Inactivation of human cells cultivated in vitro by the new mitotic inhibitors NY 4137 and NY 4138.
The effect of the two closely related drugs, the sulfone 2-(2-thenyl)sulfonyl-5-bromopyrimidine (NY 4137), and the sulfoxide 2-(2-thenyl)sulfinyl-5-bromopyrimidine (NY 4138), a sulfoxide, on the survival of cells of the human line NHIK 3025 was investigated. Cell survival was measured as the ability of single cells to form macroscopic colonies. Two-hour treatment with 0.012 mM NY 4137 resulted in 50% inactivation. The drug concentration of NY 4138 had to be adjusted about 10 times higher than that of NY 4137 for treatment periods of 2 or 24 h to obtain similar surviving fraction after treatment of asynchronous cells. Treatment of synchronized NHIK 3025 cells with NY 4137 showed that survival varied little with cell age. Following treatment with NY 4138, however, cells were particularly sensitive in G2 and in mitosis. As the survival curves for both drugs display a plateau region, where increasing the drug dose has little or no effect on cell inactivation, the presence of resistant subpopulations of cells is considered. High-performance liquid chromatography of drug solutions in cell culture medium showed that both NY 4137 and NY 4138 bound to, or were metabolized by, medium and/or cell components. The concentration of NY 4137 in cell culture medium, however, was reduced at a higher rate than NY 4138. The half-life of NY 4137 was on the order of 5 h, while the half-life of NY 4138 was over 24 h. These observations correlate well with the relative chemical reactivities for these drugs in nucleophilic displacement reactions.
Nygaard
M E
ME
Department of Tissue Culture, Norwegian Radium Hospital, Montebello, Oslo.
Pettersen
E O
EO
Dornish
J M
JM
Undheim
K
K
Oftebro
R
R
D002470:Cell Survival / Q000187:drug effects*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007399:Interphase / Q000187:drug effects; D011743:Pyrimidines / Q000378:metabolism / Q000494:pharmacology*
D011743:Pyrimidines; C047250:NY 4138; C051723:2-(2-thenyl)sulfonyl-5-bromopyrimidine