Evaluation of the immunological and toxicological properties of MVE-2 in phase I trials.
(17/26)
Pyran copolymer enhances resistance to infections and transplantable tumors in mice. It induces interferon, activates macrophages, increases antibody-dependent cellular cytotoxicity (ADCC), functions as an adjuvant, and has direct antitumor effects. MVE-2, a low-molecular-weight (15,000) component of pyran copolymer, exhibited less toxicity and essentially the same positive biological effects as pyran copolymer. MVE-2 was, therefore, chosen for clinical trials. This study was designed to determine the toxicity and immunological effects of MVE-2 in humans. Fourteen patients who received biweekly MVE-2 had lymphocyte and monocyte ADCC, natural killer activity, and monocyte to macrophage maturation measured 2, 3, 7, 10, and 13 days after each of the first three doses of MVE-2. Lymphocyte antibody-dependent cellular cytotoxicity and monocyte maturation increased significantly following MVE-2 administration and the effect persisted at least 4 weeks. Although numbers were small, the enhanced ADCC seemed related to both single dose and cumulative dose of MVE-2. Five of six patients receiving more than 2 g of MVE-2 had improvement in lymphocyte ADCC. Increases in lymphocyte and monocyte natural killer activity approached, but did not attain statistical significance. Proteinuria was the dose-limiting toxicity, but was reversible. MVE-2 induced a modest, but real enhancement of lymphocyte and monocyte function at doses that were well tolerated. (+info)
Effect of pyran copolymer on activation of murine macrophages: evidence for incomplete activation by use of functional markers.
(18/26)
The degree of activation of peritoneal macrophages elicited by pyran copolymer (MVE-2) was studied in C57BL/6J mice. When cytotoxicity was examined under endotoxin-free culture conditions, the pyran-elicited macrophages could not complete cytolysis of tumor target cells. The macrophages, however, completed cytolysis when pulsed with endotoxin. These results were obtained when either the interval between injection of the pyran copolymer and harvest of the macrophage or the dose of pyran was varied. The pyran-elicited macrophages expressed five markers considered to be typical of inflammatory macrophages, and bound tumor cells to an augmented degree. The pyran-elicited macrophages were capable of secreting a potent cytolytic proteinase when pulsed with endotoxin, but did not secrete cytolytic proteinase spontaneously. The pyran-elicited macrophages, in contrast to inflammatory macrophages, could effect cytostasis of tumor cells; their cytostatic potential was also augmented by addition of endotoxin. Taken together, the results indicated that pyran copolymer elicits primed but not fully activated murine macrophages. (+info)
Presence of DNA polymerase in lymphosarcoma in northern pike (Esox lucius).
(19/26)
Northern poke lymphosarcoma DNA polymerase was partially purified from particulate fractions banding at 1.15 to 1.16 g/ml from homogenates prepared from frozen necropsies of tumor-bearing pike. The enzyme behaves as a typical reverse transcriptase, in that it prefers ribotemplates to deoxytemplates. The isoelectric point (pl 5.5) is similar to that of avian myeloblastosis virus polymerase. The pike enzyme elutes from a phosphocellulose column at 0.22 M potassium phosphate, the same as avian myeloblastosis virus DNA polymerase. The enzyme activity is inhibited by pyran, a specific inhibitor of viral DNA polymerases. The most striking difference between the pike lymphoma polymerase and the other viral DNA polymerases tested is the low maximum temperature of 20 degrees, compared to 30 degrees for Rauscher leukemia virus polymerase and 38 degrees for avian myeloblastosis virus and Rous sarcoma virus. (+info)
Therapy of artificial and spontaneous metastases of murine tumors with maleic anhydride-divinyl ether-2.
(20/26)
A 15,500 molecular-weight fraction of a pyran copolymer, (MVE-2) was investigated for its therapeutic efficacy against artificial lung metastases of a weakly immunogenic spontaneous fibrosarcoma (NFSa), a relatively strongly immunogenic fibrosarcoma (FSa), a moderately immunogenic spontaneous mammary carcinoma (MCa-K-, and a weakly immunogenic spontaneous mammary carcinoma (MDAH-MCa-4) syngeneic to C3Hf/Kam mice. In addition, the therapeutic efficacy of this polyanionic compound against spontaneous lung metastases of NFSa was also determined. Systemic i.v. or i.p. application of MVE-2 in doses ranging from 10 to 50 mg/kg body weight greatly reduced the number of artificial NFSa lung metastases and prolonged the survival of the mice. Multiple injections of MVE-2 given at weekly intervals were more effective than were single treatments. Although various treatment schedules with MVE-2 were capable of reducing the number of metastases and prolonging survival of tumor-bearing mice, no cures were observed. A therapeutic effect was also evident against spontaneous lung metastases of NFSa. The effect, however, was more profound when MVE-2 was given before rather than after surgical removal of the primary tumor. MVE-2 was not effective in mice exposed previously to whole-body or local thoracic irradiation. In contrast, MVE-2 protected mice against enhancement of lung metastases induced by exposure of the mice to these irradiations. NFSa growing i.m. promoted the formation of lung metastases from tumor cells given i.v. This concomitant enhancement of metastases was abolished by treatment of the mice with MVE-2. MVE-2 was also effective against tumor deposits in the other three tumors. The extent of its therapeutic efficacy was independent of tumor immunogenicity. These results suggest several approaches to the clinical application of MVE-2 and provide additional data on the therapeutic activity of the pyran copolymer derivatives in different animal models. (+info)
Maleic vinyl ether activation of murine macrophages against lung-metastasizing tumors.
