[What hopes do I have for the near future of medicine?].
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Forecasting↗
Biomedical subjects
K Cantell
Publications and source records attributed to K Cantell.
Concomitant chemotherapy and IFN-alpha for small cell lung cancer: a randomized multicenter phase III study.
Patients with any stage of small cell lung cancer were given low-dose interferon-alpha (IFN-alpha) from the first day of treatment as long as possible irrespective of changes in treatment dictated by disease progression. All patients received 6 cycles of the chemotherapy (CT): cisplatin 70 mg/m2 i.v. day 1 and etoposide 100 mg/m2 i.v. days 1, 2, 3 every 28 days. Seventy-eight patients were assigned to arm 1: CT alone, 75 patients to arm 2: CT + natural IFN-alpha (3 MU three times a week i.m.), and 66 patients to arm 3: CT + recombinant IFN alpha-2a (3 MU three times a week i.m.). There was no difference in median survival between the arms (10.2 months, 10.0 months, 10.1 months, respectively), p = 0.32. The 2-year survival rates were 15%, 3%, and 11%, respectively. Grade 3 and 4 leukopenia occurred more frequently in the IFN arms than in the CT alone arm and resulted in dose reductions. Antibodies occasionally developed to recombinant IFN. We conclude that IFN-alpha can be administered concomitantly with chemotherapy but is probably better kept for maintenance therapy so that optimal full doses of induction CT can be given.
Adult↗
Conjugation of interferon alpha to a humanized monoclonal antibody (HuBrE-3vl) enhances the selective localization and antitumor effects of interferon in breast cancer xenografts.
Human mammary carcinoma xenografts (MCF-7) growing in nude mice were treated with natural interferon alpha (n-IFN-alpha) alone or conjugated to a humanized monoclonal antibody (MoAb) anti-breast mucin (HuBrE-3vl) or to irrelevant human IgG1kappa. The IFN and the conjugates were administered as 20 intra-lesional (i.l.) injections to 1 of 2 xenografts in each mouse, or i.p. The growth inhibitory effects of HuBrE-3vl/nIFN-alpha were significantly greater than those of nIFN-alpha used as a single agent or conjugated to HuIgG1kappa. These effects occurred locally in the tumors receiving i.l. injections and systemically, although to a slightly lesser extent, in the noninjected tumors of mice treated i.l. and in the xenografts of mice treated i.p. Biodistribution studies showed that the uptake of 125I-HuBrE-3vl/nIFN-alpha by the tumors 24 hours after i.l. or s.c. injection was greater than that of 125I-HuIgG1kappa/nIFN-alpha, 125I-nIFN-alpha alone, or by normal tissues, documenting a tumor targeting effect and favorable tumor:normal tissues (T:NT) ratios. The targeting effects and the resulting tumor growth inhibition were favored by the IFN-mediated up-regulation of the HuBrE-3vl reactive antigen, which was more prominent after 3 weeks of treatment with HuBrE-3vl/nIFN-alpha. These results were superior to those we obtained previously with nIFN-alpha conjugated to another MoAb of the same group (Mc5). These studies point out the potential usefulness of HuBrE-3vl/nIFN-alpha for the local and systemic treatment of breast cancer lesions by providing a means of delivering high doses of IFN to the tumors while minimizing the amount of IFN binding to normal tissues.
Animals↗
Interferon maintenance therapy for small cell lung cancer: improvement in long-term survival.
Two hundred thirty-seven patients with small cell lung cancer (SCLC), who had responded to induction chemotherapy and radiotherapy, were randomly assigned to receive low-dose natural interferon-alpha (nIFN alpha) for 6 months; or 6 cycles of maintenance chemotherapy (CAP); or no maintenance therapy (control group). Although there was no difference in median survival between the groups, there was a significant difference (p = 0.04) in the long-term survival of patients with limited disease, in favour of nIFN alpha maintenance therapy. This finding is now confirmed by a further analysis of the most recent data. Ten percent of patients in the IFN group survived for five years or more, but the 5-year-survival rate in the CAP and control groups was only two percent. All long-term survivors had good performance status. The majority had limited disease and had achieved a complete response to the induction therapy. These results suggest that interferon-alpha improves the long-term survival of SCLC patients for whom other prognostic factors are favorable.
