13-methyltetradecanoic acid exhibits anti-tumor activity on T-cell lymphomas in vitro and in vivo by down-regulating p-AKT and activating caspase-3.

13-Methyltetradecanoic acid (13-MTD), a saturated branched-chain fatty acid purified from soy fermentation products, induces apoptosis in human cancer cells. We investigated the inhibitory effects and mechanism of action of 13-MTD on T-cell non-Hodgkin's lymphoma (T-NHL) cell lines both in vitro and in vivo. Growth inhibition in response to 13-MTD was evaluated by the cell counting kit-8 (CCK-8) assay in three T-NHL cell lines (Jurkat, Hut78, EL4 cells). Flow cytometry analyses were used to monitor the cell cycle and apoptosis. Proteins involved in 13-MTD-induced apoptosis were examined in Jurkat cells by western blotting. We found that 13-MTD inhibited proliferation and induced the apoptosis of T-NHL cell lines. 13-MTD treatment also induced a concentration-dependent arrest of Jurkat cells in the G1-phase. During 13-MTD-induced apoptosis in Jurkat cells, the cleavage of caspase-3 and poly ADP-ribose polymerase (PARP, a caspase enzymolysis product) were detected after incubation for 2 h, and increased after extending the incubation time. However, there was no change in the expression of Bcl-2 or c-myc proteins. The appearance of apoptotic Jurkat cells was accompanied by the inhibition of AKT and nuclear factor-kappa B (NF-κB) phosphorylation. In addition, 13-MTD could also effectively inhibit the growth of T-NHL tumors in vivo in a xenograft model. The tumor inhibition rate in the experimental group was 40%. These data indicate that 13-MTD inhibits proliferation and induces apoptosis through the down-regulation of AKT phosphorylation followed by caspase activation, which may provide a new approach for treating T-cell lymphomas.

Effect of dietary cholesterol, trans and saturated fatty acids on serum lipoproteins in non-human primates.

Nine cynomolgus monkeys were rotated randomly through four dietary treatments with each treatment lasting 6 weeks. A wash-out period of 4 weeks was maintained between each dietary rotation. The animals were fed diets containing 32% energy fat derived from palm olein (POL), lauric-myristic-rich oil blend (LM), American Heart Association (AHA) rich oil blend and hydrogenated soybean oil blend (trans). Diets were fed with (phase 1) or without (phase 2) the addition of dietary cholesterol (0.1%). In phase 1, when animals were fed without dietary cholesterol, plasma total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) was significantly raised and high-density lipoprotein cholesterol (HDL-C) was significantly depressed by the trans diets relative to all other dietary treatments. The resulting LDL-C/HDL-C ratio was also significantly increased. The LM diet increased TC significantly relative to the AHA diet while LDL-C was significantly increased compared to both POL and AHA. Apolipoprotein (apo) B was not affected significantly by these dietary treatments. Apo A1 was significantly increased by POL relative to all other dietary treatments. The trans diet reduced apo A1 and the resulting apo B/A1 ratio was increased significantly by trans relative to all other dietary treatments. Addition of 0.1% dietary cholesterol to these diets almost doubled the plasma TC and LDL-C in all dietary treatments. However, HDL-C was only marginally higher with the addition of dietary cholesterol. The LM + C (cholesterol added) diet resulted in the highest TC and LDL-C that was significant compared to all other dietary treatments. Trans + C increased TC compared to POL + C and AHA + C diets while increases in the LDL-C did not attain significance. The addition of dietary cholesterol did not affect HDL-C between treatments whereas plasma triglycerides were significantly increased by the trans + C diet relative to all other treatments. Both the trans + C and LM + C diets increased apo B and decreased apo A1 relative to the POL + C and AHA + C diets. The resulting apo B/A1 ratio was similarly altered. These results affirm that the lauric + myristic acid combination, along with trans fatty acids, increased lipoprotein-associated coronary heart disease risk factors compared to either POL or AHA.

Interactive effects of dietary cholesterol and different saturated fatty acids on lipoprotein metabolism in the hamster.

