In vivo and in vitro biotransformation of the lithium salt of gamma-linolenic acid by three human carcinomas

Abstract

Summary 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 A5-desaturase activity on DGLA. In the in vivo studies, nude mice bearing the human carcinomas were given Li[1-14C]GLA (2.5 mg kg-') 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.

Activity and mRNA abundance of Δ‐5 and Δ‐6 fatty acid desaturases in two human cell lines

“…The sizes of the transcripts at 4.3 kb and 3.1 kb, respectively, agree well with those reported earlier in human tissues [4^6]. Our ¢ndings in Chang cells showing the lack of v-6 Table 4 Percent of radioactivity recovered in n-3 and other fatty acids of Chang and ZR-75-1 cells after a 12 h incubation with [1][2][3][4][5][6][7][8][9][10][11][12][13][14] Values are the mean þ S.D. of at least three determinations.…”

“…ND: not detected. Table 5 Percent of radioactivity recovered in n-6 desaturation and elongation metabolites of [1][2][3][4][5][6][7][8][9][10][11][12][13][14] desaturase activity for any substrate and a corresponding absence of mRNA, but, with signi¢cant v-5 desaturase activity and its mRNA, are the ¢rst to suggest that v-5 and v-6 desaturase genes have, at least in part, independent control mechanisms. However, our data are not su¤cient to distinguish between direct transcriptional control or RNA transcript stability.…”

“…Aliquots of the total lipid extracts were taken for radioactivity determination, whereas other aliquots were methylated using BF 3^m ethanol. The radiolabelled fatty acid methyl esters (FAME) were analyzed as previously described [13] using a Hewlett Packard (1090, series II) chromatograph equipped with a diode array detector set at 205 nm, a radioisotope detector (model 171, Beckman, Fullerton, CA, USA) with a solid scintillation cartridge (97% e¤ciency for 14 C detection) and a reverse-phase ODS (C-18) Beckman column (250 mmU4.6 mm i.d. ; 5 Wm particle size) attached to a pre-column with a WBondapak C-18 (Beckman) insert.…”

Multiple roles of dihomo-γ-linolenic acid against proliferation diseases

“…It was observed that of all the fatty acids tested, GLA or DGLA was the most effective in selectively killing the tumor cells [ 6 ]. In a co-culture experiment wherein normal human skin fibroblasts and human breast cancer cells were grown together in a petri dish supplemented with GLA or DGLA, only human breast cancer cells were eliminated without any effect on normal skin fibroblasts [ 65 , 68 , 70 , 71 ]. These results reconfirmed that GLA or DGLA show selective tumoricidal action at least in vitro.…”

Clinical application of C18 and C20 chain length polyunsaturated fatty acids and their biotechnological production in plants

“…Topically applied GLA is an effective agent against superficial bladder carcinoma whereas the novel compound meglumine-GLA synergistically enhanced the cytotoxicity of epirubicin toward human urothelial carcinoma cell lines (70). Encouraging data were also obtained with the lithium salt of GLA in a phase III study on pancreatic cancer patients (71,72). A propane diol GLA/EPA emulsion provided a 640fold higher dose of both GLA and EPA as compared with free PUFA.…”