Potentially lethal damage repair

Barendsen GW, Van Bree C, Franken NAP. Importance of cell proliferative state and potentially lethal damage repair on radiation effectiveness Implications for combined tumor treatments (Review). Int J Oncol 2001 19 247-56. 

An improvement in survival due to delay in trypsinization after treatment with DNA damaging agents has been termed the repair of potential lethal damage (PLDR). It is seen that for density inhibited cells PLX)R took place following exposiu s of V-79 cells to X-rays, ultraviolet light and H2O2, albeit with different rates. Normal human cells (9) or mouse cells (10) show such... 

CeU survival studies from our laboratories have shown that the poly(ADP-ribose) polymerase inhibitor 3-aminobenzamide (3AB) increased the radiation sensitivity of normal human fibroblasts (Fig. 1) (1). In addition, 3AB was also formd to inhibit the repair of potentially lethal damage (PLD) (Fig. 1). When these inhibitor studies were extended to human tumor cell lines of dij erent clinical radiation curability, a differential effect was observed. Ewing s sarcoma cells demonstrated a radiation sensitization, whereas lung adenocarcinoma cells were found to show no radiation sensitization (Fig. lA) (2). Studies with these cell lines were also extended to post-radiation repair processes, observing PLD repair inhibition in Ewing s sarcoma, but not in lung adenocarcinoma (Fig. IB). 

Fig. IB. The effect of SAB on the repair kinetics of potentially lethal damage in normal human fibroblasts, Ewing s sarcoma, and human lung adenocarcinoma. No inhibitor (open circles) 8SAB (closed circles). Data points are means 1 standard deviation. Both normal fibroblast and human tumor cell cultures were grown and maintained in Eagle s MEM supplemented with 10% (VA ) fetal bovine serum, streptomycin and penicillin, at S7°C in a humidified chamber of 95% air and 5% CO2. Stock cultures in exponential growth were detached by trypsinization and appropriate cell numbers plated in 25 cm flasks and incubated to permit cell attachment. Inhibitors of poly(ADP-ribose) synthetase (SAB or BZ) were added to the appropriate cultures 2 hr prior to irradiation in air at room temperature. Following irradiation, the cells were exposed to the inhibitors for 24 hr, washed, and replenished with fresh medium. Refeeding was performed every S days and after 10-14 days, cells were fixed and the colonies stained with Giemsa. Only colonies of 50 cells or more were scored as survivors. All experiments were performed in triplicate and the survival data expressed as the mean S.E. of three separate survival experiments.

B. Konze-Thomas, J. W. Levinson, V. M. Maher, and J. J. McCormick, Correlation among the rates of dimer excision, DNA repair replication, and recovery of human cells from potentially lethal damage induced by ultraviolet radiation, Biophys. J. 28, 315-326 (1979). 

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