Programfüzet (PDF) - DE OEC Tudományos Diákköri Tanács

G2.5. Guri, Yakir Gen.Med. IV.Biofizikai és Sejtbiológiai IntézetIN VIVO ANTIANGIOGENIC EFFECT OF ROSCOVITINE AND RELATEDNOVEL CDK INHIBITORSCDK inhibitors, with roscovitine being a prominent example, are increasinglyused in clinical trials of cancer treatment. Within the EU FP6 ProKinaseconsortium, further novel CDK inhibitor candidates have been selected fromsynthetic compound libraries and were found to effectively inhibit CDK2 andCDK5. Interestingly, while CDK5 is not involved in cell cycle regulation, itsinhibition diminished in vitro endothelial cell migration and neovascularizationas demonstrated using HUVEC migration and tube formation assays.We have set out to test using the mouse cornea micropocket angiogenesis assaywhether new compounds from our library also influence neovascularization invivo. As a first step, we have optimized the preparation of bFGF containingpellets that can be implanted subepithelially into the cornea to locally inducevascularization. Next, we have verified that pellets with bFGF inducevascularization whereas those lacking the growth factor do not. Finally, we havetested whether roscovitine and three novel compounds exert an inhibitory effectupon the bFGF pellet induced vascularization when injected intraperitoneally.Eight mice per treatment group, including also DMSO solvent and non-injectedcontrols were operated on both eyes and treated for 5 consecutive days. On thepostoperative 6th day, by quantitating the neovascularized area of the implantedcorneas, we determined that roscovitine and the novel LGR561, LGR848,LGR849 inhibited vascularization by 33%, 54%, 32% and 27%, respectively,and were well tolerated without side effects at a dose of 0.1 mg/g body weight.ANOVA has shown that the various treatments were significantly (p