EFFECT OF PIFITHRINS ON HEMOPOIETIC CLONOGENIC CELLS
Pifithrin α (PFTα), one of the first low molecular weight modulators of activity of tumor suppressor p53 [Komarov et al., 1999], increases survival of hemopoietic clonogenic cells (evaluated by the criterion of formation of endogenous spleen colonies CFU-C8 in irradiated animals. This effect appeared during administration of PFTα before and after irradiation. Increase in CFU-C8 was also observed after administration of two PFTα analogs, derivatives of 2-amino-4,5,6,7- tetrahydrobenzothiazole. These included a parent compound, 2-ATBT (2-amino-4,5,6,7- tetrahydrobenzothiazole), which is used for synthesis of PFTα, and a product of its intramolecular cyclization under physiological conditions, cyclo-PFT (2-(4-methylphenyl)imidazo[2,1-b]-5,6,7,8- tetrahydrobenzothiazole). Earlier we found that many low molecular weight compounds increasing the number of CFU-C8 (e.g. isothiourea derivatives) demonstrate NO inhibitory activity. Such activity was also found in 2-ATBT and cyclo-PFT by means of EPR spectroscopy of NO [Vanin et al., 1984]. These compounds caused more than 2-fold inhibition of NO production in vivo. Thus, it has been demonstrated that PFTα and its structural analogs increase survival of hemopoietic clonogenic cells in vivo, and NO may play a certain role in the mechanism of this effect.