cord-factors and Lung-Neoplasms

Topics: Bacterial Infections; Carcinogens; Chronic Disease; Cord Factors; Cytokines; DNA Damage; Humans; Inflammation Mediators; Lung Neoplasms; Mycobacterium tuberculosis; Neoplasms; Oxidative Stress; Risk; Time Factors; Tuberculosis, Pulmonary

Vizantin, 6,6'-bis-O-(3-nonyldodecanoyl)-α,α'-trehalose, was developed as a safe immunostimulator on the basis of a structure-activity relationship (SAR) study with trehalose 6,6'-dicorynomycolate (TDCM). It was possible to synthesize vizantin on a large scale more easily than in the case of TDCM, and the compound exhibited more potent prophylactic effect on experimental lung metastasis of B16-F0 melanoma cells. Because vizantin stimulated human macrophages, it is a promising candidate for clinical application.

Topics: Adjuvants, Immunologic; Animals; Antineoplastic Agents; Cell Line, Tumor; Cord Factors; Glycolipids; Humans; In Vitro Techniques; Lung Neoplasms; Macrophages; Melanoma, Experimental; Mice; Mice, Inbred C57BL; Phagocytosis; Stereoisomerism; Structure-Activity Relationship; Trehalose; Xenograft Model Antitumor Assays

We examined the effect of semisynthetic trehalose-6,6 '-dimycolate (TDM) and its synthetic stereoisomeric derivatives (trehalose 6,6'-dicorynomycolates; TDCMs) prepared in oil-in-water (o/w) emulsion on inhibition of lung metastasis produced by highly metastatic murine tumour cells, colon 26-M3.1 carcinoma and B16-BL6 melanoma cells, using experimental and spontaneous metastasis models. Intravenous (i.v.) administration of TDM (100 microg/mouse) 1, 3 or 8 days before tumour inoculation significantly inhibited lung metastasis of colon 26-M3.1 cells, in a dose-dependent manner. Single administration of TDM 1 day after tumour inoculation also showed the therapeutic effect on experimental lung metastasis of colon 26-M3.1 cells. Similarly, multiple administrations of TDM after tumour inoculation resulted in a significant inhibition of spontaneous lung metastasis of B16-BL6 cells (on day 35), although it showed no effect on suppression of tumour growth (on day 21). In comparison of toxicity in vivo among TDM and four TDCMs such as TDCM(2R,3R), TDCM(2S,3R), TDCM(2R,3S) and TDCM(2S,3S), all of the TDCMs appeared to be less toxic than TDM itself. Furthermore, all of the TDCMs were prophylactically as well as therapeutically active for inhibition of lung metastasis of both colon 26-M3.1 and B16-BL6 tumour cells, showing higher inhibitory activity than that of TDM. In particular, TDCMs induced a marked suppression of the growth of B16-BL6 tumour cells in vivo. These results suggest that systemic administration of TDM as well as TDCMs led to inhibition of tumour metastasis and TDCMs are more potential to suppress tumour growth and inhibit tumour metastasis than TDM.

Topics: Adjuvants, Immunologic; Animals; Antineoplastic Agents; Carcinoma, Lewis Lung; Colonic Neoplasms; Cord Factors; Female; Lung Neoplasms; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Models, Chemical; Neoplasm Metastasis; Stereoisomerism

Cord factors are mycoloyl glycolipids in cell walls of bacteria belonging to Actinomycetales, such as Mycobacterium, Nocardia and Rhodococcus. They induce granuloma formation in the lung and interstitial pneumonitis, associated with production of macrophage-derived cytokines. We studied how cord factors induce biological activities in the cells. Cord factors isolated from M. tuberculosis, trehalose 6-monomycolate (mTMM) and trehalose 6,6'-dimycolate (mTDM), enhanced protein kinase C (PKC) activation in the presence of phosphatidylserine (PtdSer), diacylglycerol and Ca2+, and mTMM activated PKC alpha more strongly than PKC beta or gamma under the same assay conditions. Kinetic studies of mTMM in response to PKC activation revealed that mTMM increased the apparent affinity of PKC to Ca2+ in the presence of both PtdSer and diolein. Although this is similar to observations with unsaturated fatty acids, such as arachidonic acid, mTMM was synergistic with PtdSer for PKC activation, but arachidonic acid was not. mTMM was also different as regards PKC activation, as phorbol ester was. A single i.p. administration of mTMM to mouse induced tumor necrosis factor-alpha (TNF-alpha) in serum and in the lung, which is a unique target tissue of cord factors. Based on our recent finding that TNF-alpha is an endogenous tumor promoter, the correlation between lung cancer and pulmonary tuberculosis is discussed.

