Comparative kinetics of poly(6-thioinosinic acid) and 6-mercaptopurine treated L1210 cells

Poly(6-thioinosinic acid), poly(s6I), a synthetic polynucleotide shown to inhibit L1210 ascites growth in vivo, was compared with 6-mercaptopurine (6-MP) for their effects on cellular kinetics of L1210 cells in vitro. These kinetic perturbations were monitored by changes in growth rates, cell volumes and cell-cycle distributions. At equimolar exposure doses (based on molar concentration of purine bases), 0.1 mM poly(s6I) was more effective than 6-MP in reducing growth rate and total cell number. A 20-fold increase in the 6-MP exposure dose (to 2 mM) was required to reduce total cell number similar to 0.1 mM poly(s6I). Concomitant determination of Coulter volume distributions of treated cell populations indicated 0.1 mM poly(s6I) increased the mean population volume more than either concentration of 6-MP. Cell-cycle distributions obtained by flow cytometry showed that, simultaneously with the increase in mean population volume, poly(s6I) exposure caused a decrease of cells in G1 and S and a pronounced accumulation of cells in G2. Treatment with 6-MP caused similar cell-cycle redistributions but always less than for poly(s6I). Flow sorting of these redistributed populations indicated the increase in mean population volume during treatment with 0.1 mM poly(s6I) was almost equally due to an increased percentage of G2 cells and to an increased volume of cells with the G2 DNA content. However, with 0.1 mM 6-MP, increased volume of G2 cells was predominant. Although poly(s6I) was synthesized in an attempt to develop more effective delivery forms of biologically active compounds like 6-MP and it has close structural similarities to 6-MP, its mechanism of action is unknown.