A PROTECTIVE EFFECT OF CHROMOSOME-11 AGAINST DNA-DAMAGE BY TPA-ACTIVATED NEUTROPHILS BUT NOT TPA ACTING ALONE

Evidence from animal models suggests that 12-O-tetradecanoylphorbol-13 -acetate (TPA) is capable of inducing genetic damage within a tissue, although the mechanism underlying this response is unknown. A favoured hypothesis is that the TPA is acting either by stimulating cells in t he tissue directly to generate DNA damaging agents or by recruiting in flammatory cells to the tissue and stimulating them to release such ag ents, These agents include reactive oxygen species, such as hydrogen p eroxide and superoxide anion, as well as products generated during lip id peroxidation and arachidonic acid metabolism. It is not known wheth er significant alterations occur in the sensitivity of cells to TPA du ring the process of tumourigenesis. In this paper the capacity of TPA to induce chromosomal breakage (measured by micronuclei induction) was found to be elevated in bladder tumour cell lines compared to two nor mal cultures, a primary epithelial culture and a fibroblast culture. T his effect was observed when cells were exposed to TPA directly or co- cultured with TPA-activated neutrophils isolated from human blood. In addition, we present evidence that loci on chromosome 11 may be involv ed in altering the response of cells to TPA. When chromosome 11 was in serted into a bladder tumour cell line, a reduction in sensitivity to TPA-activated neutrophils was observed. The chromosome insert did not protect against damage induced by direct treatment with TPA alone. In another scenario, fibroblasts from a patient with ataxia telangiectasi a, a syndrome localized to chromosome 11, were shown to have an elevat ed sensitivity to the chromosome damaging action of TPA-activated neut rophils, but not to TPA alone. These results suggest that some of the alterations occurring in a tissue during tumourigenesis could have a s ignificant impact on the responsiveness of cells to genetic damage by TPA. They also suggest that the damage induced by TPA in a cell may be different if a neutrophil is present.