DNA repair: relationship to drug and radiation resistance, metastasis and growth factors

DNA repair mechanisms are important for the recovery of both normal and malignant tissues from radiation and chemotherapy. Drug 'resistance' may merely reflect the similarity of cancer to normal tissues. Investigating the normal repair mechanisms by cloning human DNA repair genes will permit a much better comparison. Therapeutic inhibition of DNA repair may be possible with poly-ADP-ribose polymerase inhibitors. A differential effect may be obtained since less-differentiated cells have a higher poly-ADP-ribose polymerase activity. Clinical application of repair inhibitors can be achieved by using antimetabolites such as high-dose hydroxyurea which produces levels of 1-3 mmol litre -1/24 hours. The whole cell and tissue response to DNA damage is more complex than removal of adducts and joining strand breaks. DNA damage can result in an increase in growth-factor receptors, the release of soluble mediators that affect undamaged cells and stimulation of plasminogen activator. These changes may enhance growth and recovery as well as bypass or repair the damage. The generation of heterogeneity in a tumour population may be mediated by DNA rearrangements. Genetic instability is much higher in metastatic clones and a comparison of DNA strand-break repair in a metastatic and a non-metastatic line showed more rapid repair in the former. Aberrant use of DNA repair stimulated by growth factors may mediate tumour progression and heterogeneity as well as drug resistance.