Acyclic nucleotide analogues suppress growth and induce apoptosis in humanleukemia cell lines

Acyclic nucleotide analogues perturb DNA replication by terminating the gro wing DNA chain. The analogues selected for testing on human leukemia cell l ines, namely 9-[2-(phosphonomethoxy)ethyl]adenine (PMEA), 9-[2-(phosphonome thoxy)ethyl]-2,6-diaminopurine (PMEDAP), and 9-[2-(phosphonomethoxy)ethyl]g uanine (PMEG) exhibited growth-inhibiting activity at low concentrations, a nd apoptosis-inducing activity at high concentrations. A common feature was a reduction of the proportion of G(1) cell cycle phase. Activities of the analogues increased in the order PMEA<PMEDAP<PMEG. The lymphoid cell line M OLT-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-concentrati on PMEG the steady-state viable cell concentration was lower and the propor tion of G(1) phase cells was suppressed. Upon gradual removal of PMEG from the medium, the cell concentration and the DNA profile returned to values c haracteristic for the control culture. It is concluded that low concentrati ons of the analogues cause reversible slowdown of growth, due to continuous repairing of damaged DNA, while high-concentrations induce apoptosis in ir reparably damaged cells.