Effect of polyunsaturated fatty acids on the growth of murine colon adenocarcinomas in vitro and in vivo.
The effect of the polyunsaturated fatty acids (PUFAs) linoleic acid (LA) and arachidonic acid (AA) on the growth of two murine colon adenocarcinoma cell lines (MAC26 and MAC13) has been determined both in vitro and in vivo. When the serum concentrations in the medium became growth limiting, low concentrations (18-33 microM) of both PUFAs were growth stimulatory to both cell lines, while higher concentrations were growth inhibitory. Growth stimulation by AA in both cell lines, and by LA in MAC13, was effectively inhibited by both the cyclo-oxygenase and lipoxygenase inhibitor indomethacin, and the lipoxygenase inhibitor BWA4C in a dose-dependent manner. The most effective inhibition was exerted by BWA4C, suggesting metabolism of both PUFAs through the lipoxygenase pathway for growth stimulation. In vivo studies using the MAC26 tumour showed a significant stimulation of tumour growth when LA was administered orally at concentrations higher than 0.4 g kg-1 day-1. Higher concentrations did not produce a further increase in tumour growth rate. This suggests that there is a threshold dose for growth stimulation by LA which, together with that in the diet, amounted to 3.8% of the total caloric intake. The increase in tumour volume induced by LA arose from a reduction in the potential doubling time from 41 to 28 h and was effectively reversed by indomethacin (5 mg kg-1). These results suggest that PUFAs may play an important role in tumour growth and may offer a potential target for the development of chemotherapeutic agents.
Pharmaceutical Sciences Institute, Aston University, Birmingham, UK.
H J
HJ
Hussey
M J
MJ
Tisdale
D000230:Adenocarcinoma / Q000378:metabolism*; D000704:Analysis of Variance; D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism* / Q000633:toxicity; D044482:Benzeneacetamides; D002455:Cell Division / Q000187:drug effects; D003110:Colonic Neoplasms / Q000378:metabolism*; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004042:Dietary Fats, Unsaturated / Q000009:adverse effects* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006877:Hydroxamic Acids / Q000494:pharmacology; D007213:Indomethacin / Q000494:pharmacology; D019787:Linoleic Acid; D008041:Linoleic Acids / Q000378:metabolism* / Q000633:toxicity; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism
D044482:Benzeneacetamides; D016861:Cyclooxygenase Inhibitors; D004042:Dietary Fats, Unsaturated; D006877:Hydroxamic Acids; D008041:Linoleic Acids; D016859:Lipoxygenase Inhibitors; C056614:N-(3-phenoxycinnamyl)acetohydroxamic acid; D016718:Arachidonic Acid; D019787:Linoleic Acid; D007213:Indomethacin