Alkylation chemotherapy is one of the most widely used systemic therapies for cancer. The simplest type of DNA alkylation – the transfer of a single methyl group to a DNA base – demonstrates the diverse nature of such damage. Methyl donors may react with ring nitrogen (N) or oxygen (O) atoms to generate twelve distinct base lesions in DNA. Alkylating agents react with the ring nitrogens (N) and extracyclic oxygen (O) atoms of DNA bases to generate a variety of covalent adducts ranging from simple methyl groups to complex alkyl additions.Alkylating agents are a ubiquitous family of reactive chemicals that transfer alkyl carbon groups onto a broad range of biological molecules, thereby altering their structure and potentially disrupting their function. Alkylating agents are practically unavoidable due to their abundant presence in the environment and within living cells. Major sources of external alkylating agents include constituents of air, water and food such as biological byproducts (e.g. abiotic plant material) and pollutants (e.g. tobacco smoke and fuel combustion products)Numerous cellular pathways, including direct DNA damage reversal, base excision repair (BER), and mismatch repair (MMR) respond to alkylation damage to defend against alkylation-induced cell death or mutation.
Cell Cycle/DNA Damage
ABC(7) AChR(5) Antifolate(8) ATM/ATR(23) Aurora Kinase(37) CLK(15) c-Myc(16) DHFR(4) DNA Alkylator(29) DNA gyrase(7) DNA Repair Protein(21) DNA/RNA Synthesis(85) DNA-PK(11) GPR(19) HDAC(111) Hec1/Nek2(9) Integrin(38) LIM Kinase (LIMK)(4) Mps1/TTK(1) Nucleoside Antimetabolite/Analog(19) Other Targets(2) PAK(7) PARP(30) PLK(11) Potassium Channel(55) RAD51(1) Rho(5) ROCK(13) Telomerase(4) Topoisomerase(40) Wee1(2)