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. The efficacy of treatments depends on the type of molecule and on the protocol. In general, increased survival was obtained, accompanied in some cases by tumor regression and cure.

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.Treatment of cancer is generally based on surgery and radiotherapy for localized and attainable tumors, associated, in some cases, with adjuvant chemotherapy. Chemotherapy can also be used as first line treatment for disseminated diseases.The formulation of therapeutic strategies to enhance immune-mediated tumor destruction is a central goal of cancer immunology. Substantive progress toward delineating the mechanisms involved in innate and adaptive tumor immunity has improved the prospects for crafting efficacious treatments LPS and their active component lipid A, have been used in tumor therapy since the 19th century.Studies in animal models have shown promising results on different models of cancer but data from human trial are scarce. The published Phase-1 cancer studies have shown that lipid A analogues are usually well tolerated, most of the side effects being likely related to immune response, i. e., fever, chills and rigor. The administration of several lipids A analogues was shown to result in a significant increase in circulating levels of several cytokines but no objective antitumor responses were observed. Therefore clinical activity of such molecules deserves further experiments, likely in conjunction with chemotherapy.

[To stimulate or to inhibit nitric oxide production in mammary tumors?]. / Faut-il inhiber ou stimuler la production de monoxyde d'azote des cellules cancéreuses mammaires?

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. In human patients, increased amounts of NO were evidenced in blood, linked with the presence and activity of NO-synthase in breast tumors. Non-unequivocal correlations were established with tumor grade, invasiveness and metastatic potential. Studies in animal models have given hints to explain these discrepancies by the type of the involved NO-synthase, the amount of NO it produces, and its belonging to tumoral or stromal cells. Indeed, it was recently shown that NO produced by tumor cells inhibits, while NO produced by stromal cells facilitates tumor growth, at least in the model which was studied. On the one hand, NO toxicity against tumor cells is a well known phenomenon, but on the other hand, NO may promote tumor invasiveness due to its effect on extracellular matrix, and to its angiogenetic properties. So the role of NO in mammary tumor outcome is not clear-cut, and, at the present time, it cannot be ascribed a pronostic value in breast tumor. However, researches aimed at managing tumor cells to produce NO sufficient to induce their death may be fruitful since, be tumor targeting successful, no general toxicity would be encountered.

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. Their antitumoral effect has been demonstrated in animal models as well as clinical trials. Studies in animal models showed that their antitumoral effect relies mostly on the generation of an effective immune response. In humans, the antitumoral effect was correlated with an antibody response and cell-mediated cytotoxicity. So far, some encouraging results have been achieved in phase I and II clinical trials with regards to response and stabilization of the disease, but an expansion of the studies and trials is needed to find the best conditions for their clinical application.

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. Furthermore, in vivo treatment of rats with L-NAME inhibited arginase activity in tumor nodules and liver, and the effect persisted after treatment ceased. The effect of L-NAME on arginase requires consideration when it is used in vivo in animal models with the aim of inhibiting endothelial NO-synthase, another enzyme using arginine as substrate.