The effects of irradiation were evaluated in L5178Y lymphoblasts treated with the
adenosine deaminase inhibitor,
2'-deoxycoformycin, and
deoxyadenosine. A synergistic antitumor effect was observed in resting cells between irradiation and
2'-deoxycoformycin/
deoxyadenosine, with the dose required to reduce the surviving cell fraction to 0.1 being 25% lower than predicted for an additive effect. Synergy was enhanced with increasing
deoxyadenosine concentration or with increasing radiation dose. When cells were treated with
2'-deoxycoformycin/
deoxyadenosine for 1 h prior to irradiation, synergy was increased by prolonging postirradiation
drug treatment. With 4-h postirradiation exposure to
drug, varying the preirradiation incubation time did not affect synergy. In contrast, only a small enhancement of antitumor activity was observed in irradiated proliferating cells treated with
2'-deoxycoformycin/
deoxyadenosine. Incubation of resting cells with
2'-deoxycoformycin/
deoxyadenosine resulted in inhibition of the rate and extent of repair of radiation-induced
DNA single strand breaks and an increase in dATP, but had no effect on
NAD or
ATP. With removal of
drug, the dATP level fell rapidly and DNA repair resumed. Repair of
DNA single strand breaks was more rapid in proliferating cells than in resting cells and was minimally affected by
2'-deoxycoformycin/
deoxyadenosine, although the accumulation of dATP in these cells was 2-fold greater than in resting cells. The repair of
DNA single strand breaks in
chronic lymphocytic leukemia cells was as rapid as for proliferating L5178Y cells, but repair was significantly inhibited by
2'-deoxycoformycin/
deoxyadenosine. These results suggest that
2'-deoxycoformycin/
deoxyadenosine can function as a radiosensitizer, and this effect is associated with the cellular accumulation of dATP and inhibition of repair of
DNA single strand breaks.