The present study examines the interactive effects of three fatty acids: myristic, palmitic and stearic acids, with dietary cholesterol, on lipoprotein metabolism in the hamster. Each saturated fatty acid was fed at a concentration of 100 g pure synthetic triacylglycerol/kg in the presence of 100 g triolein/kg and was fed in the presence of 0.05, 1.2 or 2.4 g dietary cholesterol/kg. Dietary cholesterol increased the concentration of cholesterol in each of the major plasma lipoprotein fractions. The largest effects on VLDL and LDL were seen in the presence of tripalmitin where the increase between the lowest and highest dietary cholesterol groups were 129% and 38% respectively. In contrast, HDL showed the greatest change in the tristearin group when the equivalent increase was 59%. No interactive effects of dietary cholesterol and fat were seen on hepatic mRNA concentrations for the LDL receptor, hydroxymethylglutaryl-CoA reductase or the microsomal triacylglycerol transfer protein. As the amount of cholesterol in the diet increased, large differences were seen in the storage of hepatic cholesterol ester. At the highest dietary cholesterol intake the amount of hepatic cholesterol ester was 1.7-fold higher in the animals fed trimyristin compared with those fed tripalmitin. These results suggest that, as the amount of cholesterol in the diet is increased, palmitic acid becomes more hypercholesterolaemic. This is associated with a reduced ability to store cholesterol ester in the liver.

Effect of the dietary fat type on arterial thrombosis tendency: systematic studies with a rat model.

To study the influence of dietary fatty acids on arterial thrombosis tendency 65 groups of male rats were fed diets containing 50% of their digestible energy as fat from 32 different oils and fats. After 8 weeks their arterial thrombosis tendency was assessed by measuring the obstruction time (OT) of a loop-shaped polythene cannula inserted into the abdominal aorta. Using multiple regression analysis log10 OT was modelled as a function of the relative amounts of the various dietary fatty acids and their combinations. The best fit (R2 = 0.79) was obtained for the sums of all monoenoic and (n-6) and (n-3) polyenoic fatty acids, which appeared antithrombotic. The fit for the sum of all saturated fatty acids, which had a prothrombotic effect, was almost as good (R2 = 0.76). The ratio between dietary polyunsaturated and saturated fatty acids (P:S ratio) appeared a strong predictor of arterial thrombosis tendency (R2 = 0.77). Marine oils did not have a more powerful antithrombotic effect than could be expected on the basis of their P:S ratios. Using stepwise regression analysis myristic acid, 14:0, was shown to be the strongest prothrombotic fatty acid whereas linoleic acid, 18:2(n-6), was the strongest antithrombotic fatty acid. Since the number of marine oils was very limited the effects of the 'fish fatty acids' eicosapentaenoic acid, 20:5(n-3) and docosahexaenoic acid, 22:6(n-3), on arterial thrombus formation could not be tested reliably. The same appeared true for gamma-linolenic acid, 18:3(n-6), and stearidonic acid, 18:4(n-3), present in a few vegetable oils only.

Effect of dietary fats rich in lauric, myristic, palmitic, oleic or linoleic acid on plasma, hepatic and biliary lipids in cholesterol-fed hamsters.

Effects of different dietary fats on plasma, hepatic and biliary lipids were determined in male golden Syrian hamsters (Mesocricetus auratus) fed on purified diets for 7 weeks. Diets were made by blending different fats containing characteristic fatty acids: butter (14:0 + 16:0), palm stearin (16:0), coconut oil (12:0 + 14:0), rapeseed oil (18:1), olive oil (18:1) and sunflowerseed oil (18:2). In all diets except the sunflowerseed oil diet dietary 18:2 was held constant at 2% energy. Total fat supplied 12% of energy and cholesterol was added at 4 g/kg diet. Plasma cholesterol and triacyglycerol concentrations were increased by dietary cholesterol. After 7 weeks, plasma cholesterol concentrations were highest with the palm stearin, coconut oil and olive oil diets (8.9, 8.9 and 9.2 mmol/l) and lowest with the rapeseed oil and sunflowerseed oil diets (6.7 and 5.5 mmol/l) while the butter diet was intermediate (8.5 mmol/l). Hepatic cholesterol concentration was highest in hamsters fed on the olive oil diet and lowest with the palm stearin diet (228 v. 144 mumol/g liver). Biliary lipids, lithogenic index and bile acid profile of the gall-bladder bile did not differ significantly among the six diets. Although the gallstone incidence was generally low in this study, three out of 10 hamsters fed on the palm stearin diet developed cholesterol gallstones. In contrast, no cholesterol gallstones were found with the other diets. Rapeseed and sunflowerseed oils caused the lowest plasma cholesterol and triacyglycerol concentrations whereas olive oil failed to demonstrate a cholesterol-lowering effect compared with diets rich in saturated fatty acids. Since 18:2 was kept constant at 2% of energy in all diets, the different responses to rapeseed and olive oils could possibly be attributed to their different contents of 16:0 (5.6% v. 12.8% respectively). Other possible explanations are discussed.

