Activity of the farnesyl protein transferase inhibitor SCH66336 against BCR/ABL-induced murine leukemia and primary cells from patients with chronic myeloid leukemia

Abstract

BCR/ABL, the oncoprotein responsible for chronic myeloid leukemia (CML), transforms hematopoietic cells through both Ras-dependent and -independent mechanisms. Farnesyl protein transferase inhibitors (FTIs) were designed to block mutant Ras signaling, but they also inhibit the growth of transformed cells with wildtype Ras, implying that other farnesylated targets contribute to FTI action. In the current study, the clinical candidate FTI SCH66336 was characterized for its ability to inhibit BCR/ABL transformation. When tested against BCR/ABL-BaF3 cells, a murine cell line that is leukemogenic in mice, SCH66336 potently inhibited soft agar colony formation, slowed proliferation, and sensitized cells to apoptotic

Farnesyltransferase inhibitor SCH‐66336 downregulates secretion of matrix proteinases and inhibits carcinoma cell migration

“…In nude mice, SCH-66336 inhibits the growth of human tumor xenografts either with or without oncogenic Ras, including tumors derived from prostate, 7,8 colon, lung, pancreas, bladder, 7 glioblastoma multiforme 9 and transformed Bcr/Abl leukemia cells. 6 Similar results were obtained with H-Ras transgenic mice, where SCH-66336 induces mammary tumor regression, and in Bcr/Abl-positive acute lymphoblastic leukemia P190 transgenic mice, where the drug inhibits leukemogenesis and prolongs survival. 10 Preliminary results from a phase I trial of SCH-66336 in patients with advanced solid tumors show that they have a stabilized condition.…”

“…3,4 In cultured human tumor cells, SCH-66336 effectively inhibits the isoprenylation of H-Ras but not of K-or N-Ras as these proteins can be alternatively lipidated by GGTase I. 5 Furthermore, SCH-66336 reduces activated, GTP-bound Ras levels, 6 suggesting that pathways downstream of Ras are perturbed by the FTI. In addition, SCH-66336 selectively suppresses the anchorageindependent growth of H-, K-and N-Ras transformed cells.…”

“…11 FTIs including SCH-66336 appear to promote tumor regression by multiple mechanisms, including apoptosis and cell cycle regulation. 6,7,12 MMPs, TIMPs and serine proteases of the plasminogen activation system, including uPA, uPAR, PAI-1 and plasmin, play pivotal roles in ECM remodeling during cancer invasion, metastasis and angiogenesis. [13][14][15][16][17] Components of the plasminogen activation system are regulated by Ras isoforms.…”

Novel therapies for chronic myelogenous leukemia

“…Vehicle-treated mice died of acute leukemia within 4 weeks. In contrast, nearly all the SCH66336-treated animals were disease-free for over a year [177]. These results are encouraging.…”

“…Preliminary data of FTI in CML are now being presented at meetings. SCH66336, an oral FTI, potently inhibits in vitro CFC growth of a variety of BCR-ABL transformed cell lines, including cell lines that have been selected for STI 571 resistance and primary human CML cells [177]. Furthermore, in a control study SCH66336 or vehicle were administered for 34 days to mice with experimentally induced CML.…”