Adult↗
IFN-gamma enhances production of IFN-alpha in human macrophages but not in monocytes.
Monocytes/macrophages are efficient producers of alpha interferons (IFN), and IFN-gamma is a potent activator of these cells. The present study sought to investigate whether IFN-alpha affects the capacity of human monocytes/macrophages to produce IFN-alpha on induction with Sendai virus. Plastic-adherent human peripheral blood monocytes were grown in the presence of granulocyte-macrophage colony-stimulating factor (GM-CSF) for 3 weeks during which they were transformed into macrophages. At various times, the cultures were pretreated for 24 h with IFN-gamma and induced with Sendai virus for IFN-alpha production. Pretreatment with IFN-gamma had no effect on the production of IFN-alpha during the first days in culture. The production of IFN-alpha was thereafter significantly enhanced by the IFN-gamma pretreatment. Minute amounts of IFN-gamma, < or = 0.1 IU/ml, increased the production of IFN-alpha in macrophages cultured for more than 7 days. The cooperation between IFN-gamma and IFN-alpha in macrophages may play a role in the antiviral defense of the body.
Antiviral Agents↗
N-glycosylation of human interferon-gamma: glycans at Asn-25 are critical for protease resistance.
Human interferon-gamma (IFN-gamma) is a secretory, dimeric glycoprotein that forms a compact globular structure with potential N-linked glycosylation sites at Asn-25 and Asn-97 on the surface of the dimer. In natural leucocyte IFN-gamma (nIFN-gamma), 52%, 39% and 9% of the monomers are core-glycosylated in two, one or none of the potential N-glycosylation sites respectively. Chemical cross-linking of nIFN-gamma with glutaraldehyde revealed that 4, 3, 2 or 1 glycosylation sites occupied 28%, 40%, 26% and 6% of the dimers respectively. In baculovirus-produced wild-type (Wt) and N-linked glycosylation site-defective mutant (N25Q or N97Q, Asn-25 or Asn-97 substituted by Gln) IFN-gamma proteins, the extent of core glycosylation of monomers reflected the glycan composition of dimers. This suggests that dimers are formed randomly and independently of glycosylation. The glycan residues of IFN-gamma, especially at Asn-25, play an important role in protease resistance. Unglycosylated recombinant IFN-gamma proteins (from Escherichia coli and baculovirus) and N25Q IFN-gamma were sensitive to crude granulocyte protease, purified elastase, cathepsin G and plasmin degradation. Fully glycosylated nIFN-gamma and baculovirus Wt and N97Q IFN-gamma showed full or partial resistance to these proteases. These results emphasize the importance of glycan residues, especially at Asn-25, in the proteolytic stability of human IFN-gamma. Whether the differential glycosylation of n- and recombinant IFN-gamma (rIFN-gamma) is reflected in their biological activities in tissues or their clinical applicability is not known.
Animals↗
Inhaled recombinant interferon gamma in patients with lung cancer: pharmacokinetics and effects on chemiluminescence responses of alveolar macrophages and peripheral blood neutrophils and monocytes.
