Interferons: from virus inhibitor to modulator of amino acid and lipid metabolism.

Purity of interferons has facilitated definition of pleiotropic biological effects. Alterations that might be suspect with use of impure interferons, such as those occurring in tryptophan and lipoprotein metabolism, have been defined both in vitro and in humans. Reduction in tryptophan contributes to antimicrobial effects for intracellular pathogens and may explain some clinical observations.

Biologic-response-modifier-induced indoleamine 2,3-dioxygenase activity in human peripheral blood mononuclear cell cultures.

Degradation of tryptophan to kynurenine, catalyzed by indoleamine 2,3-dioxygenase (IDO), has been augmented in human epithelial cell lines treated with human interferon-gamma (HuIFN-gamma). Several human biologic response modifiers, including HuIFN-gamma, HuIFN-beta, HuIFN-alpha, interleukin 2 (HuIL-2), and tumor necrosis factor alpha, have now been assessed for their ability to enhance tryptophan degradation in human peripheral blood mononuclear cell (PMC) cultures. PMC were isolated from normal donors, cultivated in RPMI 1640 medium containing [3H]tryptophan, and treated with individual biologic response modifiers.

Inhibition of angiogenesis by interferons: effects on tumor- and lymphocyte-induced vascular responses.

Interferons (IFNs) have established antitumor action; the mechanism underlying this effect is, however, not yet clear. To probe the possible contribution of inhibition of angiogenesis, we have assessed angiogenesis in the mouse initiated by either human or murine tumor cell lines. Whether test cells were inoculated in the dermis or tumor fragments were grafted onto the cornea, tumor-induced angiogenesis (TIA) was inhibited by IFNs.

Assessment of the antigenic response in humans to a recombinant mutant interferon beta.

Cancer patients were given a recombinant mutant interferon beta by alternating IM and IV injections with weekly escalation of doses from 0.1 to 400 million U. Antibodies specific to the interferon of the IgG class were detected in 24 of 30 patients using an indirect enzyme-linked immunosorbent assay.

Variation in the binding of 125I-labeled interferon-beta ser to cellular receptors during growth of human renal and bladder carcinoma cells in vitro.

Studies of various established human bladder and renal carcinoma cell lines cultured in vitro demonstrated the presence of specific, saturable, high affinity binding sites for 125I-labeled human interferon Beta ser IFN-beta ser). This recombinant produced interferon labeled with approximately one atom of 125I/molecule of IFN expressed minimal or no loss of antiviral activity. A single class of binding sites (1000-2000/cell) with an affinity constant of 10(10)-10(11) L/M was measured at 4 degrees C for cells exhibiting widely different sensitivity to the antiproliferative effect of IFN-beta ser.

Enhancement of monocyte class I and II histocompatibility antigen expression in man by in vivo beta-interferon.

Changes in monocyte cell-surface markers were assessed during treatment of patients with beta-interferon (beta-IFN). Immediately after isolation monocytes were analysed using monoclonal antibodies and flow cytometry. After 2 days of beta-IFN significant increases in major histocompatibility complex (MHC) related cell-surface products were observed while no changes in Leu-M3, a non-MHC associated monocyte-specific marker, were found.

Randomized comparison of three adriamycin regimens for metastatic soft tissue sarcomas.

This study addressed two major questions regarding therapeutic use of Adriamycin ([Adr] Adria Laboratories, Columbus, OH) in adult soft tissue sarcomas: the influence of dosing schedule and the value of adding imidazole carboxamide (DTIC) to Adr. Patients with objectively measurable metastatic soft tissue sarcomas were randomized to Adr 70 mg/m2 intravenously (IV) day 1 and every 3 weeks (94 patients); Adr 20 mg/m2 IV day 1, 2, and 3, and 15 mg/m2 IV day 8 and weekly thereafter (89 patients); and Adr 60 mg/m2 IV day 1 and DTIC 250 mg/m2 days 1 to 5, repeated every 3 weeks (92 patients). The regimens using Adr as a single agent resulted in an equivalent response frequency (18% and 16%) and survival (median, 8.

High-dose lymphoblastoid interferon in advanced renal cell carcinoma: an Eastern Cooperative Oncology Group Study.