Topics: Animals; Arachidonic Acid; Calcium; Carbohydrate Sequence; Cord Factors; Diglycerides; Enzyme Activation; Lung; Lung Neoplasms; Male; Mice; Mice, Inbred BALB C; Molecular Sequence Data; Phospholipids; Protein Kinase C; Sensitivity and Specificity; Tuberculosis, Pulmonary; Tumor Necrosis Factor-alpha

Trehalose-6,6'-dimycolate (TDM) and its monosaccharide-type analogues were synthesized, and their lethal and adjuvant activities were examined in mice. All the monosaccharide-type analogues with a glucose or N-acetylglucosamine moiety were devoid of lethal toxicity to mice; in particular, D-GlcNAcM(1-deoxy) and D-GlcNM did not cause any loss of body weight at an early stage after intravenous administration as a 9% oil-in-water emulsion. Intraperitoneal administration of D-GlcNAcM(1-deoxy) in aqueous suspension, as well as TDM, could activate macrophages to become tumoricidal against tumour cells, whereas D-GlcNAcM(1-deoxy) in oil emulsion, unlike TDM, caused no granulomatous formation in the lung after intravenous injection. Squalane-treated D-GlcNAcM(1-deoxy) showed significant inhibition of spontaneous lung metastases by B16-BL6 melanoma cells when it was administered twice intratumorally. The non-toxic monosaccharide-type analogue of TDM [D-GlcNAcM(1-deoxy)] was a beneficial adjuvant for the activation of macrophages and the prevention of cancer metastasis.

Topics: Adjuvants, Immunologic; Animals; Cord Factors; Female; Glycolipids; Granuloma; Lung Neoplasms; Macrophage Activation; Mice; Mice, Inbred C57BL

Intratracheal (i.t.) administration of trehalose dimycolate (TDM) in saline as liposomes induces a transient inflammatory effect. Limited granulomas appeared in some peribronchial areas but most subsided after a few weeks. The alveolar macrophages were activated as judged by their cytostatic activity against the syngeneic P77 fibrohistiocytoma 3 days after administration of 0.2 mg TDM. The NK activity of the lymphocytes of the lung microcirculation did not increase and diminished slightly between 1 and 3 days after TDM administration, thus suggesting that macrophages might be the main effector cells responding to TDM. Repeated i.t. TDM administration protected rats against the development of colonies in the lung after i.v. injection of 5 X 10(5) P77 cells. The survival of the rats was significantly increased. Thus, in this system, a relationship exists between activation of alveolar macrophages and protection against colonies arising from i.v. injected tumor cells.

Topics: Animals; Cord Factors; Glycolipids; Killer Cells, Natural; Lung Neoplasms; Macrophage Activation; Macrophages; Male; Neoplasm Transplantation; Neoplasms, Experimental; Pulmonary Alveoli; Rats

Topics: Animals; Cord Factors; Fibrosarcoma; Glycolipids; Lung Neoplasms; Male; Mice; Sarcoma, Experimental; Skin Neoplasms

Mice bearing pulmonary metastases of the Lewis lung carcinoma were treated iv with a nonviable microbial vaccine following amputation of the primary inoculation site. The vaccine consisted of BCG cell wall skeleton, trehalose, dimycolate, and endotoxin attached to mineral oil microdroplets. Single and repeated doses ranging from 15 to 675 micrograms were tested. Survival was modestly but consistently prolonged by vaccination. A portion of the activity appeared to be due to the Tween saline-oil vehicle. A single low dose (15 micrograms) was as efficacious as higher or repeated doses.

Topics: Animals; BCG Vaccine; Carcinoma; Cell Membrane; Cord Factors; Endotoxins; Injections, Intravenous; Lung Neoplasms; Mice; Mice, Inbred C57BL; Neoplasm Transplantation; Neoplasms, Experimental; Polysorbates