Abstract
DNA damage was evaluated by flow cytometric (FCM) analysis of cells treated with Lβphenylalanine mustard (LβPAM) and stained with antiβDNA monoclonal antibody (MAb) F7β26. DNA damage was rapidly repaired, as indicated by the loss of DNA immunoreactivity after removal of LβPAM. Two types of drug combinations were found to inhibit DNA repair. Combinations containing inhibitors of DNA polymerase (araβC, aphidicolin) or these inhibitors and hydroxyurea inhibited DNA repair in A2780/PAM and A549 cells. The inhibition of DNA repair by combinations of DNAβdamaging agents thloTEPA or cisplatln and DNA polymerase inhibitors is a novel observation based on the specificity of DNA damage assay with MAb F7β26. Combinations containing thioTEPA or cisplatin inhibited DNA repair in A549 but not in A2780/PAM cells. Drug combinations which inhibited DNA repair also significantly enhanced cell killing by LβPAM. Cell survival in cultures treated with LβPAM and efficient inhibitors was 2 to 3 orders of magnitude lower than was expected for additive survival. ThioTEPA and cisplatin play a dual role in combination chemotherapy by inducing DNA damage and inhibiting repair of DNA damage. FCM analysis of DNA repair may be a useful component of drug evaluation and could be applied to determine cellβtype specific sensitivity to inhibitors of DNA repair.