Decreasing dietary lauric and myristic acids improves plasma lipids more favorably than decreasing dietary palmitic acid in rhesus monkeys fed AHA step 1 type diets.

Current dietary recommendations advocate reductions in saturated fatty acids (SFA) and cholesterol (C) as a primary intervention for achieving a more desirable plasma lipid profile. To ascertain whether it is more efficacious to decrease dietary lauric and myristic acids (12:0 + 14:0) or dietary palmitic acid (16:0) in conjunction with a reduction in dietary C, 11 rhesus monkeys (8 males, 3 females) were initially fed a control diet rich in SFA + C for 14 wk [dietary fat approximately 38% of energy (%en), SFA 16%en and C at 180 mg/1000 kcal]. Plasma lipids were measured between the 9th and 13th wk, and LDL metabolism was assessed after 13 wk. Monkeys were then split into two groups and fed one of two American Heart Association (AHA) Step 1 diets (approximately 30%en fat, 10%en SFA, 75 mg cholesterol/1000 kcal) for an additional 14 wk, and plasma lipids and LDL metabolism were re-evaluated. Group 1 received a 16:0-rich diet in which most 12:0 + 14:0 were deleted (approximately 8.6%en from 16:0 and approximately 0.3%en from 12:0 + 14:0), whereas Group 2 received a diet rich in 12:0 + 14:0 from which 16:0 was selectively removed (2.6%en from 16:0 and approximately 6.3%en 12:0 + 14:0). In all three diets, oleic and linoleic acid were held relatively constant so that only SFA, the level of total fat and cholesterol were manipulated. Only the Step 1 diet that selectively removed 12:0 + 14:0 (the 16:0-rich diet) significantly reduced all lipid fractions, including total cholesterol (TC), HDL-C, LDL-C, apolipoprotein B (apoB) and the LDL pool size. Plasma triglyceride (TG) and the ratio of TC/HDL-C were not altered by either Step 1 diet. The smaller LDL pool size following the 16:0-rich diet in Group 1 was attributable to a significantly higher fractional catabolic rate (FCR) of LDL because the transport rate of LDL apoB was unaffected. Although the FCR was increased with the 12:0 + 14:0-rich diet, the LDL apoB pool was not affected because the transport rate of LDL tended to increase as well. The data suggest that a Step 1 diet that reduces total fat by decreasing 12:0 + 14:0 in conjunction with dietary C, improves plasma lipids more favorably than a similar diet that selectively removes 16:0 and C. Previous data would imply that the benefit resulted from removal of 12:0 + 14:0 per se, but the possibility is not eliminated that removal of C (independent of 12:0 + 14:0) muted the potential interaction between C and palmitic acid that tends to raise TC.

Acute effect of high-fat meals rich in either stearic or myristic acid on hemostatic factors in healthy young men.

Suggestions have been made that saturated fatty acids with 12-18 carbon atoms, stearic acid (18:0) in particular, are prothrombogenic. These suggestions are based mainly on in vitro measurements. In the present study the effect of dietary fats high in stearic or myristic acid (14:0) on plasma triacylglycerol concentrations and key variables of blood aggregation (in vitro and in vivo), coagulation, and fibrinolysis was studied over 24 h in 10 healthy young men. For each dietary fat, two identical high-fat test meals were served: one in the morning (0 h) and one 8 h later, and blood samples were collected at 0, 2, 4, 6, 8, and 24 h. Both fats decreased platelet aggregation compared with fasting values. Stearic fat resulted in a tendency toward lower activity of plasminogen activator inhibitor 1 (PAI-1) than did myristic fat (P < 0.08). PAI-1 was also lower 24 h after consumption of either fat than initially (P < 0.05). Stearic fat, but not myristic fat, tended to cause some increase in factor VII coagulant activity and beta-thromboglobulin after 4 h. In conclusion, an acute prothrombotic effect of fats high in myristic and stearic acid was not confirmed.

Dietary myristic acid alters acylated proteins in activated murine macrophages.

