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Biomedical subjects

M A Chirigos

Publications and source records attributed to M A Chirigos.

At least 37 records · Page 2Linked to original sources
PubMed1987

Cell regulatory and immunorestorative activity of picibanil (OK432).

Picibanil (OK432), a pharmaceutical preparation of a low virulent Su strain of Streptococcus pyogenes, possesses cell regulatory activity particularly in its ability to augment natural killer (NK) cell activity and to activate macrophages to exert a tumoricidal effect both in vitro and in vivo. It is effective in retarding and/or inhibiting the growth of three different tumors: MBL-2 lymphoma, M109 alveolar adenocarcinoma, and B16 melanoma. The antitumor effect is mediated through regulation of NK cells and macrophages, possibly by its ability to stimulate the production and secretion of interferon and interleukin 1 and 2. It is a very effective adjuvant for tumor cell vaccines that elicit cytotoxic T-cell responses. Following cytoreductive chemotherapy (Cytoxan) Picibanil treatment leads to an earlier reconstitution of both bone marrow cellularity and differentiation to granulocyte-macrophage colonies.

Animals↗
PubMed1987

Immune response by biological response modifiers.

Several biological response modifiers (BRMs) were demonstrated to increase myelopoiesis and effector cell responses (M phi and natural killer cell activity) in vivo. The increased myelopoiesis was reflected by an increase in bone marrow cellularity and granulocyte-M phi colony-forming cells (GM-CFU-C). The increase in myelopoiesis appeared to be related to a concomitant increase in colony-stimulated factor (CSF) production and secretion by M phi and bone marrow cells. CSF induction by BRMs increased myelopoiesis and counteracted the myelosuppressive and immunosuppressive effects of cyclophosphamide. CSF induced in vivo by BRMs attained high titers and were maintained over a longer period than exogenously injected CSF, which was rapidly cleared from serum.

Adjuvants, Immunologic↗
PubMed1986

Biological response modifiers: regulators of the cellular immune system and adjuvants in antitumor therapy.

Pharmacokinetic studies of five biological response modifiers (BRMs) show diverse regulator functions on effector cell responses and a capacity to cause the secretion of specific soluble factors. Of the five BRMs tested, MVE-2, Poly ICLC, OK-432, and alpha beta IFN were capable of stimulating both natural killer (NK) cell and macrophage (M phi) tumoricidal activity, whereas BM 41-332 augmented only NK cells. Following one treatment with the aforementioned BRMs, M phi activity remained elevated for a longer period (10-14 days) than did NK cell activity (6-9 days). Of particular interest, multiple treatment with BRMs led to a downregulation of NK cell activity (hyporesponsiveness). Three soluble secretory products were induced by these BRMs (colony stimulating factor, CSF; prostaglandin E, PGE; and interferon, IFN). Treatment with MVE-2 and Poly ICLC led to a significant increase in bone marrow cellularity and GM-CFV-C. Results of studies with the cyclo-oxygense-inhibited indomethacin indicate that CSF and PGE are produced and/or secreted by different cellular mechanisms. The depression of effector cells (NK, bone marrow, and GM-CFU-C), as the result of cyto-reductive treatment with cyclophosphamide, could be reversed by treatment with MVE-2. A significantly earlier time to recovery of these effector cells was achieved following MVE-treatment. When MVE-2 was used as an adjuvant to initial tumor cyto-reductive chemotherapy, more successful antitumor response was achieved, indicating that MVE-2 functioned to elevate a substantial effector cell response as well as reconstituting bone marrow cellularity.

Adjuvants, Immunologic↗
PubMed1986

[Protein deficiency, host defense and natural anti-tumor immunity].

Natural immuneffector cells, namely natural killer cells and monocyte/macrophages, have become in recent years an important part of theory and practice of immunotherapy. This is especially the case for therapy of malignant tumors with biological response modifiers (BRMs). Many BRMs increase cytotoxicity against tumor cells and cell numbers of natural immuneffector cells. Protein depletion on the other hand, which often is part of malignant diseases, results in well known negative effects on acquired and specific immunity. The data which are presented here show that depressions of natural immuneffector cells in terms of cytotoxicity and cell numbers also occur after protein depletion. The same is true for their pool, the bone marrow. The potentials of BRM therapy are considerably decreased. Host defense mechanisms in normal and protein depleted nutritional status, immunological tumor defense and BRM therapy are presented in the survey.

