In vivo and in vitro biotransformation of the lithium salt of gamma-linolenic acid by three human carcinomas.
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.
de Antueno
R
R
Scotia Research Institute, Kentville, NS, Canada.
Elliot
M
M
Ells
G
G
Quiroga
P
P
Jenkins
K
K
Horrobin
D
D
D015126:8,11,14-Eicosatrienoic Acid / Q000097:blood / Q000493:pharmacokinetics; D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism; D001711:Biotransformation; D001921:Brain / Q000378:metabolism; D001943:Breast Neoplasms / Q000378:metabolism*; D002250:Carbon Radioisotopes; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D018020:Lithium Compounds / Q000097:blood / Q000493:pharmacokinetics*; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008819:Mice, Nude; D010190:Pancreatic Neoplasms / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000378:metabolism*; D013997:Time Factors; D014407:Tumor Cells, Cultured; D017965:gamma-Linolenic Acid / Q000097:blood / Q000493:pharmacokinetics*
D002250:Carbon Radioisotopes; D018020:Lithium Compounds; D016718:Arachidonic Acid; D017965:gamma-Linolenic Acid; D015126:8,11,14-Eicosatrienoic Acid