Cerulenin compounds for fatty acid synthesis inhibition

DETAILED DESCRIPTION OF THE INVENTION I.
FAS The protein FAS (also referred to herein as OA-519) is highly correlated with the most virulent carcinomas.
FAS exhibits fatty acid synthase activity.
FAS purified from a human breast carcinoma cell line has peptide sequence homology with rat fatty acid synthase, and FAS also has functional characteristics of a fatty acid synthase.
Fatty acid synthesis by FAS was demonstrated by incorporation of .
sup.
14 C malonyl coenzyme A into fatty acids, subsequent esterification of the fatty acids, and analysis by reversed-phase thin layer chromatography.
The specific activity of purified FAS was determined spectrophotometrically by following the oxidation of NADPH at 340 nm in the presence of acetyl coenzyme A and malonyl coenzyme A.
In one determination, the specific activity of FAS was measured as 586 nanomoles NADPH oxidized/min/mg protein, which compares favorably with the value of 404 obtained for FAS from human liver.
Fatty acid synthase is a large protein found in the cytosol of cells from particular tissues, including liver and lactating mammary gland, but FAS is not expressed in most normal (non-malignant) adult tissues.
Fatty acid synthase in higher organisms is a multifunctional enzyme which is well known to carry out the following seven enzymatic functions on a single molecule (Wakil, S.
J.
, Biochemistry, 28:4523-4530, 1989): acetyl transacylase malonyl transacylase beta-ketoacyl synthetase (condensing enzyme) beta-hydroxyacyl dehydrase enoyl reductase thioesterase Breast cancer cells have been found to express fatty acid synthase, while most other rumor cells have not been tested for the presence or absence of this enzyme.
Rochefort and co-workers have partially cloned FAS from breast cancer cells and found that FAS expression by breast cancer cell lines was correlated with responsiveness to progesterone (Chalbos, et al, J.
Biol.
Chem,, 262:9923-9926, 1987).
Based on this evidence, they concluded that cells expressing FAS were from tumors that were less de-differentiated and therefore less virulent (Chalbos, et al, J