This report describes a phase II Eastern Cooperative Oncology Group (ECOG) study of high-dose lymphoblastoid interferon (IFN alpha-n1) in 39 patients with measurable, advanced renal cell carcinoma. The original treatment plan was 30 X 10(6) units/m2 (30 mU) of IFN alpha-n1 im daily X 10 days; treatments were repeated every 21 days. This dose and schedule proved intolerable, with none of seven patients able to complete greater than 10 days of therapy because of fever, lassitude, hepatic dysfunction, and myelosuppression.

Phase II evaluation of dibromodulcitol and actinomycin D, hydroxyurea, and cyclophosphamide in previously untreated patients with malignant melanoma.

In this Eastern Cooperative Oncology Group (ECOG) phase II study, dibromodulcitol (DBD) and a combination of actinomycin D, hydroxyurea, and cyclophosphamide (AHC) were compared with methyl-CCNU, the current ECOG standard, in patients who had received no prior chemotherapy for disseminated malignant melanoma. The response rates were 6% (3/50) for AHC, 9% (3/34) for DBD, and 14% (7/49) for methyl-CCNU. Median survival times were 4, 5, and 6 months, respectively.

Randomized comparison of cyclophosphamide, imidazole carboxamide, and adriamycin versus cyclophosphamide and adriamycin in patients with advanced stage malignant mesothelioma: a Sarcoma Intergroup Study.

In 1980, a consensus chemotherapy intergroup study for advanced malignant mesothelioma was initiated based on a collaborative agreement among the Eastern Cooperative Oncology Group (ECOG), the Southwest Oncology Group (SWOG), and the Southeastern Cancer Study Group (SECSG). The purpose of the study was to evaluate cyclophosphamide (500 mg/m2 day 1), imidazole carboxamide (250 mg/m2 days 1 through 5), and doxorubicin (Adriamycin; Adria Laboratories, Columbus, OH) (50 mg/m2 day 1) v cyclophosphamide (500 mg/m2) and doxorubicin (50 mg/m2) in a randomized prospective clinical trial involving 76 fully evaluable patients with advanced stages II to IV malignant mesothelioma. A total of nine responses (12%) were documented, including three complete and six partial responses.

Effect of interferon alpha, interferon beta, and interferon gamma on the in vitro growth of human renal adenocarcinoma cells.

Interferon-alpha, interferon-beta, and interferon-gamma differ in their antiproliferative effects for several cell lines. Interferons were thus assessed for their activity in inhibiting proliferation of three renal cell carcinoma cell lines. The malignant epithelial phenotype of each of these cell lines was confirmed by electron microscopy, histology, karyotype and tumorigenicity.

Effects of recombinant interferon-alpha 2 treatment upon lipid concentrations and lipoprotein composition.

Interferon-alpha 2 (IFN-alpha 2) produced by recombinant DNA technology and purified to homogeneity, was assessed for effects on plasma lipids and lipoprotein composition in 10 patients with metastatic malignant melanoma. Patients received 30 X 10(6) U/m2 IFN intravenously for 5 consecutive days every 3 weeks. Plasma cholesterol concentrations were significantly decreased after 3 days of IFN administration (171 +/- 37 mg/dl, mean +/- SD) when compared with pretreatment concentrations (211 +/- 28 mg/dl, p less than 0.

Antiproliferative effects of interferons on human melanoma cells in the human tumor colony-forming assay.

The human tumor colony-forming assay (HTCFA) is an in vitro test that has been used to predict the activity of anticancer drugs against a patient's tumor. We utilized the assay to analyze the antiproliferative effects of seven interferons (IFNs) against 40 human melanomas to determine which IFN had the greatest antiproliferative activity in this drug-resistant tumor. IFNs studied included recombinant IFN-alpha 2; human lymphoblastoid IFN; IFN-alpha Cantell; native beta RPMI; two recombinant IFNs-beta; and recombinant IFN-gamma.

Separation of human natural killer cell subpopulations differentially responsive to interferon potentiation.

