Abstract
Acyclic nucleotide analogues perturb DNA replication by terminating the growing DNA chain. The analogues selected for testing on human leukemia cell lines, namely 9-[2-(phosphonomethoxy)ethyl]adenine (PMEA), 9-[2-(phosphonomethoxy)ethyl]-2,6-diaminopurine (PMEDAP), and 9-[2-(phosphonomethoxy)ethyl]guanine (PMEG) exhibited growth-inhibiting activity at low concentrations, and apoptosis-inducing activity at high concentrations. A common feature was a reduction of the proportion of G1 cell cycle phase. Activities of the analogues increased in the order PMEA<PMEDAP<PMEG. The lymphoid cell line MOLT-4 was more susceptible to the agents than the myelogenous cell lines HL-60 and ML-1. In semicontinuous cultures in the presence of low-concentration PMEG the steady-state viable cell concentration was lower and the proportion of G1 phase cells was suppressed. Upon gradual removal of PMEG from the medium, the cell concentration and the DNA profile returned to values characteristic for the control culture. It is concluded that low concentrations of the analogues cause reversible slowdown of growth, due to continuous repairing of damaged DNA, while high-concentrations induce apoptosis in irreparably damaged cells.
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