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 polycyclic aromatic hydrocarbons (PAH). cisplatin and 3' -azido-2' .3' - dideoxythymidine (AZT) by quantitative immunoassays and immunohistochemistry. Studies conducted to measure PAH-DNA adducts in blood cell DNA of Army personnel exposed to oil well fires in Kuwait. using the benzo[a]pyrene-DNA dissociation-enhanced lanthanide fluoroimmunoassay (DELFIA) and 32P-postlabeling. showed a reduction of DNA adducts in Kuwait as compared to subsequent time spent in Germany. This correlated with observations of cleaner air in Kuwait in the area of the soldiers' duty stations. A previously-observed correlation between high levels of cisplatin-DNA adduct formation in nucleated 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 on the Southwest Oncology Group 9249 protocol. Other parameters to be correlated with disease response are HPRT mutagenesis and platinum drug pharmacokinetics. Because platinum drugs are given to ovarian cancer patients during pregnancy. cisplatin-DNA adducts are being localized and adduct persistence measured in placentas and fetal tissues from pregnant patas monkey dams exposed to cisplatin. In addition. perinatal platinum drug exposure is tumorigenic in rat and mouse pups. and DNA adducts are being measured in the pups after tumorigenic cisplatin exposures. The anti-AIDS drug. AZT. has been shown to produce dose-related preneoplastic events, including drug-DNA incorporation, epithelial proliferation and alpha6-integrin staining expansion, in mouse vaginal tissue (a target for tumorigenesis) in animals given AZT in the drinking water for 28 days. AZT incorporation into liver genomic and mitochondrial DNA is under study. This drug has been shown both immunohistochemically and quantitatively to preferentially target telomeric regions of CHO cell chromosomes. Antisera is being elicited against a benzene-protein adduct, but high-titer serum has not been obtained yet. The anti serum will be used for the monitoring of benzene-exposed workers in China and in the United States.