Immunomodulating anticancer alkylating drugs: targets and mechanisms of activity.

CY and L-PAM potentiated specific anti-tumor response in addition to their killing effect. The immunomodulating effect of a low dose of either CY or L-PAM was expressed in mice bearing large s.c.

Release of tumor necrosis factor-alpha and prostanoids in whole blood cultures after in vivo exposure to low-dose aspirin.

Background: The preventive effect of low-dose aspirin in cardiovascular disease is generally attributed to its antiplatelet action caused by differential inhibition of platelet cyclooxygenase-1. However, there is evidence that aspirin also affects release of inflammatory cytokines, including tumor necrosis factor-alpha (TNF-alpha). It is not known whether this is caused by direct action on the cytokine pathway or indirectly through cyclooxygenase inhibition and altered prostanoid synthesis, or both.

Use of xenogenized (modified) tumor cells for treatment in experimental tumor and in human neoplasia.

The need to modify tumor cells in order to render them more "immunogenic" was based on the assumption that normal, nonmodified tumor cells are non- or weakly immunogenic and as such are unable to raise an efficient protective immune response. Various methods for "xenogenization" (modification of tumor cells) were suggested: induction of new foreign antigens, treatment with either chemicals or enzymes and use of mutagens. Xenogenized tumor cells by their coupling to proteins, and use of chemicals like DTIC (5-[3,3-dimethyl- 1-triazeno]-imidazole-4-carboxamide), TZC (8-carbamoyl-3-methyl-imidazo[5, 1-d]- 1,2,3,5-tetrazin-4 [3H]-one 8-carbamoyl-3-[2-chloroethyl] imidazole [5,1 -d]- 1,2,3,5-tetrazin-4[3H]-one) and antiemetic drugs, were tested in experimental models of murine leukemia.

Effect of endothelin-1 on alpha-smooth muscle actin expression and on alveolar fibroblasts proliferation in interstitial lung diseases.

Endothelin-1 (ET-1) is a potent constrictor and mitogen peptide which is expressed in several pulmonary diseases. To elucidate the involvement of ET-1 in lung interstitial pathologic events, we assessed ET-1 secretion by alveolar macrophages (AM) and fibroblasts recovered from the bronchoalveolar lavage (BAL) of patients with idiopathic pulmonary fibrosis (IPF), sarcoidosis (SA) and from control subjects. We characterized in vitro alveolar fibroblasts of all subjects using monoclonal antibody specific to alpha-smooth muscle actin (alpha-SM actin) and human fibroblast marker.

Immunopotentiating and immunotherapeutic effects of thymic hormones and factors with special emphasis on thymic humoral factor THF-gamma2.

The essential role played by the thymus in the development of the immune response was well documented in many publications. These findings prompted a long series of studies devised to define the factors produced and secreted by thymus cells, which are involved in the development and nature of immunological responsiveness. First experiments done with crude thymus extracts were followed by isolation of purified products and finally by chemical characterization and synthesis of immunologically active thymus-derived peptides.

THF-gamma 2-mediated reduction of pulmonary metastases and augmentation of immunocompetence in C57BL/6 mice bearing B16-melanoma.

Immunotherapy with the immunomodulating thymic humoral factor-gamma 2 (THF-gamma 2) octapeptide, combined with 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) chemotherapy, will be used for enhancing host immune response to arrest pulmonary metastases of a B16-F10.9 melanoma tumor. In this experimental model of pulmonary metastasis, the highly metastatic B16-F10.

One hundred years of cancer immunotherapy: a critical appraisal.

First attempts of cancer immunotherapy were made approximately 100 years ago on the assumption that tumor cells are recognized as 'foreign' by the immune system. Later on, a whole series of experimental animal tumor models were developed. They included the use of syngeneic tumors, spontaneously arising tumors and human tumor xenografts in immunodeficient mice.

