INHIBITION OF GROWTH AND INVASIVE ACTIVITY OF HUMAN PANCREATIC-CANCERCELLS BY A FARNESYLTRANSFERASE INHIBITOR, MANUMYCIN

The effects of manumycin, a competitive farnesyltransferase (FTase) in hibitor, on pancreatic cancer cell lines with or without K-ras mutatio n were studied. Manumycin inhibited the growth of human pancreatic can cer cells (SUIT-2, MIA PaCa-2, AsPC-1, BxPC-3) in a dose-dependent man ner. The 50% inhibitory concentration (IC50) in cell lines with a muta nt K-ras gene (SUIT-2, MIA PaCa-2, AsPC-1) was lower than that in BxPC -3 with a wild-type ras. Both mitogen activated protein kinase activit y after growth stimuli and the ability for chemotactic invasion were m arkedly more inhibited by manumycin in SUIT-2 than in BxPC-3. These re sults suggest that mutated Ras is more sensitive to manumycin than the wild type. Furthermore, tumor growth and liver metastasis in nude mic e inoculated with manumycin-treated SUIT-2 cells were inhibited dose d ependently. Inhibition of Ras activity might be a new anticancer strat egy in pancreatic cancer in which Ras plays a role.