutic or diagnostic purposes.

Regulation of the natural killer cell response to interferon-alpha by biogenic amines.

Monocytes, recovered from human peripheral blood by counter-current centrifugal elutriation (CCE), suppressed baseline natural killer (NK) cell cytotoxicity (NKCC) and rendered NK cells resistant to activation of cytotoxicity by human recombinant interferon-alpha (IFN-alpha) by a cell contact-dependent mechanism. Monocyte-induced suppression of resting and IFN-activated NK cells was abrogated by the biogenic amines histamine [via H2-type receptors (H2R)] and serotonin [via 5-HT1A-type receptors (5-HT1AR)]. Our data are suggestive of a monocyte/NK cell interaction that is subject to regulation by biogenic amines.

Cross-species antiviral activity of a recombinant human alpha-interferon hybrid.

Cross-species antiviral activity of a recombinant human alpha-interferon hybrid.