title: In vitro and in vivo antitumor properties of the cyclin dependent kinase inhibitor CYC202 (R-roscovitine).
abstract: CDK2 inhibitors have been proposed as effective anti-cancer therapeutics. We show here that CYC202 (R-roscovitine) is a potent inhibitor of recombinant CDK2/cyclin E kinase activity (IC(50) = 0.10 microM) with an average cytotoxic IC(50) of 15.2 microM in a panel of 19 human tumour cell lines, and we also demonstrate selectivity for rapidly proliferating cells over non-proliferating cells. A study of the cell cycle effects of CYC202 in Lovo colorectal carcinoma cells showed that the major effect was not the predicted arrest in one part of the cycle, but rather an induction of cell death from all compartments of the cell cycle. The maximum tolerated dose given intravenously to mice was in excess of 20 mg/kg. Doses up to 2,000 mg/kg were tolerated when administered orally in mice. Following repeated intraperitoneal administration (3 times daily for 5 days) of 100 mg/kg to nude mice bearing the Lovo human colorectal tumour, CYC202 induced a significant antitumour effect with a 45% reduction in tumour growth compared to controls. A second experiment using the human uterine xenograft MESSA-DX5 treated with orally administered CYC202 (500 mg/kg 3 times daily for 4 days) also exhibited a significant reduction in the rate of growth of the tumour (62%). These data, showing enzyme and cellular potency together with antitumour activity, confirm the potential of CDK2 inhibitors such as CYC202 as anticancer drugs.
authors.affiliation: Cyclacel, Ltd., Dundee, United Kingdom. smcclue@cyclacel.com
authors.forename: Steven J
authors.initials: SJ
authors.lastname: McClue
authors.forename: David
authors.initials: D
authors.lastname: Blake
authors.forename: Rosemary
authors.initials: R
authors.lastname: Clarke
authors.forename: Angela
authors.initials: A
authors.lastname: Cowan
authors.forename: Lorna
authors.initials: L
authors.lastname: Cummings
authors.forename: Peter M
authors.initials: PM
authors.lastname: Fischer
authors.forename: Mairi
authors.initials: M
authors.lastname: MacKenzie
authors.forename: Jean
authors.initials: J
authors.lastname: Melville
authors.forename: Kevin
authors.initials: K
authors.lastname: Stewart
authors.forename: Shudong
authors.initials: S
authors.lastname: Wang
authors.forename: Nikolai
authors.initials: N
authors.lastname: Zhelev
authors.forename: Daniella
authors.initials: D
authors.lastname: Zheleva
authors.forename: David P
authors.initials: DP
authors.lastname: Lane
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy; D019927:Cyclin E; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000188:drug therapy*; D011687:Purines / Q000494:pharmacology*; D011994:Recombinant Proteins; D000077546:Roscovitine; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D019927:Cyclin E; D004791:Enzyme Inhibitors; D011687:Purines; D011994:Recombinant Proteins; D000077546:Roscovitine; D018844:Cyclin-Dependent Kinases