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Biomedical subjects

P L Witt

Publications and source records attributed to P L Witt.

At least 19 recordsLinked to original sources
PubMed1996

Phase I/IB study of polyadenylic-polyuridylic acid in patients with advanced malignancies: clinical and biologic effects.

The synthetic polynucleotide polyadenylic-polyuridylic acid (polyA:polyU) has shown antitumor activity in murine studies and human breast cancer. PolyA:polyU was evaluated in 25 cancer patients receiving weekly intravenous doses between 3 and 600 mg/m2. PolyA:polyU was well tolerated up to 600 mg/m2, with no doselimiting toxicity (all < grade 3). Side effects included mild elevation in temperature, fatigue, and mild hyperglycemia. No changes outside of the normal range in hematocrit, WBC count, platelet count, total bilirubin, or alkaline phosphatase were observed. Of 25 patients, 18 completed at least one cycle of 6 weeks, and 5 completed two cycles (median 6 weeks). Four patients had stable disease over 11-13 weeks of treatment, and no clinical responses were observed. At 24 h after the first treatment, there were no significant increases in biologic response (beta 2-microglobulin and neopterin in serum, or 2',5'-oligoadenylate synthetase in peripheral blood mononuclear cells). A small increase in beta 2-microglobulin was observed 24 h after the week 3 treatment (1.1-fold, p < 0.01). By the third week of treatment, 2-5A synthetase levels decreased slightly (to 80% of baseline, p < 0.01). No changes in cytokines IL-6, IL-12, tumor necrosis factor (TNF), or IL-2 receptor in serum were detected after 24 h of treatment. Thus, at these doses, polyA:polyU had no marked modulation on biologic responses in vivo, although this preparation significantly induced 2-5A synthetase in peripheral blood mononuclear cells in vitro. PolyA:polyU was well tolerated. An MTD was not reached but was greater than 600 mg/m2 on this weekly schedule.

2',5'-Oligoadenylate Synthetase↗
PubMed1996

Hematologic and immunologic evaluation of recombinant human interleukin-6 in patients with advanced malignant disease: evidence for monocyte activation.

Eighteen advanced cancer patients received weekday subcutaneous injections of recombinant interleukin-6 (rIL-6) for 4 weeks at escalating doses. Patients were evaluated for hematologic and immune system effects. Hematologic monitoring included WBC, differential, Hgb and Hct, platelet counts, and assessment of marrow and peripheral blood progenitors. Immunologic monitoring included evaluation of acute-phase reactants (APRs), immunophenotyping, serum cytokine levels, cytokine-induced proteins, and cytokine messenger RNA (mRNA). The maximal tolerated dose (MTD) was 8.0 micrograms/kg/day, with neurocortical toxicity as the major limiting factor. All patients became anemic, and most had fever and chills. APRs were increased throughout treatment. WBCs increased transiently on day 2; granulocytes and monocytes increased again through day 26, whereas lymphocytes decreased to baseline or lower levels. Platelets responded by day 12 and increased through day 26 at the MTD with no effect on colony-forming unit-megakaryocyte (CFU-Mk). Peripheral WBC and RBC progenitors were not affected but decreased in the marrow. T-cell percentages declined with little effect on absolute numbers; T-cell activation was seen. CD45RO+ T cells decreased, but there was no significant effect on CD8+ CD28+ T cells. Neither B cells nor natural killer (NK) cells were affected. However, evidence of monocyte effects included upregulation of CD71, induction of the cytokine-induced proteins 2-5A synthetase and neopterin, and increases in tumor necrosis factor-alpha (TNF-alpha) mRNA. Serum cytokines were undetected, and mRNA for IL-1 beta, IL-2, and interferon-gamma (IFN-gamma) was not induced; however, mRNA for IL-4 and IL-10 did increase suggesting activation of Th2-like T cells. One mixed tumor response was seen. We conclude that IL-6 alone has systemic activity on the immune system, as well as the hematopoietic system, which at the MTD, primarily involves induction of APR, activation and expansion of monocytes, and activation of Th2-like T cells.

Acute-Phase Proteins↗
PubMed1995

Interferon alpha enhances expression of TAG-72 and carcinoembryonic antigen in patients with primary colorectal cancer.