Subsets of human natural killer (NK) cells were identified that differed in the capacity to be activated by interferon (IFN) or the IFN-inducer, polyriboinosinic:polyribocytidylic acid [poly(I):poly(C)]. These subsets, which represented effectors of both spontaneous and antibody-dependent cellular cytotoxicity, were physically separable on the basis of cell buoyant density changes induced by exposure of lymphocytes to hyperosmolar Ficoll-Hypaque solutions or by centrifugation of lymphocytes through hyperosmolar (350 mOs/kg) Percoll gradients. Hyperosmolar conditions per se altered neither cell viability, NK cell cytolytic activity, nor the capacity of NK cells in unseparated lymphocyte preparations to be activated by IFN.

Inhibitory effects of interferon-inducing pyrimidinones on the growth of transplantable mouse bladder tumors.

Pyrimidinones are low-molecular-weight compounds which are inducers of interferon in several animal species. They have established antiviral, immunomodulatory, and antitumor effects. Four pyrimidinones as well as another potent interferon inducer, polyriboinosinic-polyribocytidylic acid, and beta-interferon were tested for effects on growth of the transplantable mouse bladder tumor (MBT-2).

Induction of tryptophan degradation in vitro and in vivo: a gamma-interferon-stimulated activity.

Human recombinant gamma interferon (rHuIFN-gamma) was found to induce tryptophan degradation in vitro in human cell cultures and in vivo in participants in phase I clinical trials. When human lung fibroblasts were treated with various concentrations of rHuIFN-gamma, they degraded tryptophan in a dose- and time-dependent manner. No tryptophan degradation was observed when cells were incubated in growth medium alone or in medium supplemented with human recombinant beta-interferon (rHuIFN-beta ser).

Modulation of 2',5'-oligoadenylate synthetase in patients treated with alpha-interferon: effects of dose, schedule, and route of administration.

The interferon (IFN)-induced intracellular enzyme 2',5'-oligoadenylate (2-5A) synthetase was measured in extracts of peripheral mononuclear cells isolated from patients receiving a 300-fold range of doses of alpha interferon (IFN-alpha). The range of enzyme induction was 2.3- to 5.

Phase II trial of interferon-beta for treatment of recurrent glioblastoma multiforme.

Twelve patients were admitted to a Phase II study on the treatment of recurrent glioblastoma multiforme with interferon-beta (IFN-beta). All patients had previously undergone craniotomy and received a standard course of radiation therapy. Recurrence was inferred from enlargement of the lesion on computerized tomography (CT) scanning and in each case was confirmed by CT-guided stereotaxic biopsy.

Treatment of multiple myeloma with recombinant alpha-interferon.

Thirty-two patients with multiple myeloma were treated with recombinant alpha-interferon clone A (rIFN alpha A) daily by intramuscular injection with an initial dose of 12 X 10(6) U/m2. Of 27 patients evaluable for response, tumor responses were obtained in seven of 14 previously untreated patients (50%) and two of 13 who had relapsed or failed prior chemotherapy (15%). In all patients who had tumor response, there was restoration from subnormal levels of serum immunoglobulins, an effect infrequently observed with chemotherapy.

Synergistic antiproliferative effects of human recombinant alpha 54- or beta ser-interferon with gamma-interferon on human cell lines of various histogenesis.

The antiproliferative effects of human interferon (IFN), IFN-gamma, IFN-alpha 54, and IFN-beta ser, alone and in combination, were assessed on 10 human cell lines. All IFNs were produced by recombinant technology and purified to homogeneity. In all cell lines except one, the addition of IFN-gamma to either IFN-alpha 54 or IFN-beta ser resulted in a synergistic antiproliferative effect, regardless of individual IFN sensitivities or tissue of origin.

Phase II evaluation of a combination of mitomycin C, vincristine, and cisplatin in advanced non-small cell lung cancer.

The combination treatment of mitomycin C (M), vincristine (V), and cisplatin (P) (MVP) in 63 patients with advanced non-small cell lung cancer (NSCLC) were evaluated for their potential synergistic cytotoxicity. The overall response rate was 43% (27/63); in the 54 eligible and evaluable patients, the response rate was 50% (27/54). Responses were observed in all cell types and disease sites.