thiourea and Leukemia--Erythroblastic--Acute

A series of derivatives of tetramethylurea, a known inducer of the differentiation of Friend erythroleukemia cells, has been synthesized and tested for its capacity to induce erythroid maturation, as measured by the synthesis of hemoglobin. Cyclic urea and thiourea derivatives consisting of five-, six-, and seven-membered ring systems containing N-alkyl substituents were prepared. Most of these agents were relatively effective inducers od differentiation, with N-alkyl substitution appearing to be essential for maximum response. The most potent agents developed were N,N'-dimethyl cyclic ureas. Exposure to concentrations of 2 to 4 mM of these derivatives resulted in more than 90% of the cell population achieving a differentiated state. Under these conditions, the parent compound, tetramethylurea, was slightly less efficacious, causing differentiation of only 68% of the population at its maximum effective level of 4 mM.

Topics: Animals; Cell Differentiation; Cells, Cultured; Chemical Phenomena; Chemistry; In Vitro Techniques; Leukemia, Erythroblastic, Acute; Leukemia, Experimental; Mice; Thiourea; Urea

The erythroblastic leukemia produced in Long-Evans rats by the administration of 7, 8, 12 trimethylbenz (a) anthracene has been used as a model of the most immature form of the erythrocyte series. In conjunction with studies of the maturation of several other membrane functions, the permeability of this cell to water and to certain definitive non-electrolytes was measured with osmotic methods. The hydraulic conductivity, L-p was 6.2 micro (minute)-1, (atm)-1 at 25 degrees C, quite high and characteristic of mature erythrocytes, but different from values of 0.65 for immature myeloid cells. The effect of temperature provided an energy of activation of 4.4 kCal/mole, also typical of mature mammalian erythrocytes but again different from 13 to 18 kCal/mole for immature myeloid cells. Urea was compared to thiourea. The permeability coefficient for urea was 76.7 micra (minute)-1 plus or minus 13.8 (S. E.); the value for thiourea was 1.55 micra (minute)-1 plus or minus 0.18 (S. E.). Phloretin at 0.25 mM inhibited urea permeability by 90% with 50% inhibition occurring at 0.05 mM. Inhibition was reversible. Permeability to the glycols was also compatible with mature erythrocytes. We infer from these findings that the structure which underlies these basic, passive membrane functions is laid down early and persists after loss of nucleus and subsequent maturation.

Topics: Animals; Benz(a)Anthracenes; Cell Membrane; Cell Membrane Permeability; Cells, Cultured; Computers, Analog; Ethylene Glycols; Hypertonic Solutions; Leukemia, Erythroblastic, Acute; Leukemia, Experimental; Leukemia, Myeloid; Neoplasm Transplantation; Osmosis; Phloretin; Rats; Rats, Inbred Strains; Thiourea; Urea; Water