Interferons up-regulate the expression of human tumor-associated antigens in animal models and in vitro. The use of interferons may enhance the immunodetection and immunotherapy of tumors by monoclonal antibodies that detect tumor antigens. For this strategy to be effective, however, the interferon must have an effect at the site of the tumor. In this study, the induction by interferon alpha (IFN alpha) of two tumor surface antigens was evaluated in six patients with primary colorectal cancer. Patients were treated with IFN alpha and 48 h later underwent resection of the tumor. The interferon treatment induced expression of a tumor-associated glycoprotein (TAG-72) in two patients without antigen expression prior to interferon but had no effect on one TAG-72-negative tumor. IFN alpha did not induce expression of carcinoembryonic antigen (CEA) in the two patients whose tumors were CEA-negative prior to interferon. In all patients with heterogeneous expression of CEA and TAG-72 prior to IFN alpha treatment, preoperative interferon increased the percentage of cells positive for CEA in two patients and TAG-72 in one patient. This study supports the addition of interferon induction to immunotherapy regimens directed at the CEA and TAG-72 cell-surface antigens.

2',5'-Oligoadenylate Synthetase↗
PubMed1995

2',5'-oligoadenylate synthetase in interferon-alpha- and acyclovir-treated herpes simplex virus-infected cells.

The 2',5'-oligoadenylate (2-5A) synthetase pathway, induced by interferon-alpha (IFN-alpha), has been shown to be responsible for the antiviral action of IFN-alpha against some viruses. Studies were done to determine the role of this pathway in the anti-herpes simplex virus (HSV) action of IFN-alpha alone or in combination with acyclovir (ACV), a combination that leads to synergistic anti-HSV activity. Treatment of human corneal cells or Vero cells with 100 IU/ml of IFN-alpha induced expression of 2-5A synthetase mRNA and a 10-fold increase in 2-5A synthetase production compared with untreated cells. HSV infection alone did not induce 2-5A synthetase production, but when IFN-alpha-treated cells were infected with HSV, enzyme level was significantly increased (p < 0.05) compared with that in IFN-alpha-treated, uninfected cells. HSV infection actually decreased the level of 2-5A synthetase mRNA in IFN-alpha-treated cells. Although IFN-alpha treatment induced high levels of 2-5A synthetase with or without HSV infection, no activation of the latent endonuclease was detected by specific cleavage of ribosomal RNA. Treatment of infected cells with 5 microM ACV alone or combined with IFN-alpha did not increase 2-5A synthetase or endonuclease activities above those detected in cells not treated with ACV. The data indicate that the 2-5A synthetase pathway was inducible in corneal cells and Vero cells but did not appear to contribute to the anti-HSV activity of IFN-alpha alone or the synergistic activity of IFN-alpha combined with ACV.

2',5'-Oligoadenylate Synthetase↗
PubMed1993

Phase I trial of an oral immunomodulator and interferon inducer in cancer patients.

Imiquimod [1-(2-methylpropyl)-1H-imidazo[4,5c]quinolin-4-amine] is a compound of low molecular weight that, when administered p.o., induces interferon-alpha in several animal species and inhibits tumor growth in mice. To determine maximum tolerated dose, toxicity, and biological response in humans, a phase I clinical trial was conducted with 14 eligible cancer patients who received 100-500 mg imiquimod p.o. either once or twice weekly. Imiquimod induced interferon-alpha in serum in 10 of 19 doses of 200-300 mg. Interferon serum levels peaked 8-24 h after treatment and reached a maximum of 23,000 IU/ml in one patient. Significant mean increases (P < 0.01) in serum beta 2-microglobulin (1.5-fold), serum neopterin (3.5-fold), and 2-5A synthetase activity in peripheral blood mononuclear cells (7.9-fold) indicated that 200-300 mg imiquimod had biological and immunological activity in all evaluable patients. Increases in serum interferon, beta 2-microglobulin, and neopterin correlated significantly with dose (P < 0.001). No patient developed measurable antibody to interferon-alpha. Dose-limiting side effects included fatigue, malaise, fever, headache, and lymphocytopenia; no hepatic or renal toxicity or other hematological changes exceeded the normal range. Patients tolerated weekly doses of up to 500 mg, with the longest treatment lasting 4 weeks at 200 mg weekly. Twice-weekly doses up to to 300 mg were tolerated, with the longest twice-weekly treatments being 200 mg for 9 weeks and 100 mg for 25 weeks. No clinical responses were observed. Imiquimod, as an oral inducer of interferon, may have therapeutic usefulness in human cancers, viral infections, and other diseases. However, before initiation of phase II trials, additional work will be required to establish a tolerated dose and schedule for continued administration.

