gamma-linolenic-acid and Pancreatic-Neoplasms

Topics: Cachexia; gamma-Linolenic Acid; Humans; Pancreatic Neoplasms; T-Lymphocytes; Tumor Necrosis Factor-alpha

Essential fatty acids, especially gamma-linolenic acid (GLA), have been shown to directly inhibit the growth of cancer cell lines in culture. The aim of this study was to see whether an aqueous formulation of GLA works as well as the lithium-based salt. We evaluated the effect of the 1-deoxy-1-methylamino-D-glucitol salt of GLA (MeGLA) on the growth of two human pancreatic cancer cell lines (Panc-1 and MIA PaCa-2) in vitro, and compared its effects with a previously studied formulation, lithium GLA (LiGLA). The effect of time exposure (2-7 days) and difference in concentration (0-1000 micromol/l) were studied using 96-well culture plates. Cell growth was assessed by MTT assay. Control experiments were performed with meglumine alone in similar concentrations. MeGLA had cytostatic and cytotoxic effects on pancreatic cancer cell lines with 50% growth inhibition at 30-100 micromol/l and cytotoxic effects at 60-250 micromol/l. The degree of growth inhibition increased with time of exposure to MeGLA. The anti-proliferative effects of MeGLA were similar to those previously observed with LiGLA. We conclude that MeGLA has equivalent anti-proliferative activity to LiGLA when tested in vitro against pancreatic cancer cell lines and is therefore a suitable alternative to LiGLA for investigation of the in vivo activity of GLA against pancreatic adenocarcinomas.

Topics: Cell Division; Cell Survival; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; gamma-Linolenic Acid; Humans; Lithium Compounds; Meglumine; Pancreatic Neoplasms; Solutions; Time Factors; Tumor Cells, Cultured; Water

Gamma-linolenic acid (GLA) is growth inhibitory both in vitro and in vivo, at doses non-toxic to non-cancer cells. Chemotherapeutic agents have limited activity in pancreatic cancer. Interactions between GLA and cytotoxic drugs have not previously been investigated; any synergy might improve the therapeutic effect of these agents.. To investigate possible interactions between GLA and 5-fluorouracil (5-FU) or gemcitabine against pancreatic cancer cell lines in vitro.. Two pancreatic cancer cell lines were exposed to GLA alone and in combination with 5-FU or gemcitabine. Residual viable biomass was measured using the MTT assay and the results analysed by the median effect method of Chou and Talalay [Adv Enzyme Regul 1984;22:27-55].. GLA concentrations of 3.9- 125 microg/ml had a synergistic or additive growth inhibitory effect on all tested concentrations of gemcitabine. Synergism was demonstrated between GLA and 5-FU only at concentrations of 62.5-125 microg/ml of 5-FU.. GLA has a synergistic effect with gemcitabine at concentrations that correspond to in vivo therapeutic doses. GLA with 5-FU is synergistic only at a tight range of high concentrations of 5-FU. GLA lacks toxic side effects and may be useful in combination with gemcitabine.

Topics: Animals; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Pancreatic Ductal; Cell Division; Cell Line, Tumor; Deoxycytidine; Drug Synergism; Fluorouracil; gamma-Linolenic Acid; Gemcitabine; Pancreatic Neoplasms

Essential fatty acids such as (gamma)linolenic (GLA) and eicosapentaenoic (EPA) acids have been proposed as anticancer drugs. The aim of this study was to test the effect of a lipid emulsion containing both GLA and EPA in a novel chemical formulation of 1-(gamma)linolenyl-3-eicosapentaenoyl propane diol on the growth of human pancreatic carcinoma in vitro and in nude mice. This compound had a dose-dependent growth-inhibitory effect on human pancreatic cancer cell lines MIA PaCa-2 and Panc-1 in vitro. The concentration necessary for 50% growth inhibition was 25 micromol/l for MIA PaCa-2 and 68 micromol/l for Panc-1 (95% CI 20-29 and 59-77 micromol/l respectively). Nude mice bearing subcutaneous pancreatic tumours produced with the MIA PaCa-2 cell line were treated with the maximum tolerated dose (6.75 mg GLA and 7.3 mg EPA per g of body weight) administered over 10 days by daily intravenous (i.v.) bolus injections. No antitumour effect or major alteration in tumour lipid fatty acid composition was seen in comparison with control animals. Concurrent treatment with parenteral iron (iron saccharate, 5 microg/gram body weight daily) did not make a significant difference. Further improvements in fatty acid delivery mechanisms are necessary before they can become useful anticancer agents.

