Carcinogenic Acylating Agents and Mode of Action

Segal, Alvin

Abstract

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.