Interleukin-6 and interleukin-6 receptor secretion by chronic lymphatic leukaemia and normal B lymphocytes: effect of PMA and PWM.

Interleukin-6 (IL-6) and soluble interleukin-6 receptor (sIL-6R) were detected in supernatants of cultures of B chronic lymphatic leukaemia (CLL) lymphocytes. Phorbol-12-myristate 13 acetate (PMA) caused a decrease in the levels of IL-6 in 14 out of 16 cultures and an increase in levels of sIL6R in all 15 cases. The effect of pokeweed mitogen (PWM) was variable and not significant.

Cancer immunotherapy: potential involvement of mediators.

The description of a cell-free soluble anti-tumour factor by Carswell et al. in 1975 (Proc Natl Acad Sci USA, 72: 3666-3670) was followed by a long series of experimental and clinical investigations into the role of cell-free mediators in cancer immunotherapy. These investigations included research on the effects of macrophage-derived eicosanoids (cycloxygenase and lipoxygenase derivates of arachidonic acid) and of monokines such as tumour necrosis factor-alpha, interleukin-1 and granulocyte-monocyte-macrophage-colony stimulating factor) and of lymphocyte products: interleukins and interferons.

Inhibition of murine Lewis lung carcinoma metastases by combined chemotherapy and intranasal THF-gamma 2 immunotherapy.

Previous research in our laboratories has shown that the immunoregulatory octapeptide, THF-gamma 2, potentiates the efficacy of anticancer chemotherapy in experimental animal models of local plasmacytoma and repairs drug-induced defects in immunocompetence. The highly metastatic, murine D122 lung carcinoma model has been shown to be useful for evaluating the efficacy of experimental antimetastatic therapeutic modalities. The goal of the present study was to determine whether intranasal thymic humoral factor-gamma 2 (THF-gamma 2) immunotherapy, after a single dose of chemotherapy, could inhibit the development of lung metastases, restore immunocompetence, and increase survival in syngeneic C57BL/6 mice bearing highly metastatic Lewis lung carcinoma (D122) solid footpad tumors.

Cancer immunotherapy: hopes and pitfalls: a review.

Cancer immunotherapy (IT) started approximately 100 years ago with attempts to use a prepared immune serum against osteosarcoma. Since then, IT was attempted by use of various immunopotentiating agents like whole bacterial cells, bacterial cell fractions, cytokines and thymic humoral factors. The therapeutic efficiency of IT alone was limited and erratic.

Secretion of suppressor factors by EBV infected B cell lines.

The infection of human peripheral blood B cells with Epstein-Barr Virus (EBV), induced the production of suppressor factor(s) which were released into the supernatant of the B-cell cultures. The induction of suppressive activity was independent of T-cell presence. The suppression was exhibited both against T-cell activity (MLR and mitogenic stimulation) as well as against B-cell mitogenic stimulation of human or murine B lymphocytes.

Effect of IL-6 on alveolar fibroblast proliferation in interstitial lung diseases.

Alveolar macrophage-fibroblast interaction may be involved in the pathogenesis of interstitial lung diseases (ILD). Herein, we compared IL-6 secretion from alveolar macrophages (AM) and alveolar fibroblasts (AFb) recovered from patients with sarcoidosis (SA) and with diffuse interstitial fibrosis (DIF). Moreover, we evaluated the effect of IL-6 on the in vitro AFb proliferation in both diseases.

Thymic humoral factor-gamma 2 (THF-gamma 2) immunotherapy reduces the metastatic load and restores immunocompetence in 3LL tumor-bearing mice receiving anticancer chemotherapy.

In mice bearing immunogenic tumors, adding thymic humoral factor-gamma 2 (THF-gamma 2)1 immunotherapy as an adjunct to anticancer chemotherapeutic regimens not only potentiates the antitumor activity of each drug but also repairs tumor/chemotherapy-induced damage to T-cell populations and functions. The Lewis lung carcinoma (3LL) is a weakly immunogenic, highly metastatic tumor in C57BL/6 mice. To investigate whether the immunoregulatory octapeptide is also effective against a tumor that does not elicit an antitumor immune response, we assessed the effect of combination THF-gamma 2 immunotherapy and chemotherapy in 3LL-bearing mice.