2',5'-Oligoadenylate Synthetase↗
PubMed1993

Isoforms p69 and p100 of 2',5'-oligoadenylate synthetase induced differentially by interferons in vivo and in vitro.

Four isoforms of 2',5'-oligoadenylate (2-5A) synthetase have been identified (40, 44, 69, and 100 kD). The 40- and 44-kD enzymes are encoded by the same gene, probably different from the genes encoding the larger isoforms. In this study, induction of the 100- and 69-KD (p100, p69) isoforms in different individuals and in different cell types was investigated after treatment with recombinant human interferons (IFN): IFN-alpha 2, IFN-beta ser, or IFN-gamma. The p69 and p100 isoforms were quantitated in cell extracts on Western blots using specific polyclonal antibodies, or their activity was measured after purification of cell extracts on immunoaffinity columns. The p69 and p100 isoforms were differentially induced in Daudi, fibroblast, and colon adenocarcinoma cells treated with IFNs. Considerable individual variations in both basal and induced levels of p69 and p100 were observed in peripheral blood mononuclear cells from normal donors cultured with IFNs in vitro, and from cancer patients treated with IFN-alpha 2 or with IFN-beta ser. These results demonstrate that the p69 and p100 isoforms are present in vivo in peripheral blood mononuclear cells and their level is increased following IFN administration. Furthermore, both the in vivo and in vitro observations indicate that the expression of these enzymes is specific to each cell type and varies among individuals.

2',5'-Oligoadenylate Synthetase↗
PubMed1993

Pharmacodynamics of biological response in vivo after single and multiple doses of interferon-beta.

Interferons (IFNs) induce gene regulation in vivo that may be used to identify effective doses, schedules, and potential correlates of therapeutic response. To critically examine minimum effective dose, duration of response, and cumulative effects of repetitive doses, a range of subcutaneous doses of IFN beta ser was studied in 32 healthy human volunteers. IFN-induced products of gene regulation assessed were beta 2-microglobulin, neopterin, and tryptophan in serum and 2',5'-oligoadenylate (2-5A) synthetase activity in peripheral blood mononuclear cells. Eight subjects per group received 0.09, 0.9, 9, or 45 MU of IFN beta. Responses were measured at 24, 48, and 72 h after single and multiple doses. The lowest biologically effective dose was 0.9 MU; significant (p < 0.02) increases were observed at 24 h in beta 2-microglobulin and cellular 2-5A synthetase activity. At the two higher doses, 9 and 45 MU, changes were observed at 24 h in all products (p < 0.01). A dose response (p < 0.01) over the range of 0.09-45 MU was observed for all these serum and intracellular gene products. Changes in neopterin, beta 2-microglobulin, and cellular 2-5A synthetase correlated significantly with each other. The response to a single dose of IFN beta was as great in magnitude as the response to multiple doses, suggesting an alternate-day schedule would maintain biological response.

2',5'-Oligoadenylate Synthetase↗
PubMed1992

Clinical and biologic effects of combination therapy with gamma-interferon and tumor necrosis factor.

Tumor necrosis factor (TNF) and gamma-interferon (gamma-IFN) are cytokines with synergistic biologic and antiproliferative effects in vitro and in mouse models. The biologic effects of the combination of TNF and gamma-IFN, however, have not been studied well in humans. A Phase I trial was conducted of TNF and gamma-IFN therapy in 24 patients with advanced malignancies to determine the tolerability of the combination and the biologic effects of TNF and gamma-IFN in vivo. Both TNF and gamma-IFN were administered as 30-minute intravenous infusions three times per week. Doses of TNF ranged from 25 to 100 micrograms/m2; all patients received 100 micrograms/m2 of gamma-IFN. Dose-limiting toxicity consisted primarily of orthostatic hypotension and constitutional symptoms. The maximum tolerated dose level (MTDL) of 50 micrograms/m2 of TNF and 100 micrograms/m2 of IFN-gamma was less than the maximum tolerated dose (MTD) observed in previous Phase I trials of gamma-IFN and TNF alone. Biologic responses were studied in seven patients treated at the MTDL. Serum interleukin-2 receptor levels and neopterin secretion were enhanced significantly 24 hours after therapy (P = 0.002); enhancement of monocyte Fc receptor levels had borderline statistical significance (P = 0.07). With the exception of the mean fluorescent intensity on monocytes positive for histocompatibility antigen HLA-DR (P = 0.03), HLA Class I and II cell surface protein expression was not increased. The combination significantly enhanced indoleamine dioxygenase activity and serum beta 2-microglobulin expression (P less than 0.04) but not 2',5'-oligoadenylate synthetase activity, bactericidal function, or chemiluminescence. These results were compared retrospectively with those observed in previous Phase I trials of gamma-IFN and TNF alone. The combination of TNF and gamma-IFN significantly increased urinary kynurenine levels more than either TNF alone or gamma-IFN alone. Given the limitations inherent in any retrospective analysis, however, the enhancement in the other biologic parameters measured at the MTDL during this trial did not differ significantly from the changes observed at the MTD of either TNF or gamma-IFN alone. It was concluded that the combination of TNF and gamma-IFN, when administered at the MTDL of the combination, does not offer any enhancement in biologic responses over either agent alone.

