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Katayoun Djazayeri M.D., Ph.D. IIInst. of Pharmacology and PharmacotherapyEFFECT OF ROSIGLITAZONE ON MYELOTOXICITY INDUCED BYCYTOSTATIC AGENTS.Introduction: Antineoplastic therapy-associated neutropenia has beenshown to result in dose reductions, treatment delays in subsequent chemotherapycycles and mainly it could lead to increased opportunistic infections andultimately reduced survival. Insulin promotes survival of haemopoieticprogenitors. We investigated if rosiglitazone, an insulin sensitizer, could conferprotection against myelotoxicity induced by cytostatic agents in vivo in mice.Rosiglitazon’s effects were also studied on in vitro cultures of human bloodstem cells.Methods: After a single doses of the cytostatic agents the decrease in bonemarrow cellularity, frequency and content of granulocyte-macrophageprogenitors (CFU-GM) characterized myelotoxicity in mice. Insulin orrosiglitazone in variety of doses were added for 5 days before the application ofcytostatics. Additionally in vitro cultures of human mobilized peripheral bloodstem cells were studied under the influence of rosiglitazone pretreatment beforethe induction of 5-FU.Results: In mice with bone marrow damage induced by 5-FU theaccelerated recovery of hemopoiesis was observed in groups pretreated withrosiglitazone. CFU-GM colony numbers rapidly reached mean baseline, 1 and 2days earlier in groups pre-treated with 3 and 6 mg/kg of rosiglitazone,respectively, comparing with groups treated with 5-FU alone. Consequently,neutropenia was less severe, absolute neutrophil counts were significantly higherthan that of the non-pretreated mice. We considered that it could be potentiallypossible that such results may be due to direct sensitization of progenitor cells toinsulin as the 5-day-long insulin pre-treatment had similar myeloprotectiveeffects. In the case of carboplatin-induced damage of CFU-GM cells weobserved the same protective influence due to rosiglitazone pretreatment. Pretreatmentwith 1.0 uM of rosiglitazone could enhance colony formation ofhuman mobilized peripheral blood stem cells upto 25-fold, compared withcultures treated with 5-FU alone.Conclusions: These results led us to believe, that the higher intensity ofproliferation of CFU-GM cells in rosiglitazone pretreated bone marrowaccelerates recovery of granulopoiesis, results in less severe neutropenia anddecreases infections associated with neutropenia caused by cytostatic drugs.Témavezető: Dr. Benkő Ilona