(21/26)
A 16,500 molecular weight fraction of maleic vinyl ether (MVE-2) induced tumoristatic and tumoricidal activity in peritoneal macrophages of BALB/c and C57BL/6 mice following i.p. administration. Growth of B16 melanoma cells in vitro was inhibited up to 85% by MVE-2-activated, but not resident, peritoneal macrophages. In a tritiated thymidine release assay, B16 melanoma cells, and to a lesser extent Madison 109 lung carcinoma cells, were also sensitive to the cytolytic action of MVE-2-activated peritoneal macrophages. Administration i.v. of MVE-2 resulted in tumoristatic and tumoricidal activity in alveolar macrophages against radiolabeled B16 and Madison 109 lung carcinoma target cells. MVE-2-activated alveolar macrophages significantly inhibited L5178Y lymphoma colony formation following a 48-hr macrophage-tumor cell coincubation. BALB/c mice bearing the lung-metastasizing Madison 109 lung carcinoma footpad tumor were given MVE-2 i.v., using the same dosing regimen that induced alveolar macrophages to be tumoricidal in vitro. Significant increases in life span were observed, suggesting that the antitumor activity of MVE-2 in this tumor system may be mediated by the activation of alveolar macrophages, with a resulting decrease in metastatic growth in the lung. (+info)
Immunomodulatory effect of various molecular-weight maleic anhydride-divinyl ethers and other agents in vivo.
(22/26)
Various molecular-weight maleic anhydride-divinyl ether copolymer polyanions were evaluated in six in vivo systems. Low- and high-molecular-weight MVE's were effective adjuvants with irradiated L1210 tumor cell vaccine. A high percentage of L1210-challenged survivors were refractory to a second challenge of tumor cells. Azimexon and Bacillus Calmette-Guerin were also effective adjuvants, but Bestatin was without adjuvant effect. All the MVE's demonstrated a marginal antitumor effect against the L1210 and LSTRA tumors. The MVW's, regardless of molecular weight differences, were effective in enhancing macrophage tumoricidal activity and retarding the development of M109 tumor growth in the lungs. Enhancement of delayed-type hypersensitivity by all six MVE's indicates their ability to stimulate T-cells. (+info)
Role of macrophages in the immunotherapy of Lewis lung peritoneal carcinomatosis.
(23/26)
The underlying cellular mechanisms for the antitumor effects of biological response modifiers (BRMs) have not been clearly resolved. We have investigated this issue in the Lewis lung (3LL) peritoneal carcinomatosis model in which treatment with the BRM MVE-2 slows tumor growth and enhances survival. MVE-2 is a potent inducer of cytotoxic macrophages (m phi s); however, in the vivo tumoricidal properties of these m phi s remain to be firmly established. To directly establish that m phi s were at least in part responsible for the in vivo efficacy of MVE-2, a novel method of obtaining highly enriched m phi suspensions was developed which gave high purity, satisfactory yield, and excellent viability without affecting antitumor activity. Using the 3LL peritoneal carcinomatosis model and adoptive transfer techniques, we directly demonstrate that the majority of antitumor activity was associated with the adherent cell fraction enriched for m phi s. Histological observations supported this conclusion, indicating that MVE-2 treatment initially activated cells associated with nonspecific immunity, retarding tumor growth in the ascites long enough for a multifaceted immune response to develop. (+info)
Macrophage involvement in the protective effect of pyran copolymer against the Madison lung carcinoma (M109).
(24/26)
Pyran copolymer (NSC 46015) therapy markedly enhanced host resistance to a murine lung carcinoma (M109) implanted s.c. Multiple dose schedules were not significantly better than single doses at increasing lifespan. Although tumor necrosis was much more extensive in the lesions of pyran-treated mice, pyran copolymer was not directly toxic to M109 cells in vitro. A comparative histopathological study revealed an intense histiocytic reaction in the connective tissue surrounding the primary tumor in mice receiving pyran as compared to 0.9% NaCl solution-treated controls. Macrophages were often associated with necrobiotic tumor cells. Morphologically activated macrophages were recovered from pyran-treated animals which potently inhibited DNA synthesis of M109 tumor cells in vitro. This response peaked 6 days after drug treatment and was to a large extent specific for neoplastic cells. Our results from both in vivo and in vitro studies support the concept that pyran enhances host resistance to neoplasia by mobilization and activation of the reticuloendothelial elements of the host's defense. (+info)