Adjuvants, Immunologic↗
PubMed1985

Secretion of colony-stimulating factors by human monocytes and bone marrow cells after in vitro treatment with biological response modifiers.

The results of this study indicate that human interferons (hIFNs) may have bimodal effects in vitro on human myelopoiesis. Low concentrations of hIFN alpha (1-10 U/ml), hIFN beta (1-100 U/ml), and hIFN gamma (1 U/ml) stimulated in vitro increased secretion of colony-stimulating factors (CSF) by human blood monocytes, which induced growth and differentiation of granulocyte-macrophage progenitor cells. High concentrations of hIFNs alpha, beta, gamma (greater than 100 U/ml), however, had direct antiproliferative effects on granulocyte-macrophage progenitors. Both effects could be blocked by monoclonal antibodies against hIFN alpha and hIFN gamma, as well as by heteroantiserum against hIFN beta. Human IFNs did not appear to be involved in mediating the response to the chemically defined biological response modifiers (BRMs) poly ICLC (polyriboinosinic-polycytidylic acid poly-L-lysine) and BM 41.332 (2-cyano-1-[(2-methoxy-6-methyl-pyridin-3yl)-methyl]-aziridine), since neutralizing antibodies against the human IFNs (anti-IFN alpha, beta, gamma) did not block the poly ICLC and BM 41.332-induced secretion of CSF by human blood monocytes. In contrast to hIFNs, poly ICLC and BM 41.332 also stimulated adherent human mononuclear bone marrow cells to secrete CSF, which induced growth and differentiation of nonadherent granulocyte-macrophage progenitors. The studies presented here thus support the concept that selected BRMs might be useful to stimulate in vivo secretion of myelopoietic growth factors and thereby promote granulocyte and monocyte/macrophage functions.

Antigen-Antibody Complex↗
PubMed1985

Development of hyporesponsiveness of natural killer cells to augmentation of activity after multiple treatments with biological response modifiers.

Four biological response modifiers (BRMs), MVE-2 (maleic anhydride divinyl ether), Corynebacterium parvum (C. Parvum), PolyICLC (polyinosinic:polycytidylic acid stabilized with poly-L-lysine), and mouse alpha beta-interferon (alpha beta-IFN), were tested to assess whether repeated treatments would repeatedly induce or sustain augmented levels of natural killer (NK) cell activity and/or macrophage (M0)-mediated inhibition of tumor cell growth. In contrast to a significant increase in splenic NK activity obtained with a single treatment with each of the agents, multiple treatments with these BRMs led to a progressive decrease in the degree of augmentation of NK activity. In contrast, multiple injections with these agents resulted in sustained augmentation of M0-mediated reactivity. Separation of the spleen cells by Percoll discontinuous density gradient centrifugation indicated that with mice treated once with each BRM high levels of NK activity were detected in the lower density fractions and that these fractions contained a higher percentage of large granular lymphocytes (LGLs) than that found in comparable fractions from normal mice. In contrast, cells in the lower density fractions from mice that received multiple treatments had decreased NK activity and an appreciably lower proportion of LGLs. These results indicate that the development of hyporesponsiveness to augmentation of splenic NK-cell activity following multiple treatments with BRMs may be attributable to a decreased percentage of LGLs, the effector cell population responsible for NK cell-mediated cytotoxicity.

Animals↗
PubMed1985

Effects of protein depletion on NK cell cytotoxicity and bone marrow cellularity.