2',5'-Oligoadenylate Synthetase↗
PubMed1992

Absence of biological effects of orally administered interferon-beta ser.

To assess biological effectiveness of interferon (IFN) administered orally, we measured serum IFN and several proteins and metabolites induced by IFN after oral administration of 2.5 mg or 7.5 mg of recombinant IFN-beta ser to 6 healthy volunteers. These IFN-induced metabolites, beta 2-microglobulin, and neopterin in serum, and 2',5'-oligoadenylate (2-5A) synthetase in peripheral blood mononuclear cells, are more sensitive to the presence of IFN than bioassay of IFN in serum. Up to 48 h after oral IFN was administered, serum IFN, beta 2-microglobulin, neopterin, or 2-5A synthetase were not generally increased compared to pretreatment levels, indicating that oral IFN had no significant biological effects.

Adenine Nucleotides↗
PubMed1991

Biological and clinical effects of intravenous tumor necrosis factor-alpha administered three times weekly.

Tumor necrosis factor (TNF) is a cytokine with pleiotropic biological and antitumor effects in vitro and in mouse models. The immunological effects of the molecule as a single agent, however, have not been well studied clinically. We conducted a Phase I trial of TNF in 53 patients with advanced malignancies in order to determine the biological and clinical effects of TNF when administered as a 30-min i.v. infusion three times/week. Dose levels of TNF ranged from 5 to 275 micrograms/m2; doses of TNF were escalated between patient groups. The most common clinical toxicities of TNF consisted of rigors, anorexia, headache, and fatigue. Dose-limiting toxicity consisted of hypotension, fatigue, and nausea. Four patients treated at the maximally tolerated dose of 225 micrograms/m2 received dexamethasone to determine whether the toxicities of TNF could be ameliorated. No significant differences in hypotension or subjective symptomatology were observed in those patients receiving dexamethasone and those who did not or between injections in which dexamethasone was administered and when it was not. One patient with colorectal carcinoma treated with 50 micrograms/m2 had a partial response lasting about 9 months. Biological responses were evaluated in 8 patients treated at the maximally tolerated dose before therapy and 24 h afterward. TNF significantly (P less than 0.05 for all) enhanced serum beta 2-microglobulin, serum neopterin, and serum interleukin-2 receptor (Tac antigen) levels. Indoleamine 2,3-dioxygenase activity was also increased 24 h following the administration of TNF, although this increase was only of borderline statistical significance (P = 0.07). TNF did not enhance granulocyte bactericidal activity. The expression of cell surface proteins on monocytes, including HLA-DR, HLA-DQ, beta 2-microglobulin, and the Fc receptor, and serum interleukin-1 activity also were not significantly increased by the administration of TNF. Thus, in humans TNF caused biological response modulation with evidence of HLA Class I (beta 2-microglobulin) increase and T-cell (Tac antigen) and monocyte (neopterin) activation.

2',5'-Oligoadenylate Synthetase↗
PubMed1991

2',5'-oligoadenylate synthetase, neopterin and beta 2-microglobulin in asymptomatic HIV-infected individuals.

