CARCINOGENIC ACYLATING AGENTS AND MODE OF ACTION

在以前的研究中，我们已经表明二甲基氨基甲酰氯(DMCC)是一种 雌性ICR/Ha小鼠局部应用强致癌物和 皮下注射。研究所的其他人已经证明了吸入 由DMCC引起的大鼠高发病率鳞状细胞癌 鼻腔上皮。在当前的授权期内，我们已经展示了 DMCC与小牛胸腺DNA的体外反应生成06-鸟氨酸 衍生物06-二甲基氨基甲基鸟嘌呤(Dmcg)和 2-氨基-N6-二甲基腺嘌呤(ADMA)。ADMA是由亲核芳烃形成的 二甲胺取代二甲氨基甲氧基的研究 在DMCC的水解过程中。二乙基氨基甲酰的体外反应 氯化物(DECC)与小牛胸腺DNA反应生成06-二乙氨基甲基鸟嘌呤。 二甲基磺酰氯(DMSc)与dGuo反应生成 2-氨基-N6-二甲基-2-脱氧腺苷的分离。这样做的目的是 建议扩大对DECC，DMSc， 氯甲酸乙酯(ECF)、二氯乙酰氯(DCC)和 1-哌啶甲酰氯(PCC)与DNA的结合：测定DMSc 和PCC通过局部应用和皮下注射在小鼠中具有致癌作用 注射；测定~(14)C-DMCC与组蛋白的选择性结合 小鼠表皮染色质体外反应后再测定 为了确定DMCC的相对转化能力， 细胞培养中的DECC和DMSc[Balb/c 3T3细胞(NCI)]； 细胞同时暴露于染毒物的细胞培养中的致癌作用 DMCC、DECC或DMSc与小鼠皮肤致癌物质的组合， 邻苯二酚和佛波醇酯，并测定 染毒大鼠呼吸道中DMCC的结合量 14C-DMCC蒸气。

In previous studies we had shown that dimethylcarbamyl chloride (DMCC) is a powerful carcinogen in female ICR/Ha mice by topical application and subcutaneous injection. Others at the Institute had shown that inhalation by rats of DMCC caused a high incidence of squamous cell cancers of the nasal epithelium. During the current Grant Period we have demonstrated that in vitro reaction of DMCC with calf thymus DNA forms the 06-guanine derivative 06-dimethylcarbamyl guanine (DMCG) and 2-amino-N6-dimethyladenine (ADMA). ADMA is formed by nucleophilic aromatic substitution of the dimethyl-carbamyloxy group by dimethylamine formed during the hydrolysis of DMCC. In vitro reaction of diethylcarbamyl chloride (DECC) with calf thymus DNA yielded 06-diethylcarbamyl guanine. Reaction of dimethylsulfamyl chloride (DMSC) with dGuo resulted in the isolation of 2-amino-N6-dimethyl-2 -deoxyadenosine. The objectives of this proposal are to extend the studies on the in vitro reactions of DECC, DMSC, ethyl-chloroformate (ECF), dichloroacetyl chloride (DCC) and 1-piperidine-carbonyl chloride (PCC) with DNA: to determine whether DMSC and PCC are carcinogenic in mice by topical application and subcutaneous injection; to determine the selective binding of 14C-DMCC to histones in mouse epidermal chromatin following in vitro reaction and then to determine adduct formation; to determine the relative transforming abilities of DMCC, DECC and DMSC in cell culture [Balb/c 3T3 cells (NCI)]; to examine cocarcinogenesis in cell culture with cells exposed concurrently to combinations of DMCC, DECC or DMSC with the mouse skin cocarcinogens, anthralin, catechol and phorbol myristate acetate and to determine the amounts of binding of DMCC in the respiratory tract of rats exposed to 14C-DMCC vapors.