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-tetrade-canoylphorbol-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 the tissue directly to generate DNA damaging agents or by recruiting inflammatory cells to the tissue and stimulating them to release such agents. These agents include reactive oxygen species, such as hydrogen peroxide and superoxide anion, as well as products generated during lipid peroxidation and arachidonic acid metabolism. It is not known whether significant alterations occur in the sensitivity of cells to TPA during 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 normal cultures, a primary epithelial culture and a fibroblast culture. This 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 involved in altering the response of cells to TPA. When chromosome 11 was inserted 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 telangiectasia, a syndrome localized to chromosome 11, were shown to have an elevated sensitivity to the chromosome damaging action of TPA-activated neutrophils, but not to TPA alone. These results suggest that some of the alterations occurring in a tissue during tumourigenesis could have a significant 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.