Induction of macrophage antitumor activity by a mycobacterial fraction. In vivo and in vitro studies.

A Methanol Extraction Residue (MER) of BCG tubercle bacillus induced cytostatic activity in vitro against the murine tumor-cell lines YAC-1 and MOPC-315 in resident murine peritoneal macrophages isolated from BALB/c mice. The induction of antitumor activity was not associated with increase in release of TNF-alpha. Macrophages from mice hyperimmunized with MER (MER 3x) or from mice injected once with MER in aqueous suspension released more PGE2 following stimulation in vitro with LPS.

Modulation of antitumour activity of macrophages by regulation of eicosanoids and cytokine production.

Production and release of arachidonic acid (AA) compounds (eicosanoids: prostaglandins-cyclooxygenase and leukotrienes-lipoxygenase) and monokines (TNF-alpha, IL-1 and others) play an essential role in the expression of antitumour activity of macrophages (MO). We investigated the possibility of inducing the antitumour activity of peritoneal murine and human MO by regulating their production of eicosanoids and monokines. The antitumour activity of MO was inversely correlated to production of PGE2 and directly correlated to production of leukotrienes (LTC4 and LTD4).

Activation in vitro of peritoneal macrophages by a nocardia fraction.

The Nocardia fraction NLD-RB1040 (Nocardia Lysozyme Digest) induced cytostatic activity in vitro against the YAC-1 tumor-cell line, in resident murine peritoneal macrophages isolated from BALB/c mice. The induction of antitumor activity by the Nocardia fraction was not correlated with induced changes in production of TNF alpha, PGE2 or nitrite by human peritoneal macrophages collected from renal patients on Continuous Ambulatory Peritoneal Dialysis (CAPD), or changes in production of TNF a by murine macrophages.

Differential Proliferative Characteristics of Alveolar Fibroblasts in Interstitial Lung Diseases: Regulative Role of IL-1 and PGE(2).

Fibroblasts (Fb) from patients with sarcoidosis (SA) and hypersensitivity pneumonitis (HP) exhibited a lower proliferative capacity compared with Fb obtained from control (CO) and diffuse interstitial fibrosis patients (DIF). Proliferation of Fb from SA or lip patients was suppressed by autologous LPS-stimulated alveolar macrophages (AM) supernatants but not by those from CO patients. Similarly, alveolar macrophages (AM) derived supernatant, obtained from CO, did not suppress the proliferation of SA and HP Fb.

Therapeutical effect of activated human macrophages on a human tumor line growing in nude mice.

Human peritoneal macrophages were collected from dialysis bags of renal patients on Continuous Ambulatory Peritoneal Dialysis (CAPD), during an inflammation-free period. The macrophage suspension was cultured in presence of bacterial lipopolysaccharide (LPS) and phorbol myristate acetate (TPA). The cultured macrophages were tested for therapeutic effectiveness against a human tumor-cell line, RC43, implanted subcutaneously in NMRI nude mice.

Involvement of inflammatory mediators in macrophage antitumor activity.

This review describes the potential role of macrophages in defense against cancer cells and the regulatory involvement of inflammatory mediators in this role. Interactions between macrophage-derived cytokines (tumor necrosis factor alpha, interleukin-1, IL-6) and their interrelationships with eicosanoids (mainly the cyclooxygenase product prostaglandin E2 and some lipoxygenase metabolites) represent a network that controls the expression of antitumor activity of macrophages either in a cell-to-cell contact system between the effector and the target tumor cell or as cell-free soluble products. Attention is given to the influence of tumor burden on production of cytokines and eicosanoids by macrophages and to the production of these mediators by tumor cells.