Tumor bearing patients have repeatedly been shown to develop states of protein (PD). PD has frequently been associated with depression of acquired immunity. In contrast, little is known about the effects of PD on natural killer (NK) cell cytotoxicity and on bone marrow cellularity and how modulation of these parameters by maleic anhydride divinyl ether copolymer (MVE-2) would be affected. BALB/c mice 6-10 weeks old were fed normal diets (18% protein) (ND mice) or protein deficient isocaloric diets (PD mice) for 35 days. On days 5, 9, 15, 23, and 35 assays were performed. Three days prior to each assay day, some groups received MVE-2 i.p. In PD mice spontaneous NK activity was reduced by some 80%. After MVE-2 the levels only rose to half the amount of activity of ND mice, although in both groups an increase of NK activity took place. BMC levels of PD mice were also strongly decreased. After MVE-2, increases of BMC in PD mice were quite weak and did not reach the level of normal unstimulated BMC. In PD mice we found body weight loss of 46%, reduction in albumin and total protein of 22% and complete disappearance of prealbumin after 5 days of diets. Preliminary results indicate that repletion with amino acids (NeoAminomel L12.5 o.K.H. Salvia, Boehringer Mannheim Co.) is able restore NK activities and BMC levels.

Animals↗
PubMed1985

Development of hyporesponsiveness to augmentation of natural killer cell activity after multiple doses of maleic anhydride divinyl ether: association with decreased numbers of large granular lymphocytes.

A single injection of mice with maleic anhydride divinyl ether (MVE-2) resulted in significantly augmented natural killer (NK) activity. However, multiple injections with MVE-2 led to a hyporesponsive to boosting of NK activity. Stimulation of prostaglandin E secretion of induction of suppressor macrophages (M phi) or lymphocytes were shown not to be responsible for the depressed NK cell responses. Rather the hyporesponsiveness to NK boosting was associated with a decreased number of large granular lymphocytes (LGLs). Percoll discontinuous-density-gradient studies showed that the augmented NK activity of spleen cells after a single injection with MVE-2 was associated with an increase in the percentage of LGLs in the lower-density fractions (Fraction 1 and 2). In contrast, the NK activity and percentage of LGLs in the lower-density fractions were markedly decreased after multiple injections with MVE-2. Polyinosinic: polycytidylic acid stabilized with poly(L-lysine) in carboxymethylcellulose, another BRM capable of augmenting NK activity, was able to substantially augment NK activity in mice hyporesponsive to MVE-2 and this was accompanied by an increase in the percentage of LGLs in the lower-density Percoll fractions.

Animals↗
PubMed1985

Modulation of myelopoiesis by CSF or CSF-inducing biological response modifiers.

We have compared the effects on number and function of bone marrow progenitors and peripheral effector cells of the myelomonocytic lineage of treatment with the 2-cyanaziridine compounds Azimexone and BM 41.332 to those of maleic anhydride divinyl ether copolymer (MVE-2) or granulocyte-macrophage colony stimulation factor (GM-CSF). Within a few hours after i.p. injection of either Azimexone or BM 41.332, there was a dose-dependent increase in serum CSF levels, CSF secretion by mononuclear bone marrow cells (BMC) and macrophages (M phi), which was followed by an increase in granulocyte-M phi committed stem cells (GM-CFU-C), nucleated BMC, and peripheral blood leukocytes. Optimal effects occurred 3 days after 50 mg/kg Azimexone or 25 mg/kg BM 41.332. Three i.p. injections of 50 mg/kg Azimexone into mice pretreated with cyclophosphamide (CY) (150 mg/kg) were able to significantly restore suppressed bone marrow cellularity (GM-CFU-C and nucleated BMC). Azimexone also increased the number of peripheral M phi in normal or CY-treated mice, without inducing detectable tumoricidal activity. These M phi, however, retained their capacity to become fully activated (cytotoxic) by appropriate activation signals such as IFN or LPS. Analogous to the 2-cyanaziridines. MVE-2 (at 25 mg/kg) had similar stimulatory effects on myeloid functions in normal mice. MVE-2 induced, in addition, a significant augmentation of cytoxicity by both M phi and NK cells. In contrast, single or multiple injections of semipurified GM-CSF into normal mice (1000 U or 5000 U per mouse) failed to detectably stimulate myelopoietic growth and differentiation. 2-cyanaziridine compounds thus offer the potential of selectively augmenting growth and differentiation of myelomonocytic cells in normal and bone marrow-depressed mice without appreciably affecting their immunological status.

