INSULIN AND INSULIN-LIKE GROWTH-FACTOR-I (IGF-1) INHIBIT REPAIR OF POTENTIALLY LETHAL RADIATION-DAMAGE AND CHROMOSOME-ABERRATIONS AND ALTERDNA-REPAIR KINETICS IN PLATEAU-PHASE A549 CELLS

Plateau-phase A549 cells exhibit a high capacity for repair of potenti ally lethal radiation damage (PLD) when allowed to recover in their ow n spent medium. Addition of either insulin or insulin-like growth fact or-1 (IGF-1) to the spent medium 60 to 120 min before irradiation sign ificantly inhibits PLD repair. The 9-h recovery factor (survival with holding/survival without holding) is reduced from 10.8 +/- 0.7 to 3.4 +/- 0.3 by insulin and to 3.0 +/- 0.4 by IGF-1. Neither growth factor alters the cell age distribution of the plateau-phase cells, increases the rate of incorporation of 5-bromo-2'-deoxyuridine into DNA, or alt ers the extent of radiation-induced mitotic delay in cells subcultured immediately after irradiation. Both insulin and IGF-1 alter the kinet ics for rejoining of DNA double-strand breaks (DSBs), slowing the fast component of rejoining significantly, However, these growth factors h ave no effect on the initial level of DSBs or on the percentage of res idual unrejoined breaks at 120 min postirradiation. Both growth factor s affect repair of lesions leading to dicentric, but not to acentric, chromosome aberrations significantly. In control cells (treated with p hosphate-buffered saline, 90 min prior to irradiation), the half-time for disappearance of dicentrics was 4.1 h (3.4 to 5.1 h), and 47.1 +/- 3.7% of the residual damage remained at 24 h postirradiation. Insulin and IGF-1 increased the half-time for disappearance of dicentrics to 5.2 h (3.9 to 7.7 h) and 5.7 h (5.5 to 5.9 h), respectively, and incre ased residual damage to 56.1 +/- 5.9% and 60.8 +/- 6.0%, respectively. Overall, these data show that insulin and IGF-1 inhibit PLD repair in A549 cells by mechanisms which are independent of changes in cell cyc le parameters. The data suggest that the growth factors act by inducin g changes in chromatin conformation which promote misrepair of radiati on-damaged DNA. (C) 1995 by Radiation Research Society