This study examined 2',5'-oligoadenylate (2,5A) synthetase activity in 26 individuals during the asymptomatic phase of HIV infection and its correlation with neopterin or beta 2-microglobulin. In HIV-antibody-positive (HIV-Ab+) asymptomatic people, both neopterin and beta 2-microglobulin levels in sera were significantly elevated; in contrast, 2,5A-synthetase activity in peripheral blood mononuclear cells was not significantly higher than in HIV-antibody-negative controls. The 2,5A-synthetase levels in symptomatic people (AIDS-related complex and AIDS) were significantly higher than in either asymptomatic or control individuals. However, within the group of HIV-infected asymptomatic individuals, all three markers were positively correlated. In this group, neopterin values were negatively correlated with the number of CD4+ lymphocytes while a positive correlation was found between 2,5A-synthetase and the number of CD8+ lymphocytes. Asymptomatic people with detectable serum HIV p24 antigen had significantly higher 2,5A-synthetase, neopterin, beta 2-microglobulin and number of CD8+ lymphocytes. This study suggests that elevated 2,5A-synthetase activity may reflect a different aspect of host response to HIV infection than do elevated neopterin or beta 2-microglobulin.

2',5'-Oligoadenylate Synthetase↗
PubMed1991

Immunological effects of levamisole in vitro.

Levamisole, an anthelminthic drug with immunological properties, has recently been reported to have antitumor activity when administered with 5-fluorouracil in patients with Duke's C colorectal carcinoma. The mechanism of this antitumor effect is unknown, but has been postulated to be related to levamisole's immunomodulatory properties. To define further the immunomodulatory activities of levamisole, we studied the in vitro effects of levamisole on monocyte and lymphocyte cytotoxicity, activation, and proliferation; induction of cytokine-induced proteins; and expression of tumor-associated antigens. Experiments utilized peripheral blood mononuclear cells from normal donors incubated in the presence of increasing concentrations of levamisole (0.1 to 100 micrograms/ml). Levamisole had no consistent effect on induction of 2',5'-oligoadenylate synthetase activity or indoleamine-2,3-dioxygenase activity, or production of tumor necrosis factor. Levamisole had no effect on monocyte cytotoxicity or expression of HLA-DR, HLA-DQ, HLA-DP, and the Fc receptor. Similarly, levamisole had no significant effect on NK or LAK cytotoxicity or the immunological activation of T-lymphocytes, assessed by expression of CD3, CD4, CD8, CD16, CD25, and CD56. Proliferation of lymphocytes from normal donors, patients with benign polyps, and patients with malignancies, with or without IL-2 or irradiated LS174T cells, was not significantly increased overall. No significant enhancement in the expression of three tumor-associated antigens (880364, NRCO-4, and ING-1) and the intercellular adhesion molecule-1 (ICAM-1) antigen on four human cancer cell lines was observed following in vitro exposure to levamisole. We conclude that levamisole is not a potent modulator of the immune parameters we examined, and that the mechanism behind the unique clinical interaction between levamisole and 5-fluorouracil in colorectal carcinoma remains to be identified.

2',5'-Oligoadenylate Synthetase↗
PubMed1990

Regulation of carcinoembryonic antigen expression in different human colorectal tumor cells by interferon-gamma.

The regulation of carcinoembryonic antigen (CEA) expression by recombinant human interferon-gamma (IFN-gamma) was studied in a series of 7 human colorectal tumor cell lines at various stages of differentiation. Two of the colorectal cell lines were poorly differentiated and did not constitutively express CEA. IFN-gamma treatment, however, induced CEA expression in one of those lines (i.e., DLD-1) as evidenced by the appearance of CEA-related mRNA transcripts, as well as the cell surface expression of the antigen as measured by flow cytometry and radioimmunoassay. In the highly differentiated colorectal tumor cell lines, IFN-gamma treatment resulted in no detectable change in CEA content in whole cell extracts or in the percentage of cells positive for cell surface CEA expression. In fact, IFN-gamma treatment of the highly differentiated LS174T cell line not only failed to alter CEA expression, but also failed to induce class II human leukocyte antigen expression. Therefore, the highly differentiated LS174T cell line and the poorly differentiated MIP cell line represent colorectal tumor cell types that are unresponsive to the ability of IFN-gamma to induce alterations in tumor (i.e., CEA) or normal (i.e., class I and class II human leucocyte antigen) surface antigen expression. The most responsive of human colorectal tumor cells to the ability of IFN-gamma to alter CEA expression were the moderately differentiated cell lines (i.e., HT-29, WiDr, etc.). IFN-gamma treatment of those cell types increased the CEA content in cell extracts by 300-400%, and increased the percentage of cells positive for surface CEA expression from 30-45% to greater than 80%. The effect of IFN-gamma treatment on 2',5'-oligoadenylate synthetase (2'-5' A) activity was also studied using 4 of the 7 colorectal cell lines. Constitutive 2'-5' A activity varied approximately 14-fold and was not correlated with degree of cellular differentiation. IFN-gamma treatment increased 2'-5' A activity in all 4 colorectal tumor cells tested. In particular, the ability to enhance 2'-5' A activity in the MIP and LS174T cells, 2 colorectal tumor cell types that previously were shown to be unresponsive to IFN-gamma-mediated changes in their antigenic phenotype, clearly separates cellular events regulating 2'-5' A activity from those involved in regulating cell surface antigen expression. The findings also suggested that the regulation of CEA expression by IFN-gamma is not related to the degree of cellular differentiation and, furthermore, provide some insight into which human tumor cell populations may be the most amenable to tumor antigen augmentation by IFN-gamma in an adjuvant setting with a monoclonal antibody.