After stimulation with select activating agents such as lipopolysaccharide (LPS) or recombinant interferon-gamma (rIFNgamma), several macrophage proteins may be induced, acylated with myristic acid, or both. Our goal in this study was to determine whether altering the levels of myristic acid in the diet would modulate the levels of a specific acylated macrophage protein, MacMARCKS (myristoylated, alanine-rich C kinase substrate), because that fatty acid can be found in substantial quantities in some foods. Thioglycollate-elicited peritoneal macrophages from groups of mice fed diets with various levels of myristic acid (from 0.2 to 99 g/100 g fatty acids) were treated with LPS, phorbol myristate acetate (PMA), or rIFNgamma plus LPS, which are well-established macrophage activating agents. Levels of MacMARCKS were measured by enzyme-linked immunosorbent assay using a rabbit anti-mouse polyclonal antibody against the first 10 amino acids of murine MacMARCKS. A 42-kDa protein with the same molecular weight as MacMARCKS was identified in macrophage lysates by Western analysis using the antibody. Lipopolysaccharide- and PMA-activated macrophages from mice fed the trimyristin diet had significantly greater levels of MacMARCKS than LPS- and PMA-activated macrophages of mice fed the safflower oil-containing diet. The levels of MacMARCKS were also greater in lysates of LPS plus rIFNgamma-stimulated macrophages from mice fed the trimyristin diet and mice fed a diet containing a moderate level of myristic acid (12 g/100 g fatty acids) compared with the lysates of macrophages from mice fed the safflower oil diet. These results indicate that altering the level of myristic acid in the diet may alter the production of specific proteins that may be involved in macrophage activation.

Improved cationic lipid formulations for in vivo gene therapy.

The problem of assessing in vivo activity of gene delivery systems is complex. The reporter gene must be carefully chosen depending on the application. Plasmids with strong promoters, enhancers and other elements that optimize transcription and translation should be employed, such as the CMVint and pCIS-CAT constructs. Formulation aspects of cationic lipid-DNA complexes are being studied in several laboratories, and the physical properties and molecular organization of the complexes are being elucidated. Likewise, studies on the mechanism of DNA delivery with cationic lipids are accumulating which support the basic concept that the complexes fuse with biological membranes leading to the entry of intact DNA into the cytoplasm. Naked plasmid DNA administered by various routes is expressed at significant levels in vivo. This observation is not restricted to skeletal and heart muscle, but has been observed in lung, dermis, and in undefined tissues following intravenous administration. Most of the widely available cationic lipids, including Lipofectin, Lipofectamine and DC-cholesterol have a very poor ability to enhance DNA expression above the baseline naked DNA level, at least in lung. In this report we have revealed a novel cationic lipid, DLRIE, which can significantly enhance CAT expression in mouse lung by 25-fold above the naked DNA level. Other compounds are currently being evaluated which can enhance the naked DNA expression even higher. Plasmid vector improvements have led to further increase in in vivo lung expression, so that the net improvement is > 5,000-fold. Results of this nature are advancing the pharmaceutical gene therapy opportunities for synthetic cationic lipid based gene delivery systems.

LDL receptor activity is down-regulated similarly by a cholesterol-containing diet high in palmitic acid or high in lauric and myristic acids in cynomolgus monkeys.

To determine the mechanisms whereby diets differing widely in fatty acid composition affect plasma LDL cholesterol and apolipoprotein B concentrations, LDL kinetics and receptor- and nonreceptor-mediated LDL catabolism were investigated in 27 cynomolgus monkeys fed diets containing 0.05 mg cholesterol/kJ and 40% fat energy as corn oil alone (unsaturated fat diet rich in oleic and linoleic acids), nonhydrogenated coconut oil alone (saturated fat diet, rich in lauric and myristic acids) or an oil blend (rich in palmitic acid). Consumption of the oil blend and saturated fat diets significantly elevated total cholesterol, LDL cholesterol and apolipoprotein B concentrations relative to the unsaturated fat diet and the saturated fat diet significantly increased plasma total cholesterol and LDL cholesterol compared with the oil blend diet. However, despite the greater increases in plasma total cholesterol, LDL cholesterol and apolipoprotein B in the saturated fat vs. the oil blend dietary group, the receptor-mediated LDL fractional catabolic rate was comparable in the oil blend and saturated fat diet groups. In addition, consumption of the oil blend or saturated fat diet increased the production rate of LDL apolipoprotein B and nonreceptor-mediated LDL apolipoprotein B transport (disposal) relative to the unsaturated fat diet. Our data, therefore, suggest that consumption of the oil blend or saturated fat diet elevated plasma total cholesterol and LDL cholesterol relative to the unsaturated fat diet, and the oil blend diet abundant in palmitic acid seems to have down-regulated the LDL receptor as much as a more saturated fat diet abundant in lauric and myristic acids.

