Antitumoral effects of lipids A, clinical studies.

Cancer remains the second leading cause of death, after cardiovascular diseases, in industrialized countries. The first goal to achieve is to prevent cancer occurrence or to diagnose it at an early and curable stage. Some screening strategies have been developed, with controversies across countries, for several cancer type; colorectal, breasts or prostate cancer for example.

Lipid A in cancer therapies preclinical results.

Studies in animal models showed that the antitumoral effect of LPS and of their biologically active moiety, lipid A, is indirect and relies on the induction of an immune response both innate and specific, leading to cytokine production. They also affect tumor development by inhibiting tumor blood flow and induce necrosis as well as apoptosis of tumor cells. Lipids A have been tested in animals, either alone or as adjuvant in therapeutic vaccines.

[To stimulate or to inhibit nitric oxide production in mammary tumors?].

NO is a molecule produced in different amounts by two types of enzymes, constitutive NO-synthases and inducible NO-synthase, the last one produce large amount of NO. In tumor outcome, its role may be either beneficial or detrimental due to its actions in the different steps of tumor growth and metastasis. This review deals with mammary tumors and the mechanisms lying behind NO effects.

Arginase activity is inhibited by L-NAME, both in vitro and in vivo.

The present study investigated the ability of the arginine analog L-NAME (N(omega)-Nitro-L-arginine methyl ester) to modulate the activity of arginase. L-NAME inhibited the activity of arginase in lysates from rat colon cancer cells and liver. It also inhibited the arginase activity of tumor cells in culture.

Mechanisms of the antitumoral effect of lipid A.

Bacterial lipopolysaccharide (LPS) and its active component, lipid A, have been used either alone or as adjuvant in therapeutic anticancer vaccines. Lipid A induces various transcription factors via intracellular signaling cascades initiated by their receptor CD14-TLR4. These events lead to the synthesis of cytokines, which either have direct cytotoxic effect or stimulate the immune system.

Nitric oxide inhibits proliferation but increases life-span of T lymphocytes in tumour-bearing rats.

Nitric oxide (NO) has been shown to inhibit the proliferation of lymphocytes. However, in tumour-bearing rats treated with the immunomodulator OM 163, the regressing nodules were heavily infiltrated by T lymphocytes, although they contained high levels of NO. We show here that NO, while inhibiting the proliferation of lymphocytes, increased their life-span, pointing to the ambivalence of this molecule in the course of tumour growth and regression.

IL-13 restores an in vitro specific cytolytic response of spleen cells from tumor-bearing rats.

In a model of colon cancer, spleen cells from tumor-bearing rats are neither cytotoxic nor proliferative in vitro in the presence of tumor cells. Interleukin-13 (IL-13) induced an in vitro cytolytic activity of spleen cells from tumor-bearing rats in response to the tumor they bore, but had no effect on spleen cells from normal rats. This cytotoxic response was dependent on both adherent and non- adherent cells, involving both an antigen-presenting activity that was enhanced by IL-13 and a cytolytic activity of lymphocytes.

Interleukin-8 antitumour effect is associated with a local infiltration but not with a systemic activation of T lymphocytes.

In a model of colon cancer in rats (peritoneal carcinomatosis), IL-8 was found to have a highly reproducible antitumoural effect. During IL-8-induced tumour regression the infiltration of nodules by CD4+ T lymphocytes was enhanced. However, splenic lymphocytes did not proliferate in response to tumour cells in vitro.

CD4+ T cells recovered from a mixed immune lymphocyte-tumor cell culture induce thymidine incorporation by naive rat lymphocytes in response to tumor cells.

Spleen cells from tumor-immune rats incorporate thymidine when co-cultured for 4 days with syngeneic cancer cells. Non-adherent cells, recovered from a 7-day mixed culture with cancer cells, had lost their capacity for incorporating thymidine when exposed again to the same tumor cells; however, in these conditions, the non-adherent cells induce thymidine incorporation by fresh naive spleen cells. This response is restricted to tumor lines which originate from the same tumor as the cells used for immunization and is due to memory and/or activated CD45RC- CD4+ T cells.

Interleukin-8 has antitumor effects in the rat which are not associated with polymorphonuclear leukocyte cytotoxicity.

The antitumor effect of lipopolysaccharides (LPS) has been observed in several experimental models and is likely to be mediated by macrophages. Stimulation of macrophages with LPS results in the release of several cytokines, including tumor necrosis factor, interleukin-1 and neutrophil-activating peptide-1/interleukin-8 (IL-8), which activates polymorphonuclear leukocytes (PMN) in vitro. Since PMN have an antitumor activity, we tested the in vivo effect of IL-8 on the growth of peritoneal carcinomatoses induced by PROb colon cancer cells in syngeneic rats.

In vivo and in vitro reactivity of rat spleen cells against regressor and progressor colon-cancer cell variants.

Previous reports demonstrated that progressor and regressor tumor-cell variants isolated from the same colon carcinoma chemically induced in a BD-IX rat differed in their capacity to induce an immune response. The present study was aimed at analyzing the characteristics of the responses to the regressor REGb and progressor PROb clones. Spleen cells from rats bearing early REGb tumors neutralized PROb cell tumorigenicity in a Winn-type local transfer assay, but responded occasionally to REGb and PROb cells in vitro.

Influence of the injection site on the tumorigenicity of a cloned colon tumor cell line in the rat.

The cloned DHD/K12/TSb line obtained from a chemically-induced rat colon carcinoma, presents tumors which always regress when injected subcutaneously to the syngeneic animal. This study reports that an intraperitoneal injection of the DHD/K12/TSb cells induces a progressive carcinomatosis in a high proportion of the syngeneic rats. This result underlines the effect that the local environment has on tumorigenicity.