2',5'-Oligoadenylate Synthetase↗
PubMed1990

Biological and clinical effects of the combination of beta- and gamma-interferons administered as a 5-day continuous infusion.

A phase I trial involving continuous infusion of both beta- and gamma-interferon (IFN-beta and IFN-gamma) was conducted in 20 patients in order to determine whether combinations of high doses of IFN-beta and IFN-gamma were tolerable when administered under conditions which mimic conditions of in vitro antiproliferative studies. Patients received a 5-day continuous infusion of IFN-beta/IFN-gamma, followed by a 9-day rest period. Two cycles were administered. Doses of IFN-beta/IFN-gamma were escalated between 4 dose levels, with 5 patients per dose level. Dose-dependent side effects, consisting primarily of constitutional symptoms typical of those experienced with IFN, were observed. The maximally tolerated dose of continuous IFN-beta/IFN-gamma infusion was 3 x 10(6) units of IFN-beta and 200 micrograms of IFN-gamma. Dose-limiting side effects consisted of severe headache, fatigue, fever, and hepatic toxicity. No clinical responses were observed. Serum IFN was measurable only at the highest 3 dose levels. Only 5 patients (4 at the highest dose level) had total serum levels which exceeded 50 laboratory units/ml (55, 63, 800, 800, and 550 laboratory units/ml, respectively). In order to confirm the biological effectiveness of this schedule, we measured IFN-inducible proteins prior to therapy, 24 h after the initiation of the infusion, and at the completion of the 5-day infusion. 2'-5'-Oligoadenylate synthetase, serum beta 2-microglobulin, neopterin, and p78 levels all increased significantly, and serum tryptophan decreased significantly within 24 h after the initiation of treatment (P less than 0.0001). A dose-response effect was observed for serum beta 2-microglobulin, neopterin, and p78 (P less than 0.02). We retrospectively compared the results of this trial with those of another IFN-beta/IFN-gamma trial in which IFN-beta and IFN-gamma were administered by i.v. bolus. Within the limitations of a retrospective comparison, continuous infusion was less well tolerated than our previous schedule of bolus administration 3 times/week. However, the continuous infusion schedule appeared to be more effective in enhancing 2'-5'-oligoadenylate synthetase levels in mononuclear cells. We conclude that tolerable doses of IFN-beta and IFN-gamma do not result in serum IFN levels which produce significant synergistic antiproliferative responses in vitro. This study and other findings suggest that, unless higher doses can be achieved, combinations of IFN-beta and IFN-gamma are unlikely to have significant therapeutic activity.

2',5'-Oligoadenylate Synthetase↗
PubMed1990

Inhibition of hormone-dependent and independent breast cancer cell growth in vivo and in vitro with the antiestrogen toremifene and recombinant human interferon-alpha 2.