PURPOSE: A Phase I trial was conducted to investigate clinical toxicity, pharmacokinetics, and chemiluminescence (CL) responses of alveolar macrophages (AM) and peripheral blood neutrophils and monocytes after inhalation of recombinant interferon (r IFN)-gamma. METHODS AND MATERIALS: Eight patients with lung cancer inhaled r IFN-gamma as single doses of 0.1, 0.2, 0.6, 1.8, or 5.4 mg. Bronchoalveolar lavage was performed three times, 21 h before as well as 3 and 27 h after inhalation. RESULTS: Interferon-gamma was detectable in bronchoalveolar lavage fluid (BALF) samples taken 3 h after inhalation in doses of > or = 0.6 mg. Before inhalation, AM in four out of seven patients studied showed vigorous lucigenin-enhanced CL responses to N-formyl-methionyl-leucyl-phenylalanine and opsonized zymosan particles. Furthermore, the responses were markedly increased 3 h after inhalation. In three out of seven patients, AM in the pretreatment BALF samples showed low or no CL responses, and the responses did not increase after inhalation of IFN-gamma, suggesting that the patients were anergic. Postinhalation CL responses did not correlate with the dose of IFN-gamma inhaled. Circulating IFN-gamma was detected in one patient receiving the highest dose. No changes referable to IFN-gamma inhalation were found in the CL responses of blood neutrophils and monocytes. During the 24 h follow-up, two patients developed transient fever-reactions. CONCLUSIONS: The findings suggest that inhalation may provide a way to increase alveolar concentrations of IFN-gamma and to augment respiratory burst capacity of AM without any major side effects. This approach may have clinical implications for the treatment of tumors and infections of the respiratory tract.
Adult↗
Regression of human breast cancer xenografts in response to intralesional treatment with interferons alpha and gamma potentiated by tumor necrosis factor.
The potentiating effects of human recombinant tumor necrosis factor-alpha (rTNF-alpha) on the antitumor actions of recombinant interferon-gamma (rIFN-gamma) and of natural interferons alpha and gamma combined (nIFN-alpha/nIFN-gamma) were studied on human breast cancer xenografts growing bilaterally in nude mice. The cytokines were injected singly or in combination in one of the two tumors of each mouse to study local effects while the opposite tumor was left undisturbed to evaluate systemic effects. The tumors received 20 intralesional injections (four cycles of 5 daily injections each). In injected tumors the best results were obtained with nIFN-alpha/nIFN-gamma supplemented with rTNF-alpha. The responses were dose dependent, resulting in complete regression of 9 of 9 tumors with rTNF-alpha used at the dose of 5 micrograms per injection, of 6 of 8 tumors at the dose of 2.5 micrograms, and of 4 of 8 tumors at the dose of 0.5 microgram. Mostly mild to moderate partial responses were seen in the other groups. The systemic effects on the contralateral tumors were significantly less than the local effects on the corresponding tumors. Histologically, responding tumors showed reactive fibrosis and inflammatory cell infiltration. No vascular alterations were seen, presumably because of the immunodeficiency of nude mice. It was concluded that the potentiation of the antitumor actions of IFNs by rTNF-alpha was effective at the local but not at the systemic level.
Adjuvants, Immunologic↗
Regression of skin recurrences of breast carcinomas treated with intralesional injections of natural interferons alpha and gamma.
Two groups of patients with disseminated breast carcinomas who had failed radiotherapy, chemotherapy, and hormonotherapy were treated with natural interferon alpha (nIFN-alpha) alone or in combination with nIFN-gamma delivered in cycles of 10-12 intralesional (i.l.) injections to recurrent and metastatic lesions. In group, I, 16 skin lesions in 12 patients received nIFN-alpha alone resulting in 7 complete regressions verified histologically (CR), 7 partial regressions (PR), and no regressions (NR) in 2. Group II included 4 patients in whom 7 cutaneous recurrences were treated with nIFN-alpha/nIFN-gamma (5 CR, 2 PR), 2 were injected with nIFN-alpha alone (1 CR, 1 PR), and 1 received nIFN-gamma alone (PR). Two additional patients in group II were given i.l. injections of nIFN-alpha/nIFN-gamma to lymph node metastases (1 CR, 1 PR). Clinical toxicity was experienced by 5 of 12 patients in group I and by all the patients in group II and was controlled in most instances by antipyretics. Systemic antitumor effects were not appreciable clinically. Nevertheless, noninjected lesions exposed only to systemic levels of IFNs, when studied immunohistochemically, displayed an immunological response similar to that of IFN-injected lesions, although less intense. Therefore, IFNs can be useful in controlling locoregional recurrences of breast cancer even in patients who are not responding to other forms of therapy. Furthermore, in addition to the local antitumor actions, they appear to be capable of eliciting systemic immunological effects.