Topics: Animals; Carcinoma; Dose-Response Relationship, Drug; Drug Combinations; Drug Screening Assays, Antitumor; Eicosapentaenoic Acid; Fatty Acids; gamma-Linolenic Acid; Humans; Iron; Mice; Mice, Nude; Neoplasm Transplantation; Pancreatic Neoplasms; Statistics, Nonparametric; Tumor Cells, Cultured

Topics: 5-Lipoxygenase-Activating Proteins; Amides; Apoptosis; Arachidonate 5-Lipoxygenase; Carrier Proteins; Cell Survival; Drug Synergism; gamma-Linolenic Acid; Humans; Indoles; Lipoxygenase Inhibitors; Male; Membrane Proteins; Pancreatic Neoplasms; Prostatic Neoplasms; Proto-Oncogene Proteins c-bcl-2; Pyridines; RNA, Messenger; RNA, Neoplasm; Tumor Cells, Cultured; U937 Cells

Topics: Aged; Female; gamma-Linolenic Acid; Humans; Liver; Male; Middle Aged; Pancreas; Pancreatic Neoplasms

Essential fatty acids, especially gamma linolenic (GLA) and eicosapentaenoic acids, have been proposed as potential anticancer drugs. Our aim was to study the effect of the lithium salt of gamma linolenic acid (LiGLA) on the growth of two human pancreatic cancer cell lines (MIA PaCa2 and Panc 1) and primary human fibroblasts (HFF 5) in vitro. Cell growth was assessed by a microculture tetrazolium (MTT) assay. LiGLA had a selective growth inhibitory effect on pancreatic cancer cell lines with 50% growth inhibition (IC50) at approximately 6-16 mumol/l compared with approximately 111 mumol/l for the fibroblasts. The degree of growth inhibition increased with the time of exposure to LiGLA. Special attention was paid to the influence of albumin and iron on LiGLA-mediated growth inhibition. Albumin incorporated into essentially serum-free culture medium inhibited the effect of LiGLA in a dose-dependent manner, associated with reduced GLA uptake by cancer cells. Ferric ions were confirmed as potentiators of the growth inhibitory effect of LiGLA but more physiologically relevant transferrin-bound iron was ineffective. With further improvements in the fatty acid delivery mechanism, LiGLA may become a useful adjunct in the management of pancreatic cancer patients.

Topics: Albumins; Cell Division; Chlorides; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Ferric Compounds; gamma-Linolenic Acid; Humans; Lithium Compounds; Pancreatic Neoplasms; Tumor Cells, Cultured

The lithium salt of gamma-linolenic acid (Li-GLA) is growth inhibitory to pancreatic cancer cells in vitro and is reported to prolong the survival of patients with pancreatic cancer. The effect of Li-GLA on the growth of human pancreatic carcinoma in vivo is not known. In this study the effect of parenterally administered Li-GLA on the growth of human pancreatic carcinoma in nude mice was tested.. Pancreatic tumours were produced in nude mice by subcutaneous implantation of MIA PaCa-2 cells. This cell line is sensitive to Li-GLA in vitro. Mice were randomly treated with intraperitoneal, intravenous or intratumoral Li-GLA. Each group also had controls.. Both intravenous and intraperitoneal administration of Li-GLA had no significant effect on tumour growth or tumour phospholipid fatty acid composition. Intratumoral administration of Li-GLA was, however, associated with a significant antitumour effect.. Within the limitations of this tumour model, the benefit seen with intravenous Li-GLA in patients with pancreatic carcinoma cannot be explained by tumour growth inhibition. Local administration appears to be more effective than intravenous or intraperitoneal therapy.