Mechanism of the cytostasis mediated by blood unstimulated neutrophils on syngeneic rat colon cancer cells.

Non-activated polymorphonuclear neutrophils (PMNs) isolated from the blood of non-stimulated rats were spontaneously and selectively cytostatic in vitro against a syngeneic colon cancer cell line. In this experimental model, the mechanism of PMN-mediated cytostasis did not depend on oxidative metabolites, but involved soluble factor(s), possibly granule proteases.

Non-activated rat neutrophils kill syngeneic colon tumor cells by the release of a low molecular weight factor.

The mechanisms of cancer cell destruction by unelicited peripheral blood neutrophils has never been reported in a syngeneic model. We demonstrated that in vitro, unelicited polymorphonuclear neutrophils isolated from rat blood were toxic against syngeneic colon cancer cells. The tumor cell lysis was not due to oxygen metabolites released by PMNs, but was due to a cytolytic factor.

Involvement of effector cells in the treatment with endotoxins of peritoneal carcinomatosis induced by colon tumour cells.

Peritoneal carcinomatoses, an ordinary way for human colon carcinoma to spread, are incurable. When rat peritoneal carcinomatoses of colon origin were treated with endotoxins i.p.

Comparative effect of rat and fetal calf serum on measurement of the natural tumoricidal activity of rat lymphocytes, macrophages and polymorphonuclear cells.

The effect of rat serum versus fetal calf serum on the in vitro natural cytolytic activity of rat lymphocytes, macrophages and polymorphonuclear cells against syngeneic tumour cells was compared. The cytolysis level mediated by the three varieties of effector cells was lower when rat serum was used instead of fetal calf serum to supplement the culture medium. This could explain in part the discrepancies found between in vitro and in vivo studies.

Correlation between the synergistic effect of liposomes and endotoxins on the activation of macrophage tumoricidal activity and the effect of liposomes on the rough endoplasmic reticulum of macrophages.

Treatment of resident peritoneal macrophages of rats with small unilamellar vesicles of dipalmitoylphosphatidylcholine (DPPC SUV) potentiated their activation for tumor cell lysis by endotoxins. The fluorescence polarization of diphenylhexatriene (DPH) embedded in rough endoplasmic reticulum membranes isolated from DPPC SUV-treated macrophages was enhanced. The average fluorescence lifetime of DPH and the rotational correlation time deduced from anisotropy decay were unchanged, whereas the residual anisotropy and hence the order parameter were increased.

In vivo and in vitro effects of fish-containing diets on colon tumour cells in rats.

Polyunsaturated n-3 fatty acids, abundant in sea fish, can inhibit the growth of chemoinduced or transplanted mammary tumours in the rat. Since mammary and colonic cancers have both been linked to a high fat consumption, we studied the effect of 2 diets moderately (7% fish meal) or strongly (9% fish oil) enriched in fish fatty acids on the growth of colon cancer cells subcutaneously inoculated into syngeneic rats. The diets had no effect on the in vivo tumor growth and on the in vitro tumouricidal activity of peritoneal macrophages or splenic lymphocytes.

Differential sensitivity to natural cell-mediated cytotoxicity of two rat colon adenocarcinoma variants differing in their tumorigenicity: identification of the effector cells as natural killer cells.

DHD/K12 TRb (PROb) and DHD/K12 TSb (REGb) are two cancer cell variants originating from the same rat colon adenocarcinoma. They differ in their tumorigenicity: when inoculated into syngeneic BDIX rats, PROb cells induce progressive tumors whereas REGb cells induce tumors which always regress. As previously described, there is an inverse relation between their tumorigenicity and their susceptibility to NCMC mediated by syngeneic spleen or peripheral blood lymphocytes: PROb cells are significantly less sensitive to NCMC than REGb cells.

Regression induced by lentinan, of peritoneal carcinomatoses in a model of colon cancer in rat.

Lentinan has been tested in a model of colon cancer in rats. Peritoneal carcinomatoses were induced in BDIX rats by i.p.

In vitro natural killer activity against progressive and regressive variants of a rat colon adenocarcinoma. Effect of treatments with anti-asialo GM1 plus complement.

In a previous work, a cell line (DHD/K12) was established from a colon adenocarcinoma induced in a BDIX rat by 1,2-dimethylhydrazine. From this line, two cloned sublines, PROb and REGb, were then isolated. When subcutaneously inoculated into syngeneic rats, PROb cells yield progressive tumors, whereas REGb cells yield tumors which regress.

Treatment with endotoxins of peritoneal carcinomatosis induced by colon tumor cells in the rat.

Peritoneal carcinomatosis, a common spreading of human colon carcinoma, can be obtained by intraperitoneal injection of colon tumor cells in rats. When BDIX rats are injected with 10(6) syngeneic tumor cells, isolated and cloned from a chemically induced colon carcinoma, they die within 2-3 months with solid peritoneal tumors and hemorrhagic ascites. Repeated intraperitoneal injections of 20 micrograms endotoxins (Escherichia coli W0128:B12) from day 3 after tumor cell challenge inhibited tumor growth.

Lack of effect of a high polyunsaturated fat diet on the growth of transplantable colon tumors and on the cytolytic activity of macrophages in rats.

The effect of a high dietary level of polyunsaturated fat was tested on the growth of three different colon cancer cell lines injected subcutaneously into syngeneic rats. This effect was also tested on the in vitro cytolytic activity of resident peritoneal macrophages, natural or endotoxin and/or indomethacin-modulated. A 12% corn oil dietary supplement had no effect in any of the cases tested.