Breast Neoplasms↗
Development of antiviral therapy with alpha interferons: promises, false hopes and accomplishments.
This overview describes the development of interferon therapy in four different types of viral diseases. (1) Upper respiratory infections: despite extensive efforts interferons have not found a place in the treatment of these very common diseases. (2) Herpes keratitis: alpha interferons are highly active in combination therapy, but have gained only very limited clinical use. (3) Papillomavirus infections: alpha interferons have been approved for the treatment of papillomavirus infections of skin and mucous membranes and are in fairly wide clinical use. (4) Chronic hepatitis B, C and D: alpha interferons have become the treatment of choice and are used very extensively worldwide. The four examples illustrate both the clinical potentials and the limitations of alpha interferons and give some guidelines for future work. The overall conclusion is that chronic viral diseases lend themselves to interferon therapy more readily than acute viral infections. The general trend is toward the use of interferons in combination therapy.
Hepatitis, Viral, Human↗
The elimination of indigenous measles, mumps, and rubella from Finland by a 12-year, two-dose vaccination program.
BACKGROUND: In the 1970s measles, mumps, and rubella were rampant in Finland, and rates of immunization were inadequate. In 1982 a comprehensive national vaccination program began in which two doses of a combined live-virus vaccine were used. METHODS: Public health nurses at 1036 child health centers administered the vaccine to children at 14 to 18 months of age and again at 6 years, and also to selected groups of older children and young adults. Vaccination was voluntary and free of charge. In follow-up studies, we focused on rates of vaccination, reasons for noncompliance, adverse reactions, immunogenicity, persistence of antibody, and incidence of the three diseases. Since 1987, paired serum samples have been collected from all patients with suspected cases of measles, mumps, or rubella. RESULTS: Over a period of 12 years, 1.5 million of the 5 million people in Finland were vaccinated. Coverage now exceeds 95 percent. The vaccine was efficient and safe, even in those with a history of severe allergy. No deaths or persistent sequelae were attributable to vaccination. The most frequent complication requiring hospitalization was acute thrombocytopenic purpura, which occurred at a rate of 3.3 per 100,000 vaccinated persons. The 99 percent decrease in the incidence of the three diseases was accompanied by an increasing rate of false positive clinical diagnoses. In 655 vaccinated patients with clinically diagnosed disease, serologic studies confirmed the presence of measles in only 0.8 percent, mumps in 2.0 percent, and rubella in 1.2 percent. The few localized outbreaks were confined to patients in the partially vaccinated age groups. There are now fewer than 30 sporadic cases of each of the three diseases per year, and those are probably imported. CONCLUSIONS: Over a 12-year period, an immunization program using two doses of combined live-virus vaccine has eliminated indigenous measles, mumps, and rubella from Finland. Serologic studies show that most reported sporadic cases are now due to other causes, but a continued high rate of vaccination coverage is essential to prevent outbreaks resulting from exposure to imported disease.
Child↗
Role of N-glycosylation in the synthesis, dimerization and secretion of human interferon-gamma.
