Strong inhibition of replicative DNA synthesis in the developing rat cerebral cortex and glioma cells by roscovitine.
The effects of the cyclin-dependent kinase inhibitors roscovitine and olomoucine on DNA synthesis rate during normal rat brain development were studied by using short time (90 min) incubation. Both purine analogues at 100 microM concentration decreased the DNA synthesis of rat cerebral cortex in an age-dependent manner. The maximum inhibitory effect (approximately 90% for roscovitine, approximately 60% for olomoucine) occurred in rats of 2-13 days postnatal age. In adult rats (> 60 days postnatal age), the effect of both purine analogues was low. Roscovitine even at 200 microM concentration did not inhibit the fraction of DNA synthesis insensitive to hydroxyurea (unscheduled DNA synthesis (UDS)). In addition, in the RG2 rat glioma model, roscovitine produced a strong inhibition of DNA synthesis in glioma cells when compared to adult normal tissue. Since in adult rat brain more than 60% of DNA synthesis is related to DNA repair, usually measured as UDS, our results indicate that roscovitine strongly blocks ongoing DNA synthesis connected with replicative processes.
Yakisich
Juan Sebastian
JS
Department of Clinical Neuroscience, Huddinge Division of Neurology, Karolinska Institute, Huddinge University Hospital, SE-141 86 Stockholm, Sweden. Sebastian.Yakisich@ki.se
Vita
Marina Fernanda
MF
Siden
Ake
A
Tasat
Deborah Ruth
DR
Cruz
Mabel
M
D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D016588:Anticarcinogenic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D002540:Cerebral Cortex / Q000187:drug effects* / Q000378:metabolism*; D004247:DNA / Q000096:biosynthesis* / Q000187:drug effects; D004249:DNA Damage / Q000187:drug effects; D004260:DNA Repair / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D005910:Glioma / Q000188:drug therapy*; D006801:Humans; D066298:In Vitro Techniques; D007701:Kinetin / Q000494:pharmacology / Q000627:therapeutic use; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D011687:Purines / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077546:Roscovitine
D016588:Anticarcinogenic Agents; D019384:Nucleic Acid Synthesis Inhibitors; D047428:Protein Kinase Inhibitors; D011687:Purines; D000077546:Roscovitine; C090046:olomoucine; D004247:DNA; D007701:Kinetin