INHIBITION OF FATTY-ACID SYNTHESIS DELAYS DISEASE PROGRESSION IN A XENOGRAFT MODEL OF OVARIAN-CANCER

One of the key limiting factors in the treatment of advanced stage hum an epithelial malignancies is the lack of selective molecular targets for antineoplastic therapy. A substantial subset of human ovarian, end ometrial, breast, colorectal, and prostatic cancers exhibit increased endogenous fatty acid biosynthesis and overexpress certain enzymes in the pathway. Cell lines derived from these tumors use endogenously syn thesized fatty acids for cellular functions, whereas normal cells and tissues appear to utilize dietary lipids preferentially. We have previ ously shown that the difference in fatty acid biosynthesis between can cer and normal cells is an exploitable target for metabolic inhibitors in vitro. Here, we report observations in vivo using the i.p. model o f the multiply drug-resistant OVCAR-3 human ovarian carcinoma in nude mice which demonstrate that: (a) fatty acid synthase overexpression in OVCAR-3 is comparable to levels in primary human tumors assessed by i mmunohistochemistry; (b) fatty acid synthetic activity of OVCAR-3 is c omparably elevated in vitro and in vivo and is 4 to >20-fold higher th an normal murine tissues; (c) treatment with the specific fatty acid s ynthase inhibitor, cerulenin, markedly reduces tumor cell fatty acid b iosynthesis in vivo; (d) fatty acid synthase inhibition produces regre ssion of established ascites tumor; and (e) treatment with cerulenin c auses reduction in ascites incidence, delay in onset of ascites, and s ignificantly increased survival (P < 0.04).