Human interferon-gamma (IFN-gamma) is a secretory glycoprotein, which has two potential N-linked glycosylation sites at positions Asn-25 and Asn-97 of its 143 amino acid long mature polypeptide chain. In order to understand the role of glycan residues in the synthesis and secretion of human IFN-gamma, both or either one of the potential N-linked glycosylation sites were mutated to Gln. The mutant and the wild-type (Wt) polypeptides were expressed in insect cells using a baculovirus vector. Elimination of the N-glycosylation site at position Asn-97 (N97Q) resulted in secreted protein yields of 70-90% as compared with the Wt production, whereas only 10-25% (N25Q) and 1-10% (N25Q,N97Q) levels of protein production was observed when the first or both sites were mutated, respectively. Although there was a difference between extracellular levels of produced protein, the kinetics of secretion was similar for all different IFN-gamma molecules. The Wt and the N-glycosylation site mutants were all secreted as dimers. The formation of biologically active dimers was more efficient for IFN-gamma polypeptides that had the intact glycosylation site at Asn-25 as compared with the other two mutant forms of IFN-gamma. The extent of dimerization correlated well with the observed secretion. The specific antiviral activity was of the same order (1 x 10(7) i.u./mg of protein) for the glycosylated IFN-gamma molecules, whereas it was slightly lower (0.5 x 10(7) i.u./mg of protein) for the unglycosylated mutant form.
Amino Acid Sequence↗
Experimental immunotherapy of breast cancer using alpha interferon conjugated to monoclonal antibody Mc5.
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Animals↗
Pharmacokinetics and toxicity of inhaled human natural interferon-beta in patients with lung cancer.
Eight patients with a thoracic malignancy inhaled single doses of 3-100 x 10(6) IU of human natural interferon (IFN)-beta via a dosimeter-equipped jet nebulizer. After inhalation IFN-beta was not detectable in any of the serum samples as measured using an antiviral bioassay. Except for a slight body temperature rise and an 18% decrease in peak expiratory flow rate observed in 1 patient the patients did not experience any major side effects. Inhaled natural IFN-beta in this study was tolerated better than inhaled IFN-alpha or IFN-gamma in our previous studies. IFN-beta might thus be a promising local treatment for pulmonary diseases. Further work is needed to investigate the concentrations of biologically active IFN in alveolar epithelial lining fluid after inhalation and the therapeutic effect of inhaled IFN-beta.
Administration, Inhalation↗
Alpha- and gamma-interferon inhibit plasminogen activator inhibitor-1 gene expression in human retinal pigment epithelial cells.
The effect of interferons IFN-alpha and IFN-gamma on the production of plasminogen activators (PAs) and plasminogen activator inhibitors (PAIs) was examined in human retinal pigment epithelial (RPE) cells in culture. Cultures of human RPE cells were incubated with either of the interferons for 48-96 h. The cell cultures were assayed using mRNA analysis and solid-phase immunocapture assay. Both interferons caused a marked decrease in PAI-1 mRNA expression after 48 h with no change in urokinase-type plasminogen activator (u-PA) mRNA expression. A marked decrease in PAI-1 activity and concomitant increase in u-PA activity in the culture medium appeared only after 72-96 h. We conclude that IFN-alpha and IFN-gamma stimulate plasminogen-mediated pericellular proteolysis of human RPE cells in culture by inhibiting PAI-1 gene expression.
Adolescent↗
Subcutaneously administered recombinant interferon-gamma in humans: pharmacokinetics and effects on chemiluminescence responses of alveolar macrophages, blood neutrophils, and monocytes.
A Phase I trial was conducted to investigate the clinical toxicity, pharmacokinetics, and chemiluminescence (CL) responses of alveolar macrophages (AMs), peripheral blood neutrophils, and monocytes after subcutaneous injection of recombinant interferon-gamma (rIFN-gamma). Six patients with lung cancer received rIFN-gamma subcutaneously as single doses of 0.2, 0.6, and 1.8 mg. Bronchoalveolar lavage was performed three times: 21 h before as well as 6-7 and 27 h after injection. Serum samples were taken five times during the 27-h follow-up. IFN concentrations were measured from alveolar epithelial lining fluid (ELF) and serum by using an antiviral bioassay. IFN-gamma was not detectable in ELF after subcutaneous injection. AMs did not effect an increase in CL responses to N-formyl-methionyl-leucyl-phenylalanine or to phosphate-buffered saline. Circulating IFN-gamma was detectable at 3-12 h after an injection of 1.8 mg of rIFN-gamma, the highest dose given. CL responses of peripheral blood monocytes increased in all patients after injection, whereas the responses of neutrophils were less clear-cut. All patients developed systemic side effects such as transient fever, nausea, headaches, and flu-like symptoms. The findings suggest that rIFN-gamma passes poorly from the blood to the pulmonary alveoli. On the basis of this and our previous findings of increased CL responses in AMs and measurable IFN concentrations in ELF after inhalation of rIFN-gamma, we recommend inhalation rather than the parenteral route of IFN-gamma for the treatment of respiratory diseases.
