Modifications in repair and expression of potentially lethal damage (α-PLD) as measured by delayed plating or treatment with β-araA in plateau-phase Ehrlich ascites tumor cells after exposure to charged particles of various specific energies.

The ability of Ehrlich ascites tumor cells (EAT cells) to repair potentially lethal damage (α-PLD) as demonstrated by either an increase in survival after delayed plating or a decrease in survival after treatment with β-arabinofuranosyladenine (β-araA) was investigated after exposure to protons, deuterons, 3He, 4He, and heavy ions of various specific energies. A significant amount of repair or fixation was observed after delayed plating or treatment with β-araA, respectively, in cells that were exposed to protons of 6-21 MeV energy, reflecting mainly variations in the survival curve shoulder width. Four-hour treatment with 80 μM/liter β-araA resulted in an exponential survival curve for all proton energies tested. A decrease in particle energy increased killing and caused a reduction in D(q) without a significant change in D(O). The survival curve obtained after exposure of cells to 3.4 MeV protons had only a small shoulder and was only slightly modified by either delayed plating or treatment with β-araA, suggesting a decrease in the induction rate of α-PLD. Similar results were also obtained after exposure to deuterons and 4He ions. The results are interpreted as indicating the importance of the specific particle energy and the δ-electron spectrum in the induction of α-PLD. When the results of delayed plating of cells exposed to protons, deuterons, or helium ions were pooled, an exponential relationship between D(q) and penumbra radius was indicated. After exposure to 40Ar ions of 18 MeV specific energy, a shouldered survival curve was obtained, and β-araA significantly enhanced killing by modifying D(q) as well as D(O), a result that also suggests induction of repairable damage by the δ particles produced and interaction of lesions induced within the core of the ion path with penumbra lesions. Based on these results a model is proposed assuming that α-PLD results from interaction, during the course of repair, of pairs of DNA lesions induced within a distanced (i). The model assumes (a) the existence of a critical separation distance d(ic), with the property that pairs of lesions induced with separation distance shorter than d(ic) (expressed as number of base pairs) will always be expressed as lethal, and (b) the existence of a maximum separation distance d(im), with the property that pairs of lesions induced with separation distance larger than d(im) will not interact. Further, it is assumed that the interaction of lesions induced at a distance d(i) such that d(ic) ≤ d(i) ≤ d(im) depends on the postirradiation conditions employed. It is thought that d(i) decreases if cells are kept under conditions preventing proliferation (DP) and that it increases after treatment with β-araA. In both cases variation in d(i) is attributed to treatment-associated alterations in chromatin structure. The observed reduction in the induction of PLD with decreasing particle energy is interpreted as an increase in the fraction of pairs of lesions induced at distances shorter than d(ic), and a concomitant decrease in the fraction of pairs of lesions induced at distances between d(ic) and d(im). These hypothetical lesions are thought either to be located within the particle's penumbra or to arise from combinations of ionizations induced in the particle's core and its penumbra. Finally, the possibility of distinction between LET-dependent effects in D(O) and particle specific energy-dependent effects in D(q) is explored