USE OF IMMUNOLOGICAL TECHNIQUES TO STUDY THE INTERACTION OF CARCINOGENS WITH DNA

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Antibodies specific for carcinogen-DNA adducts have been used to quantify DNA modification in biological samples substituted with cisplatin, 3'-azido-2',3'-dideoxythymidine (AZT) and polycyclic aromatic hydrocarbons (PAHs) by quantitative immunoassays and immunohistochemistry. A previously-observed correlation between high levels of cisplatin-DNA adduct formation in blood cell DNA of ovarian cancer patients and favorable clinical responses is being validated in blood samples from previously-untreated Stage III ovarian cancer patients. Because platinum drugs are given to ovarian cancer patients during pregnancy, cisplatin-DNA adducts have been localized and adduct persistence measured in placentas and fetal tissues from pregnant patas monkey dams exposed to cisplatin. Cisplatin perinatal exposure is tumorigenic in rat and mouse pups grown to adulthood; and to understand the mechanisms involved, DNA adducts were measured in genomic and mitochondrial DNA of rat maternal and fetal tissues. Maternal tissues had higher adduct levels than fetal tissues in genomic DNA, and mitochondrial DNA in brain and liver had 2- to 40-fold more adducts than genomic DNA. A dose-response for cisplatin-DNA adducts has been obtained in adult male mouse testis, liver and kidney. In human breast cancer cell lines the epidermal growth factor (EGF) receptor was shown to modulate cisplatin genotoxicity. Cisplatin-DNA adducts are being measured in tumor, skin and blood of cancer patients. The anti-AIDS drug, AZT, has been shown to produce dose-related preneoplastic events in mouse vaginal tissue (a target for tumorigenesis) in animals given AZT in the drinking water for 28 days. AZT was shown to incorporate into liver mitochondrial DNA in the same experiment. AZT preferentially targets telomeric regions of Chinese hamster ovary cell chromosomes. US Army personnel exposed to Kuwaiti oil well fires experienced less PAH exposure and DNA damage in Kuwait than in Germany. Antisera is being elicited against a benzene-protein adduct and will be used for monitoring benzene-exposed workers in China and in the United States.