Adult↗
The use of natural interferon alpha conjugated to a monoclonal antibody anti mammary epithelial mucin (Mc5) for the treatment of human breast cancer xenografts.
An immunoconjugate composed of natural interferon alpha (nIFN alpha) bound in a noncleavable fashion to a monoclonal antibody (MoAb) recognizing a breast epithelial membrane mucin (Mc5) was used to to treat xenografts of a human mammary carcinoma cell line (MCF-7) growing in nude mice. The immunoconjugate (nIFN alpha/Mc5) was administered as 20 intralesional (i.l.) injections to 1 of 2 xenografts in each animal. It was found that nIFN alpha/Mc5 produced a significant enhancement of the growth inhibitory actions of nIFN alpha on the injected tumors. Further enhancement was obtained when nIFN gamma or nIFN gamma together with Mc5 (at a dose 10 times larger than that present in nIFN alpha/Mc5) were added to the immunoconjugate. Biodistribution experiments showed that the uptake of 125I-nIFN alpha/Mc5 by the tumors was greater and its elimination slower than for 125I-nIFN alpha alone or conjugated to irrelevant mouse IgG1. In addition, the immunoconjugate up-regulated the antigenic expression of a breast epithelial membrane mucin by the carcinoma cells, an up-regulation which was not significantly different from that produced by nIFN alpha alone. The contralateral noninjected tumors exposed to systemic levels of the immunoconjugate showed an enhancement of antitumor effects, but to a lesser extent than the injected tumors. These findings suggest that the enhancement of the growth inhibitory action of the immunoconjugate was related to the specific binding of Mc5 which targeted the IFN to the carcinoma cells and impeded its elimination. It is likely that the targeting was favored by the IFN-mediated up-regulation of antigenic expression by the carcinoma cells, thereby producing a cascade of interrelated effects. The results of this study point out the feasibility and potential usefulness of IFN treatment by means of immunoconjugates as well as the worth of pursuing and improving this form of therapy.
Animals↗
Vaccination-induced HI antibody to influenza A(H1N1) viruses in poorly primed adults under circumstances of low antigenic drift.
In Autumn 1990, trivalent split influenza virus vaccine containing A/Taiwan/1/86(H1N1) was used to immunize healthy female employees (n = 104). The 11-12 amino acid differences in the HA1 domain of virus haemagglutinin between A/Taiwan/1/86 and representative epidemic H1N1 strains in Finland in 1991 did not result in lowered haemagglutination-inhibiting (HI) antibody responses to the latter viruses. In fact, higher prevaccination, postvaccination and postepidemic antibody titres were recorded against the new field strains than against the vaccine virus; the highest being against field strains grown exclusively in MDCK cell cultures. This pattern is primarily explained by differences in the sensitivity of the viruses for detecting HI antibodies. Postvaccination protection rates of 98-100% for the MDCK-grown avid viruses were noted in subjects who exhibited prevaccination antibody. Lower protection rates were recorded in initially seronegative subjects, the lowest (54-57%) being among older people, i.e. among vaccines born in 1930-1955 (p < 0.001). Moreover, conspicuous decreases in protection rates were detected during the following epidemic season in the initially seronegative subjects. Diagnostic findings during outbreaks due to H1N1 subtype viruses also support the impression that many middle-aged people are poorly primed. Thus, vaccination with two doses may be worth considering when such people join the high-risk group and receive influenza vaccine for the first time.
Adult↗