Overcoming Resistance to Alkylating Agents by Inhibitors of O 6-Alkylguanine-DNA Alkyltransferase

Abstract

Despite a myriad of toxic side effects, alkylating agents still represent a major class of cancer chemotherapeutic agents. DNA is the primary target for these agents and the correct repair of DNA damage provides protection from them (1,2). Virtually every DNA repair pathway is able to interact with one or more facets of alkylation damage. Alkylated bases are repaired via base excision repair (BER), nucleotide excision repair (NER), and direct reversal. Mechanisms for the repair of single- and double-strand breaks, poly(ADP)ribose polymerase binding, also aid in protection from alkylating agents. NER is also involved in the repair of intrastrand crosslinks and, probably, interstrand crosslinks, although these mechanisms have not been characterized fully. As described in more detail in this chapter, mismatch repair (MMR) also recognizes alkylation damage in the form of the O 6-methylguanine (m6G), but, in this case, it causes apoptosis rather than repair. This review is focused on the role played in alkylating agent resistance by the direct reversal reaction brought about by O 6-alkylguanine-DNA alkyltransferase (AGT) and the possibilities for improving therapy by using O 6-benzylguanine (BG), an inactivator of AGT. This field has expanded rapidly in recent years and only a limited number of key and recent citations can be provided in this short review chapter. Further material for the interested reader is contained within these citations and in several recent reviews (2–11).