Growth inhibition and eicosanoid metabolism in the R3230AC mammary adenocarcinoma by interferon.
The mode of action of rat interferon (IFN) on growth of the R3230AC mammary adenocarcinoma was studied in vivo in Fischer female rats. A dose of 1 X 10(4) units of rat IFN given thrice weekly inhibited the growth of the transplanted mammary tumors. Of the five eicosanoids measured in the tumor, the content of four arachidonate products, prostaglandin (PG) E2, PGF2 alpha, 6-keto-PGF1 alpha, and thromboxane (TX) B2, was higher in mammary tumors from IFN-treated rats than the control rats. PGE2 was the major eicosanoid. In vitro PG synthesis (PGE1, PGE2, and PGF2 alpha) was lower in tumor microsomes prepared from IFN-treated tumors. These data suggest that the tumor content of four arachidonate products in the IFN-treated tumors was related to the in vivo effects of rat IFN. Indomethacin, a cyclooxygenase inhibitor, also inhibited tumor growth. Furthermore, when indomethacin was administered daily in combination with rat IFN, the tumor-inhibiting effect of rat IFN was reduced. These observations suggest that the effects of eicosanoids appear to be biphasic in this tumor model. Inhibition of arachidonic acid metabolism resulted in tumor growth inhibition, a finding consistent with the view that eicosanoid production is required for tumor enhancement. Conversely, in the experiments with rat IFN, retardation of tumor growth is associated with a greater amount of arachidonic acid metabolism, and indomethacin prevents this effect. Eicosanoids appear to be required for tumor-inhibiting effects of rat IFN, and yet inhibition in vivo of eicosanoid synthesis also resulted in retardation of tumor growth. Although the precise mechanism of action in each situation is unclear, these apparently contradicting results are consistent with the biphasic actions of eicosanoids reported in some normal tissues and transformed tumor cell lines.
R A
RA
Karmali
H
H
Schellekens
F
F
Lefevre
J
J
Marsh
C
C
Fuchs
M
M
Krim
D000230:Adenocarcinoma / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D000818:Animals; D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000378:metabolism; D005260:Female; D007213:Indomethacin / Q000494:pharmacology; D007372:Interferons / Q000494:pharmacology*; D008325:Mammary Neoplasms, Experimental / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D011451:Prostaglandin-Endoperoxide Synthases / Q000032:analysis; D011453:Prostaglandins / Q000032:analysis / Q000378:metabolism*; D051381:Rats; D011916:Rats, Inbred F344
D001095:Arachidonic Acids; D011453:Prostaglandins; D016718:Arachidonic Acid; D007372:Interferons; D011451:Prostaglandin-Endoperoxide Synthases; D007213:Indomethacin