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• W2054879107 abstract "When considering the mechanisms for tumor cell resistance to chemotherapeutic agents, the converse situation must also be considered, namely the mechanisms for tumor cell sensitivity to chemotherapeutic agents. This manuscript will describe serendipity, where we tried to find a mechanism for tumor cell kill by chloroethylnitrosoureas (CNUs) and found a mechanism by which some tumor cells are resistant to these anti-tumor agents. A unique DNA repair system found in all normal human cells, and in a large percentage of human tumor cell lines examined to date will be discussed. Although the chloroethylnitrosoureas (BCNU, CCNU) have been used in the clinic for nearly 20 years, it is only in the past few years that their mechanisms ofaction have begun to be understood. The CNUs under physiological conditions decompose to yield an alkylating moiety capable of interacting with nucleic acids and proteins, and some nitrosoureas such as BCNU and CCNU also generate a carbamoylating moiety which can react with proteins, and has been shown to be capable of inhibiting a variety of enzymes including enzymes that are involved with DNA repair (10). In 1977 Kohn demonstrated that the CNUs were capable of producing DNA interstrand crosslinks (ISC) in purified bacterial DNA reacted with the drugs in saline ( 12). A unique feature of the reaction was that the formation of the crosslink took place over a number of hours after removal of the drug. Kohn proposed that the crosslink might form via an initial attack by a chloroethyl carbonium ion at a nucleophic site on the Watson strand of the DNA producing a DNAchloroethyl monoadduct. He suggested that the crosslink could then form between two DNA bases by displacement of the chlorine atom from the chloroethyl monoadduct by a nucleophilic site on the Crick strand of DNA in a delayed reaction. Kohn further suggested that one accessible site in DNA where the initial chloroethyl monoadduct might form was" @default.
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• W2054879107 date "1984-03-01" @default.
• W2054879107 modified "2023-09-25" @default.
• W2054879107 title "Induction and repair of macromolecular damage by alkylating agents" @default.
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• W2054879107 doi "https://doi.org/10.1016/0305-7372(84)90040-9" @default.
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