Topics: Animals; Cell Division; gamma-Linolenic Acid; Lithium Compounds; Mice; Mice, Inbred BALB C; Neoplasm Transplantation; Pancreatic Neoplasms

Lipid metabolism has been considered recently as a novel target for cancer therapy. In this field, lithium gamma-linolenate (LiGLA) is a promising experimental compound for use in the treatment of human tumours. In vivo and in vitro studies allowed us to assess the metabolism of radiolabelled LiGLA by tumour tissue and different organs of the host. In vitro studies demonstrated that human pancreatic (AsPC-1), prostatic (PC-3) and mammary carcinoma (ZR-75-1) cells were capable of elongating GLA from LiGLA to dihomo-gamma-linolenic acid (DGLA) and further desaturating it to arachidonic acid (AA). AsPC-1 cells showed the lowest delta5-desaturase activity on DGLA. In the in vivo studies, nude mice bearing the human carcinomas were given Li[1-(14)C]GLA (2.5 mg kg(-1)) by intravenous injection for 30 min. Mice were either sacrificed after infusion or left for up to 96 h recovery before sacrifice. In general, the organs showed a maximum uptake of radioactivity 30 min after the infusion started (t = 0). Thereafter, in major organs the percentage of injected radioactivity per g of tissue declined below 1% 96 h after infusion. In kidney, brain, testes/ovaries and all three tumour tissues, labelling remained constant throughout the experiment. The ratio of radioactivity in liver to tumour tissues ranged between 16- and 24-fold at t = 0 and between 3.1- and 3.7-fold at 96 h. All tissues showed a progressive increase in the proportion of radioactivity associated with AA with a concomitant decrease in radiolabelled GLA as the time after infusion increased. DGLA declined rapidly in liver and plasma, but at a much slower rate in brain and malignant tissue. Seventy-two hours after the infusion, GLA was only detected in plasma and tumour tissue. The sum of GLA + DGLA varied among tumour tissues, but it remained 2-4 times higher than in liver and plasma. In brain, DGLA is the major contributor to the sum of these fatty acids. Data showed that cytotoxic GLA and DGLA, the latter provided either by the host or by endogenous synthesis, remained in human tumours for at least 4 days.

Topics: 8,11,14-Eicosatrienoic Acid; Animals; Arachidonic Acid; Biotransformation; Brain; Breast Neoplasms; Carbon Radioisotopes; Female; gamma-Linolenic Acid; Humans; In Vitro Techniques; Lithium Compounds; Liver; Male; Mice; Mice, Nude; Pancreatic Neoplasms; Prostatic Neoplasms; Time Factors; Tumor Cells, Cultured

Cachexia is common in patients with pancreatic cancer and has been associated with persistent activation of the hepatic acute phase response and increased energy expenditure. Fatty acids have been shown to have anticachectic effects in animal models and to reduce inflammatory mediators in healthy subjects and patients with chronic inflammatory disease. Eighteen patients with unresectable pancreatic cancer received dietary supplementation orally with fish oil capsules (1 g each) containing eicosapentaenoic acid 18% and docosahexaenoic acid 12%. Anthropometric measurement, body composition analysis, and measurement of resting energy expenditure and serum C-reactive protein were performed before and after supplementation with a median of 12 g/day of fish oil. Patients had a median weight loss of 2.9 kg/month (IQR 2-4.6) prior to supplementation. At a median of 3 months after commencement of fish oil supplementation, patients had a median weight gain of 0.3 kg/month (IQR 0-0.5) (p < 0.002). Changes in weight were accompanied by a temporary but significant reduction in acute phase protein production (p < 0.002) and by stabilisation of resting energy expenditure. This study suggests a component fish oil, perhaps EPA, merits further investigation in the treatment of cancer cachexia.

Topics: Acute-Phase Proteins; Cachexia; Dietary Fats, Unsaturated; Eicosapentaenoic Acid; Energy Metabolism; Fish Oils; gamma-Linolenic Acid; Humans; Pancreatic Neoplasms; Weight Gain