Cytotoxicity of poly(phenolic)sulfonates and their sodium salts in l1210 lymphoid leukemia cells

Poly(phenolic)-sulfonates demonstrated very good cytotoxicity against the growth of tumor cell lines (L1210, Tmolt-(3), HeLa-S(3)) and are comparable in potency with typical clinically used anticancer drugs. Four of the most active compounds, i.e. GL-2021, GL-2029, GL-2041 and GL-2063, were selected for a mode of action study in L1210 lymphoid leukemia cells at concentration of 25muM to 100muM for 60 min. The agents did not alkylate bases of ct-DNA, cause intercalation between base pairs, produce cross linking of ct-DNA strands or generate free radicals although L1210 DNA fragmentation was observed after 24 hr incubation. L1210 DNA synthesis was preferentially inhibited which was achieved by (1) suppressing DNA polymerase alpha activity which reduced the synthesis of new strands of DNA, (2) reducing of de novo purine synthesis at the regulatory enzyme PRPP amido transferase which reduced d(GMP) levels, and (3) inhibiting of nucleoside kinase activities which further reduced DNA synthesis. DNA template activity was altered by the poly(phenolic)sulfonates since they reduced DNA polymerase alpha and m-RNA and t-RNA polymerase activities. The kinetic studies at 50 muM over 2 hr demonstrated that the agents' effect on PRPP-amido transferase activity is probably a major target of the compounds.