Adjuvants, Immunologic↗
PubMed1985

Therapy of peritoneal murine cancer with biological response modifiers.

We have used a murine renal adenocarcinoma of spontaneous origin (Renca) inplanted in the peritoneal cavity to study the therapeutic potential of biological response modifiers (BRMs) used alone or in conjunction with chemotherapy. This tumor model is therapeutically challenging since following intraperitoneal (i.p.) injection, the tumor grows progressively with hemorrhagic ascites, abdominal metastases to lymph nodes, liver, spleen, most serous membranes, and, in some animals, metastases to extra-abdominal sites (lungs). In the absence of therapy, death invariably occurs within 36 +/- 2 days. The tumor is efficiently lysed in 4 hours by peritoneal cells isolated from mice treated with BRMs. Both MVE-2 and rIL-2 significantly increased the survival time of tumor-bearing mice, but only treatment with MVE-2 led to definite cures of i.p. Renca. A single i.p. injection of MVE-2 cured 20% of the tumor-bearing mice, while repeated i.p. administration of this drug at 12 day intervals cured 70% of i.p. Renca-bearing mice. Combined therapy with doxorubicin hydrochloride and a single dose of MVE-2 cured 90% of tumor-bearing animals. The superior therapeutic efficiency of MVE-2 compared to that of the rIL-2 may be due to its ability, after i.p. inoculation, to generate and maintain high levels of cytotoxic effector cell activity for an elevated period of time within the peritoneal cell population. Additionally, MVE-2 augments effector cell activity in the liver, lungs, spleen, and blood and may therefore more efficiently interfere with metastasis formation in those compartments. The additive effects of MVE-2 and the chemotherapeutic agent suggest that more effective therapy may be achieved by the combination of immunotherapy with BRMs with chemotherapeutic drugs.

Adenocarcinoma↗
PubMed1985

Hyporesponsiveness to augmentation of murine natural killer cell activity in different anatomical compartments by multiple injections of various immunomodulators including recombinant interferons and interleukin 2.

Augmentation of natural killer (NK) cell activity has been observed after the single administration of a wide variety of biological response modifiers (BRM); however, multiple injections of BRM have resulted in hyporesponsiveness to NK augmentation in both preclinical and clinical studies. In these studies, hyporesponsiveness to augmentation of NK cell activity occurred after multiple injections of interferon (IFN recombinant human IFN-alpha A/D and recombinant IFN-gamma) and interleukin 2 and was found to be systemic (lungs, liver, blood, and spleen). In contrast, hyporesponsiveness to augmentation by multiple injections of maleicanhydride divinyl ether (MVE-2) or Propionibacterium acnes was limited to the spleen and peripheral blood lymphocytes, with continued augmentation of NK cell activity in the peritoneum, lungs, and liver. Despite the hyporesponsiveness to augmentation of NK activity by multiple IFN injections, NK activity could still be augmented by a single injection of another BRM. The NK cell hyporesponsiveness induced in the spleen by MVE-2 was also reversed by a single administration of IFN or polyinosinic-polycytidylic and poly-L-lysine solubilized by carboxymethyl cellulose but not by OK-432 or P. acnes. These results demonstrate that the nature of the hyporesponsiveness to NK augmentation, which is induced by multiple treatments with BRM, varies with the type of agent. The noncytokine BRM that were studied induced hyporesponsiveness only in specific lymphoid compartments but not in major nonlymphoid organs, whereas cytokine BRM induced a systemic hyporesponsiveness. The hyporesponsive state induced by the different types of BRM, also varied in regard to the pattern of susceptibility to augmentation of NK activity by unrelated BRM.

Adjuvants, Immunologic↗
PubMed1985

Immunomodulatory effects in mice of polyinosinic-polycytidylic acid complexed with poly-L-lysine and carboxymethylcellulose.