Effect of fats high in individual saturated fatty acids on plasma lipoprotein[a] levels in young healthy men.

Plasma lipoprotein[a] (Lp[a]) is associated with atherogenesis and thrombogenesis. We examined how plasma Lp[a] in healthy young men was affected by fats high in stearic (C18), palmitic (C16), and lauric+myristic (C12+ C14) acid (experiment I, 15 subjects), and by fats high in myristic (C14) and palmitic (C16) acid (experiment II, 12 subjects). Strictly controlled isocaloric diets with 36% of energy from test fats were served in random order for 3 weeks separated by wash-out period(s). Diets high in C18 gave significantly higher levels of Lp[a] (51(12-560) mg/L) than diets high in C16 (38(12-533 mg/L) (P = 0.020) and C12 + C14 (34(12-534) mg/L) (P = 0.002). These differences were observed in several of the subjects in experiment I. In experiment II we saw no difference in plasma Lp[a] after diets high in C16 and C14. Our observations suggest that a fat high in stearic acid might affect Lp[a] in a different way than fats high in palmitic and myristic+lauric acid. Lp[a] concentrations were not associate with changes in tissue-plasminogen activator (t-PA) activity, factor VII coagualant activity, or plasma LDL cholesterol.

Regulation of guinea pig very low density lipoprotein secretion rates by dietary fat saturation.

We investigated the effects of dietary fat saturation on very low density lipoprotein (VLDL) production in guinea pigs fed semipurified diets containing 15% (w/w) fat, either corn oil (CO, 58% linoleic acid), lard (LA, 42% oleic and 24% palmitic acids) or palm kernel oil (PK, 52% lauric and 18% myristic acids) for 4 weeks. Animals were given an intravenous injection of Triton WR 1339 to block VLDL catabolism and rates of VLDL triacylglycerol (TAG) and apolipoprotein (apo) B secretion were measured over time. Plasma TAG concentrations increased linearly for 8 h (r = 0.99) and VLDL-TAG secretion rates were significantly higher (P < 0.01) in guinea pigs fed LA (72.7 +/- 14.7 mg/kg-h, n = 12) compared to animals fed PK (55.4 +/- 13.4 mg/kg-h, n = 12) or CO (48.6 +/- 17.5 mg/kg-h, n = 15). VLDL apoB secretion rates were highest in PK-fed animals (3.1 +/- 1.8 mg/kg-h) compared to guinea pigs fed LA (1.5 +/- 0.8 mg/kg-h) or CO (1.1 +/- 0.6 mg/kg-h) diets (P < 0.005). Concurrent with analysis of VLDL secretion, turnover of 125I-labeled LDL was measured. Low density lipoprotein (LDL) fractional catabolic rates were not altered by Triton treatment and LDL apoB specific radioactivity (cpm/microgram) did not change over time indicating that: a) the Triton blockage of VLDL catabolism was complete, and b) there was no direct secretion of LDL by the liver. These data demonstrate that intake of lard increases the rate of VLDL-triacylglycerol secretion and that nascent VLDL particles from the lard and corn oil diet groups have the same relative triacylglycerol content, whereas palm kernel oil intake increases secretion of VLDL particles which have a reduced triacylglycerol content. These results demonstrate that dietary fat chain length and saturation have specific effects on VLDL secretion rates affecting both particle number and composition.

Dietary saturated and trans fatty acids and cholesterol and 25-year mortality from coronary heart disease: the Seven Countries Study.

BACKGROUND: In the Seven Countries Study associations between intake of individual fatty acids and dietary cholesterol were studied in relation to serum cholesterol and 25-year mortality from coronary heart disease. All analyses concern only intercohort comparisons. METHODS: In the baseline surveys carried out between 1958 and 1964, risk factors for coronary heart disease were measured among 12,763 middle-aged men constituting 16 cohorts in seven countries. In 1987 and 1988 equivalent food composites representing the average food intake of each cohort at baseline were collected locally and analyzed in a central laboratory. The vital status of all participants was verified at regular intervals during 25 years of follow-up. RESULTS: Of the individual saturated fatty acids, the average population intake of lauric and myristic acid was most strongly related to the average serum cholesterol level (r > 0.8, P < 0.001). Strong positive associations were observed between 25-year death rates from coronary heart disease and average intake of the four major saturated fatty acids, lauric, myristic, palmitic, and stearic acid (r > 0.8, P < 0.001); the trans fatty acid elaidic acid (r = 0.78, P < 0.001); and dietary cholesterol (r = 0.55, P < 0.05). CONCLUSIONS: Interpreted in the light of experimental and clinical studies, the results of these cross-cultural analyses suggest that dietary saturated and trans fatty acids and dietary cholesterol are important determinants of differences in population rates of coronary heart disease death.

