[PROC. AMER. ASSOC. CANCER RES. 40, March 1999]
Copyright © 1999 by the American Association for Cancer Research
#440 AG3340, a selective MMP inhibitor, has broad antiangiogenic activity across oncology and
ophthalmology models in vivo. Shalinsky, D.R., Zou, H., McDermott, C.D., Brekken, J., Niesman, M.R., Rivero,
M.E., Garcia, C.R., Freeman, W.R. & Appelt, K. Agouron Pharmaceuticals, Inc., Depts. of Pharmacology
(D.R.S., H.Z., C.D.M., J.B., M.R.N.) and Opthalmology Research (K.A.), San Diego, CA and Dept. of
Opthalmology (M.E.R., C.R.G., W.R.F.), Shiley Eye Center, U.C. San Diego, San Diego, CA.
Oral administration of AG3340 produces profound growth delays in human colon (COLO-320DM) (Proc. AACR
39:2059, 1998), human NSCLC (Proc. NCI-EORTC, 73:A278, 1998), and human prostatic PC-3 tumors (Proc.
AACR 39:4400, 1998) grown subcutaneously in nude mice. Angiogenesis in tumors was quantified by CD-31 staining
after mice underwent extended oral treatment with AG3340. In NSCLC tumors, AG3340 decreased the number of
blood vessels by up to 77% in a dose-dependent manner over the range of 50-200 mg/kg given twice daily. In colon
and prostatic tumors, mice were dosed with 100 mg/kg twice daily; AG3340 decreased CD-31 staining by
approximately 50% (p <= 0.05). In an ophthalmic model in new born mice, AG3340 also inhibited oxygen-induced
retinal neovascularization by 69.3% (p < 0.04) in a dose-dependent manner when given intraperitoneally. These data
demonstrate a broad inhibition of angiogenesis by AG3340 across human tumor and murine ophthalmology models in
vivo, supporting clinical trials of AG3340 in diseases with pathological angiogenesis.
|