In this report, we describe the immunomodulatory characteristics of poly(I,C)-LC, a synthetic, double-stranded nucleic acid polymer, polyinosinic-polycytidylic acid, that is complexed with poly-L-lysine and solubilized by the addition of carboxymethylcellulose. We consistently observed, both in vitro and in vivo, stimulation of macrophage cytotoxicity and augmentation of natural killer-cell activity by poly(I,C)-LC. This immunomodulator also increased the allogeneic mixed-lymphocyte response, without any blastogenic effect on responder cells cultured in the absence of allogeneic stimulator cells. Further, the addition of poly(I,C)-LC to an allogeneic mixed-lymphocyte tumor reaction did not stimulate the development of cytotoxic effector T-cells. Poly(I,C)-LC did, however, have adjuvant activity when admixed with irradiated tumor cells in the immunization of syngeneic mice. Unlike classic adjuvants, poly(I,C)-LC also enhanced the development of specific cytotoxic T-lymphocytes when it was injected either i.v. or i.p. in conjunction with a vaccine delivered at an intradermal site. The results indicate that poly(I,C)-LC has considerable potential as an immunotherapeutic agent, with the ability not only to induce macrophage and NK cell activation but also to stimulate specific cytotoxic T-lymphocytes.

Adjuvants, Immunologic↗
PubMed1985

In vivo modulation of myelopoiesis and immune functions by maleic anhydride divinyl ether copolymer (MVE-2) in tumor-free and MBL-2 tumor-bearing mice treated with cyclophosphamide.

Treatment of normal or MBL-2 tumor-bearing mice with cyclophosphamide (CY) caused severe suppression of myelopoiesis and macrophage (M phi) functions, both of which may limit further use of chemotherapy. Additional treatment with the chemically defined biological response modifier maleic anhydride divinyl ether copolymer (MVE-2) was able to ameliorate the myelosuppressive effects of CY and to restore normal bone marrow cellularity. The stimulatory effects on myelopoiesis, however, could only be obtained by administering MVE-2 at greater than or equal to 3 days after CY, which correlated with an MVE-2-induced simultaneous increase in granulocyte and/or macrophage colony-stimulating factor secretion by bone marrow cells or M phi. Injection of MBL-2 tumor-bearing mice with MVE-2, at 3 days after Cy treatment, caused a decrease in tumor burden and a significant increase in median survival time as compared to treatment with CY alone. At the same time, MVE-2 induced an increase in the number of cytotoxic M phi and a complete restoration within the myelopoietic lineage, which might prevent delayed side effects of CY, such as secondary infections, and might permit more intensive chemotherapeutic treatment. Treatment of MBL-2 tumor-bearing mice with MVE-2, at 6 days after CY, induced a significant increase in M phi cytotoxicity but did not prolong median survival time, probably due to a rapid regrowth of tumor after treatment with CY. Our studies thus show that successful combined therapy with the primary cytotoxic agent CY and the biological response modifier MVE-2 depends on precise timing of the drug regimen and is influenced by the extent and reversibility of CY-induced immunosuppression, as well as by the kinetics of recruitment of new effector cells from bone marrow and by the tumor burden present at the time of treatment.

Animals↗
PubMed1985

Effects of poly(I,C)-LC on growth and differentiation of normal and malignant myelopoietic progenitor cells.