Effect on blood lipids, coagulation, and fibrinolysis of a fat high in myristic acid and a fat high in palmitic acid.

The hypothesis that myristic acid (C14:0) has a stronger cholesterol-increasing potential than does palmitic acid is based on very few experimental observations. A randomized, strictly controlled dietary study was therefore designed to investigate the effect of a synthetic fat that was high in myristic acid, and palm oil, which is high in palmitic acid, on lipoproteins and hemostatic variables. Twelve men were served two diets (40% of energy as fat) with 41% of fat as myristic (diet M) or palmitic acid (diet P) for 3 wk with 1 mo between the two dietary schedules. Plasma HDL cholesterol was 8% higher with diet M than with diet P: 1.10 +/- 0.06 (mean +/- SEM) vs 1.01 +/- 0.05 mmol/L (P < 0.006). Diet M raised factor VII coagulant (F VIIc) activity to 98% (77-117%) vs 96% (71-109%) (medians and ranges) after diet P (P = 0.02). Total and LDL-cholesterol concentrations did not differ between the diets. In conclusion, the myristic acid test fat was not more cholesterolemic than was palm oil, but it did induce a minor rise in F VIIc activity.

Comparison of the effects of diets rich in stearic acid versus myristic acid and lauric acid on platelet fatty acids and excretion of thromboxane A2 and PGI2 metabolites in healthy young men.

The present study compared the effects of diets rich in stearic acid (C18:0) versus one high in lauric and myristic acid (C12:0, C14:0) on platelet phospholipid fatty acid levels and concentrations of urinary thromboxane B2 (TXB2) and 6-keto-PGF1 alpha, which are stable metabolites of thromboxane A2 (TXA2) and PGI2 and indicators of cardiovascular hemostasis. A diet high in dairy butter (B) was the source of C12:0 and C14:0; C18:0 was provided by diets high in cocoa butter (CB), milk chocolate (CHOC) or CB+B in a 4:1 ratio (MIX). A randomized, crossover double-blind experimental design was used. Experimental subjects (n = 15) consumed each diet for 26 days, with a 1-month washout period between each experimental period. Urine and blood were collected from each subject at the beginning and end of each dietary period. Urinary TXB2 and 6-keto-PGF1 alpha were analyzed by radioimmunoassay (RIA). There were no effects of diet on the 24-hour excretion of either metabolite or on the ratio of 6-keto-PGF1 alpha/TXB2, even though there were significant changes in the eicosanoid precursor, arachidonic acid (C20:4n-6), in platelet phospholipids. C20:4n-6 levels increased (44.8% +/- 1.0% to 47.1% +/- 1.3%; P < .05) in the phosphatidylethanolamine phospholipid subclass in subjects on the B diet and decreased in the phosphatidylcholine subclass on the CB diet (16.5% +/- 1.0% to 14.2% +/- 1.1%; P < .05) compared with baseline values.(ABSTRACT TRUNCATED AT 250 WORDS)

Antitumoral activity of a xanthate compound. II. Therapeutic studies in murine leukemia and tumor models in vivo.

The combinations of tricyclodecan-9-yl-xanthogenate (D 609) with undecanoic acid (C11) and D 609 with myristic acid (C14) were tested in 3 rodent tumor models in vivo. D 609 in combination with C11 or C14 did not show antitumoral efficacy in 3-Lewis lung carcinoma (3-LL) growing in syngeneic C57BL6-mice (primary tumor and metastasis) or in WEHI-3B myelomonocytic leukemia growing in Balb/c mice, when given in a dose range lower than the lethal dose for 10% of the treated animals (LD10). In L 1210 mouse lymphoid leukemia growing in CD2F1 mice the combination of D 609/C11 given intraperitoneally in a concentration of 100 mg/kg for more than 1 day effected a significant difference in the survival curves between the control and therapeutic groups in 1 out of 2 experiments. In conclusion, the treatment schedules of D 609/C11 or D 609/C14 used in this study has not revealed significant therapeutic effects in mouse tumors or leukemias in vivo.