Effects of the Tricyclic Nucleoside 6-Amino-4-methyl-8-(β-d-ribofuranosyl)-pyrrolo[4,3,2-de]pyrimido[4,5-c]pyridazine on the Viability and Cell Cycle Distribution of L1210 Cells in Vitro¹ Free

TCN (1 µm) totally inhibited the growth of L1210 cells in culture and caused progressive loss of cellular viability, as indicated by a decreased clonogenicity and nigrosin dye exclusion. After 24 h or more of TCN treatment, a significant fraction of the cells had shrunk in size but did not fragment into dye-impermeable vesicles as reported previously for N1S1-67 hepatoma cells (P. G. W. Plagemann, J. Natl. Cancer Inst., 57: 1283–1295, 1976). TCN-induced growth inhibition was accompanied by a block of cell cycle progression in G₁ or at the G₁-S boundary. At all TCN concentrations studied, progression of cells out from behind this block was evident as a depletion of the early S-phase population in comparison to controls, while increasing the concentration of TCN (0.1 to 1 µm) led to a progressive retention of cells in S phase, suggesting a slowing of progression through S phase. The fraction of S-phase cells incorporating [methyl-³H]thymidine and the amount of [methyl-³H]thymidine incorporated per labeled cell were both decreased by TCN treatment. Increasing the concentration of TCN (0.1 to 1 µm) progressively decreased DNA synthesis and increased cell lethality. Thus it appeared that inhibition of DNA synthesis might cause the retention of cells in S phase which is associated with TCN lethality.