IN-VITRO AND IN-VIVO EFFECTS OF KT6352, A DERIVATIVE OF INDOLOCARBAZOLE COMPOUNDS, ON MURINE MEGAKARYOCYTOPOIESIS

We investigated the in vitro and in vivo effects of KT6352, a derivati ve of indolocarbazole compound, on murine megakaryocytopoiesis. When s erum-free megakaryocyte (Meg) colony assay was performed with 100 U/mL of recombinant mouse interleukin-3 (rmIL-3), the addition of 1x10(-11 )M to 1x10(-9)M of KT6352 increased the number of Meg colonies. An add itional increase of Meg colonies by KT6352 was observed in the serum-f ree culture containing rmIL-3 plus recombinant mouse interleukin-6 or rmIL-3 plus recombinant mouse stem cell factor. KT6352 did not stimula te Meg colony formation without rmIL-3. When KT6352 was administered i ntraperitoneally to normal BALB/c male mice at a dose of 10 mg/kg dail y for 5 consecutive days, a 2.1-fold increase in the platelet count wa s observed on day 14, and the prolonged thrombocytopoiesis was detecta ble from 9 to 27 days after KT6352 administration. A marked increase i n the white blood cell count was also observed from 5 to 14 days after KT6352 treatment. Before the gradual increase of platelet counts, 8 d ays after KT6352 administration, a marked increase in the number of co lony-forming units of megakaryocytes (CFU-Megs) in bone marrow and spl een was observed, and a substantial increase in the number of splenic CFU-Megs was observed 14 and 23 days after KT6352 administration. Bone marrow Meg ploidy analysis by two-color flow cytometry showed a shift in the modal ploidy class from 16 to 32 and an increase in the freque ncy of 64 cells in KT6352-treated mice. These results suggest a possib le therapeutic benefit of KT6352 in the management of thrombocytopenia .