Release of immunosuppressive factor(s) by MOPC-315 murine plasmacytoma cells: a possible mechanism of defence.

Supernatants were collected from suspensions of MOPC-315 tumor cells harvested from ascitic tumors and kept for 24 hours in culture medium and from cultures of an MOPC-315 tumor-cell kept for a long period of time in vitro. The MOPC-315 supernatants were tested for immunosuppression of mitogenic stimulation of BALB/c spleen cells by ConA or LPS, of allogeneic response of effector BALB/c spleen cells against target C57BL spleen cells, of generation of antibody response against SRBC and of induction of LAK activity. The immunosuppression was marked in all the test systems, was not related to secretion of either C-type particles or of anti-TNP antibodies and was also induced by MOPC-315 tumor cells kept in serum-free medium.

Asialo-positive cells are overexpressed whereas IL-2 induced LAK activity is impaired in mice hyperimmunized with an immunomodulating mycobacterial fraction.

Previously reported studies revealed that extensive immunization with the Methanol Extraction Residue (MER) of BCG tubercle bacillus in Incomplete Freund's Adjuvant (IFA) induced marked suppression of T and B cell functions and that immunosuppression was correlated with marked decrease in splenic T-cell population and marked increase in the splenic macrophage population. The purpose of the present work was to determine if extensive immunization with MER in IFA also induced changes in splenic asialo antigen positive (NK) population and in the potential of induction of splenic LAK activity in vitro by recombinant IL-2. By comparison with other test groups, namely mice injected with IFA only, injected once with MER in aqueous suspension and normal, untreated mice, hyperimmunization with MER resulted in marked increase in expression of asialo positive (NK) splenic cells whereas induction of splenic LAK activity by IL-2 was markedly depressed.

Suppressive mechanisms of alveolar macrophages in interstitial lung diseases: role of soluble factors and cell-to-cell contact.

Alveolar macrophages (AMs) from patients with interstitial lung diseases, such as sarcoidosis and idiopathic pulmonary fibrosis, suppress the phytohaemagglutinin (PHA) stimulation of autologous peripheral lymphocytes. The aim of this study was to determine whether the suppressive effect of alveolar macrophages of patients with interstitial lung disease is due, not only to the secretion of soluble factors prostaglandin E2 (PGE2), interleukin-1 (IL-1) but is also correlated to a direct effect of AMs on the expression of IL-2 receptors (IL-2R: CD25) and on the induction of IL-2 activity. We studied 26 subjects, 8 with sarcoidosis, 7 with idiopathic pulmonary fibrosis, and 11 controls.

Activity of human peritoneal macrophages against a human tumor: role of tumor necrosis factor-alpha, PGE2 and nitrite, in vitro studies.

Human peritoneal macrophages collected from renal patients on continuous ambulatory peritoneal dialysis (CAPD) during inflammation-free periods were induced to express antitumor activity in vitro when cultured in the presence of bacterial lipopolysaccharide (LPS) and even more activity when they were kept in the presence of LPS + IND (indomethacin). The antitumor activity was expressed against a human tumor-cell line, RC43, either in a cell-to-cell contact set-up between the macrophages and the RC43 target cells or when the tumor cells were exposed to supernatants of the cultured macrophages. The antitumor activity of macrophages was correlated to a marked increase in production of tumor necrosis factor-alpha (TNF alpha), not correlated to an increase in nitrite production and inversely correlated to the production of PGE2.

Protective effect of diclofenac sodium against endotoxic shock in anaesthetized pigs.

The effect of diclofenac sodium was investigated on haemodynamics, haematologic and blood glucose values as well as the release of eicosanoids, tumor necrosis factor (TNF) and platelet activating factor (PAF) in anaesthetized pigs receiving 5 micrograms.kg-1 Escherichia coli lipopolysaccharide (LPS) over 60 min into the superior mesenteric artery. The animals were observed for an additional period of 2 h after the termination of LPS infusion.