The antiproliferative action of the antiestrogen toremifene and recombinant human interferon-alpha 2a (IFN-alpha 2a) were examined on human breast cancer cell lines grown in culture and in the athymic mouse. Solid tumors grew from an inoculation of a 99:1 ratio of hormone dependent (MCF-7) and hormone independent (MDA-MB-231) breast cancer cells without estrogen administration. However, estradiol supplementation significantly increased the rate of tumor growth. The daily administration of 1.35 x 10(6) U of recombinant human IFN-alpha 2a resulted in a marked rduction of tumor growth in both estradiol-treated and non-treated mice. Toremifene administration (130 micrograms/day from a sustained release preparation) markedly inhibited estradiol stimulation of mouse uterine weight and partially reduced estradiol-stimulated tumor growth. The combination of IFN-alpha 2a (1.35 x 10(6) u/day) with toremifene (130 micrograms/day) reduced estradiol-stimulated growth much below that of toremifene alone but not below that seen with interferon alone. Toremifene (10(-10)-10(-6) M) did not inhibit the growth of hormone-independent MDA-MB-231 breast cancer cells in vitro whereas it did inhibit the growth of hormone-dependent MCF-7 cells in phenol red containing media. IFN-alpha 2a (1-10,000 u) inhibited the growth of both MCF-7 and MDA-MB-231 cells in culture; however, MCF-7 cells were approximately 10-fold more sensitive to interferon inhibition. This was consistent with the MCF-7 cells showing a greater sensitivity to interferon than MDA-MB-231 cells in the induction of 2'5'-oligoadenylate synthetase.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Basal and interferon-induced 2',5'-oligoadenylate synthetase in human monocytes, lymphocytes, and peritoneal macrophages.

2',5'-Oligoadenylate (2-5A) synthetase is an intracellular enzyme induced during viral diseases and after clinical administration of interferons (IFN). Because monocytes and T and B lymphocytes in peripheral blood are targets of viral infection, we compared the basal levels and induction of 2-5A synthetase activity in these three cell types. IFN-beta induced significant, three- to eightfold increases in 2-5A synthetase activity in monocytes and T and B lymphocytes, both in vitro and in vivo. IFN-gamma was less effective in inducing 2-5A synthetase than IFN-beta, yielding up to 2.6-fold increases in monocytes and slight increases in lymphocytes in vitro. IFN-beta also had greater 2-5A synthetase-inducing activity than IFN-gamma in HL-60 and U937 monocytic cell lines and in human peritoneal macrophages. Baseline levels of 2-5A synthetase in untreated peripheral blood monocytes separated by adherence or density gradients were three- to fivefold higher than in lymphocytes. 2-5A synthetase levels were twofold higher in B than in T lymphocytes separated by fluorescence-activated cell sorting. Tumor necrosis factor-alpha (TNF-alpha) did not induce this enzyme in peripheral blood mononuclear cells (PBMCs) or peritoneal macrophages. Thus, monocytes had greater basal and induced levels of 2-5A synthetase activity than did lymphocytes and contributed disproportionately to total 2-5A synthetase activity in peripheral blood.

2',5'-Oligoadenylate Synthetase↗
PubMed1990

A direct comparison of biological response modulation and clinical side effects by interferon-beta ser, interferon-gamma, or the combination of interferons beta ser and gamma in humans.

To directly compare clinical side effects and biological response modification, IFN-beta ser, IFN-gamma, or the combination of IFN-beta ser plus IFN-gamma was administered to 21 cancer patients. Each IFN or the combination was given intravenously on days 1, 8, and 15 in varied order. Each IFN and the combination resulted in significant (P less than 0.05) modulation of IFN-induced proteins. IFN-beta ser was more effective than IFN-gamma in enhancing 2-5A synthetase activity (P = 0.001). IFN-gamma was more effective than IFN-beta ser in enhancing serum beta 2 microglobulin expression (P = 0.05) and indoleamine dioxygenase activity, as assessed by decreased serum tryptophan (P = 0.03). The combination enhanced tryptophan catabolism more effectively than IFN-beta ser in a dose-dependent manner (P less than 0.03). IFN-beta ser/IFN-gamma did not potentiate natural killer cells or antibody-dependent cellular toxicity (ADCC). IFN-beta ser/IFN-gamma enhanced monocyte guanylate cyclase activity, as assessed by serum neopterin, more effectively than IFN-gamma alone (P = 0.005). Both IFNs and the combination resulted in increases in HLA class II expression on monocytes. However, no significant difference in the level of induction of HLA DQ and HLA DR expression between IFN-beta ser/IFN-gamma and either IFN-beta ser or IFN-gamma was noted. Although frequency and servity of side effects of IFN-beta ser, IFN-gamma, or the combination were dose related, induction of induced proteins (with exception of influences on tryptophan catabolism) were not a function of dose administered over the 10-fold range. Continued treatment with the combination intravenously three times a week for 4 wk sustained but did not further potentiate, most of the changes in interferon-induced proteins. Thus, IFN-beta ser and IFN-gamma each resulted in effective and essentially equivalent patterns of induction of induced proteins. When combined, however, these IFNs did not result in potentiation of biological response modification in vivo.

2',5'-Oligoadenylate Synthetase↗