Inhibition of prostaglandin synthetase by anti-tumour agents.
The effect of a number of anti-tumour agents on prostaglandin (PG) production from arachidonate by sheep seminal vesicles has been investigated. Of the drugs examined only those belonging to the alkylating agent type series showed inhibition of enzyme activity. Unlike most inhibitors of PG synthetase (EC 1.14.99.1) these agents caused an inhibition of prostaglandin E2 (PGE2) production, while unaffecting the formation of prostaglandin F 2alpha (PGF2 alpha). This suggests the site of inhibition is the isomerase converting prostaglandin H2 (PGH2) to PGE2. Kinetic studies indicated that merophan [DL-o-micron-(di-2-chloroethylamino)phenylalanine] inhibited the synthetase competitively with respect to substrate. The kinetics of the inhibition were also consistent with the formation of a reversible enzyme-alkylating agent complex prior to irreversible inactivation of the enzyme. The inactivation process could be described by the Main equation from which a dissociation constant (Kd) and a reaction rate constant (k2) were calculated. The inhibition of PG synthetase may be important in the anti-tumour effect of these agents.
D000477:Alkylating Agents / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D016861:Cyclooxygenase Inhibitors; D066298:In Vitro Techniques; D007700:Kinetics; D008297:Male; D008861:Microsomes / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors*; D011458:Prostaglandins E / Q000096:biosynthesis; D012669:Seminal Vesicles / Q000201:enzymology / Q000648:ultrastructure; D012756:Sheep; D013997:Time Factors
D000477:Alkylating Agents; D000970:Antineoplastic Agents; D016861:Cyclooxygenase Inhibitors; D011458:Prostaglandins E; D006899:Mixed Function Oxygenases