Polyriboinosinic-polycytidylic acid with poly-L-lysine stabilized with carboxymethylcellulose [poly(I,C)-LC] augmented, in a dose- and time-dependent manner, secretion of colony-stimulating factor (CSF) by peritoneal macrophages (M phi) and bone marrow cells (BMC). Optimal effects were found after 2 days of in vitro culture of the cells with 50 micrograms/ml of poly(I,C)-LC or 14 h to 3 days after a single intraperitoneal injection of 1-2 mg/kg of poly(I,C)-LC into normal mice. The increase in CSF secretion by M phi and BMC was paralleled in vivo by an increase in serum CSF levels, followed by a rise in committed granulocyte and M phi progenitor cells (GM-CFU-C), nucleated BMC, and blood leukocytes of myelomonocytic origin. Poly(I,C)-LC at doses greater than 4 mg/kg, however, were strongly myelosuppressive. In vitro treatment of undifferentiated myelomonocytic leukemia cells from the WEHI-3B cell line with 10-1,000 micrograms/ml of poly(I,C)-LC resulted in a significant increase in CSF secretion by the leukemic cells and a concomitant inhibition of their proliferation. Incubation of cells from the WEHI-3B D+ subline, which differentiate in response to GM-CSF or G-CSF, with 50-100 micrograms/ml poly(I,C)-LC in agar cultures induced in approximately 45% of the leukemic colonies a differentiation into granulocytes and/or M phi. Poly(I,C)-LC, however, had no effect on differentiation of cells from the CSF unresponsive WEHI-3B D- subline. The CSF-inducing biological response modifier poly(I,C)-LC thus has the potential to stimulate growth and differentiation of normal, as well as differentiation of malignant myelopoietic progenitor cells.

Animals↗
PubMed1985

Role of organ-associated NK cells in decreased formation of experimental metastases in lung and liver.

Mice treated with anti-asialo GM1 (asGM1) serum exhibited increased formation of experimental metastases in lung and liver after i.v. challenge with B16 melanoma or Lewis lung carcinoma. This increased metastasis formation coincided with decreased splenic NK activity and increased survival of i.v. injected radiolabeled tumor cells. In contrast, the injection of mice with the pyran copolymer maleic anhydride divinyl ether (MVE-2) augmented NK activity in the spleen and significantly depressed the formation of experimental metastases in the lungs and liver. However, a single or double administration of anti-asGM1 antiserum to MVE-2-pretreated mice failed to inhibit the immunoprophylaxis associated with MVE-2 administration, although it did decrease splenic NK activity and also increased the survival of i.v.-injected radiolabeled tumor cells. To address the mechanism for this dichotomy, we examined NK activity not only in the spleen but also in the blood, lungs, and livers of MVE-2-treated mice. Levels of NK activity in the lungs and liver were several-fold higher than those observed in spleen and blood. However, MVE-2-augmented NK activity in lung and liver was more resistant to depletion by the standard regimen of anti-asGM1 treatment than was NK activity in blood and spleen, and required two high-dose administrations of a higher titered antiserum for depletion of the augmented response. This high-dose regimen removed all detectable NK activity from the lung and liver, and concomitantly eliminated the metastasis-inhibiting effect of MVE-2. These data are consistent with a role for organ-associated NK cells in inhibiting metastasis formation during the extravasation and/or early postextravasation phases of the metastatic process. The results also suggest that biologic effects of NK activity in spleen and blood can be dissociated from those mediated by NK activity in other organs by use of different treatment regimens with anti-asGM1 serum. Finally, because NK activity in target organs can be augmented to an even greater extent than in the blood and spleen by at least some biologic response modifiers (BRMs), organ-associated NK activity should be considered as a possible mechanism for the therapeutic effects of BRM treatment.

Animals↗
PubMed1985

Pharmacokinetic and therapeutic activity of polyinosinic-polycytidylic acid stabilized with poly-L-lysine in carboxymethylcellulose [poly(I,C)-LC].

Polyinosinic-polycytidylic acid stabilized with poly-L-lysine in carboxymethylcellulose [poly(I,C)-LC] significantly augmented natural killer (NK) cell activity in several tissues. Macrophage (M phi) tumoricidal activity was also markedly increased. Both effector cells were active for 9 days. Poly(I,C)-LC also increased effector cell response in vitro. Injections of poly(I,C)-LC resulted in elevated effector cell responses in four of five routes tested. Treatment with poly(I,C)-LC led to an earlier reconstitution of bone marrow cells, NK cell activity, and M phi effector cell activity in mice pretreated with cyclophosphamide (Cytoxan). Combined treatment of MBL-2 tumor cells with cytoreductive chemotherapy and poly(I,C)-LC resulted in an enhanced therapeutic response.

Animals↗