Benkő, IlonaDjazayeri, Katayoun2007-05-042007-05-042005http://hdl.handle.net/2437/2148Antineoplastic therapy-associated hematopoietic toxicity often results in neutropenia, anemia and thrombocytopenia. Neutropenia specifically has been shown to force dose reductions, cause treatment delays in subsequent chemotherapy cycles, lead to increased opportunistic infections and ultimately reduce survival. Insulin promotes survival of hematopoietic progenitors in vitro. We studied effect of insulin on granulopoiesis in vivo in mice. However the use of insulin in vivo is impractical therefore it is much more convenient to use an agent with similar properties and more moderate metabolic effects such as insulin sensitizers namely rosiglitazone. Our new results: 1. Although insulin is widely used to support colony formation in cultures of hematopoietic progenitor cells, its effects regarding hematopoiesis in vivo have not been documented. Insulin had no effects on colony formation of CFU-GM in healthy bone marrow, but it can preserv more progenitor cells in damaged marrow. 2. An insulin sensitizer drug, namely rosiglitazone in insulin-sensitizing dose had similar effects on normal and damaged bone marrow than insulin. 3. Rosiglitazone pre-treatment accelerated recovery of 5-fluorouracil-damaged bone marrow. Consequently neutropenia was milder. 4. G-CSF, the recently used agent supporting bone marrow regeneration, prior to chemotherapy actually may worsen the toxic effects on bone marrow. In contrast to these observations concurrent use of rosiglitazone with 5-FU repeatedly during 7 consecutive days did not unfavourably influence the population of the CFU-GM progenitor cells. 5. The accelerated recovery based upon a decreased susceptibility of CFU-GM progenitors to 5-FU-toxicity by the end of the 5-day rosiglitazone pre-treatment. 6. Myeloprotection was partly due to direct effects on progenitors, regarding similar effects were observed in the in vitro bone marrow cell cultures than in vivo. 7. In vitro rosiglitazone’s beneficial effects were neutralized by a peroxisome-proliferator-activated receptor gamma (PPARγ) antagonist. 8. Rosiglitazone‘s beneficial modifying effect was observed in the similar dose range on the human progenitor cells than on the murine CFU-GM. Thus rosiglitazone might be a real alternative to the existing myeloprotective drugs in the future but further studies are warranted to evaluate the optimal treatment schedules.76, [12], 20 p167039 bytes158150 bytes425000 bytesapplication/pdfapplication/pdfapplication/pdfhuA kéziratos egyetemi doktori Ph.D. értekezések csak a szerzői jogok maradéktalan tiszteletben tartásával használhatókno_restrictionGyógyszertudományokOrvostudományok