Myeloprotective effects of rosiglitazone, an insulin sensitizer, on 5-fluorouracil-induced toxicity

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dc.contributor.advisorBenkő, Ilona
dc.contributor.authorDjazayeri, Katayoun
dc.contributor.departmentDE -- Orvos- és Egészségtudományi Centrum -- Általános Orvostudományi Kar -- Farmakológiai és Farmakoterápiai Intézeten
dc.contributor.departmentGyógyszertudományok doktori iskolahu
dc.date.accessioned2007-05-04T15:08:52Z
dc.date.available2007-05-04T15:08:52Z
dc.date.created2005
dc.date.defended2005-11-25
dc.date.issued2007-05-04T15:08:52Z
dc.description.abstractAntineoplastic 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.en
dc.description.bibliographyBibliográfiát tartalmazhu
dc.description.correctorNE
dc.description.degreePhDen
dc.format.extent76, [12], 20 pen
dc.format.extent167039 bytes
dc.format.extent158150 bytes
dc.format.extent425000 bytes
dc.format.mimetypeapplication/pdf
dc.format.mimetypeapplication/pdf
dc.format.mimetypeapplication/pdf
dc.identifier.urihttp://hdl.handle.net/2437/2148
dc.languagehunhu
dc.language.isohuen
dc.language.isoenen
dc.rightsA kéziratos egyetemi doktori Ph.D. értekezések csak a szerzői jogok maradéktalan tiszteletben tartásával használhatókhu
dc.rights.accessno_restrictionen
dc.subject.disciplineGyógyszertudományokhu
dc.subject.sciencefieldOrvostudományokhu
dc.titleMyeloprotective effects of rosiglitazone, an insulin sensitizer, on 5-fluorouracil-induced toxicityen
dc.title.subtitlethesis for degree of doctor of philosophy : Ph.Den
dc.title.translatedAz inzulin érzékenyítő roziglitazon 5-fluorouracil okozta csontvelő toxicitást mérséklő, myeloprotectív hatásaen
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