Inhibition of DNA repair and the enhancement of cytotoxicity of alkylating agents.
DNA damage was evaluated by flow cytometric (FCM) analysis of cells treated with L-phenylalanine mustard (L-PAM) and stained with anti-DNA monoclonal antibody (MAb) F7-26. DNA damage was rapidly repaired, as indicated by the loss of DNA immunoreactivity after removal of L-PAM. Two types of drug combinations were found to inhibit DNA repair. Combinations containing inhibitors of DNA polymerase (ara-C, aphidicolin) or these inhibitors and hydroxyurea inhibited DNA repair in A2780/PAM and A549 cells. The inhibition of DNA repair by combinations of DNA-damaging agents thioTEPA or cisplatin and DNA polymerase inhibitors is a novel observation based on the specificity of DNA damage assay with MAb F7-26. 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 L-PAM. Cell survival in cultures treated with L-PAM 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 cell-type specific sensitivity to inhibitors of DNA repair.
Frankfurt
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Oncology Laboratory, Cedars Medical Center, Miami, FL 33136.
D000477:Alkylating Agents / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D016590:Aphidicolin; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects*; D002945:Cisplatin; D003561:Cytarabine / Q000494:pharmacology; D004249:DNA Damage; D004260:DNA Repair / Q000187:drug effects*; D004224:Diterpenes / Q000494:pharmacology; D005260:Female; D006801:Humans; D008175:Lung Neoplasms; D008558:Melphalan / Q000494:pharmacology*; D019384:Nucleic Acid Synthesis Inhibitors; D010051:Ovarian Neoplasms; D013852:Thiotepa / Q000494:pharmacology
D000477:Alkylating Agents; D000970:Antineoplastic Agents; D004224:Diterpenes; D019384:Nucleic Acid Synthesis Inhibitors; D003561:Cytarabine; D016590:Aphidicolin; D013852:Thiotepa; D002945:Cisplatin; D008558:Melphalan