Cellular macromolecules in hypoxic tumor cells

Cellular macromolecules in hypoxic tumor cells refer to the collective set of biological polymers and small molecules, such as DNA, proteins, and glutathione, that serve as the ultimate targets for hypoxia-activated prodrugs (HAPs) (Phillips, 2016). In the oxygen-deprived microenvironment of solid tumors, these prodrugs undergo enzymatic reduction by intracellular reductases (e.g., cytochrome P450, POR) to form highly reactive intermediates, such as radical anions or alkylating agents (Hunter et al., 2016). These reactive species then form covalent adducts with or cause oxidative damage to DNA and critical enzymes, leading to the inhibition of replication, induction of double-strand breaks, and eventual apoptosis of the hypoxic cell fraction (Wilson & Hay, 2011). Because hypoxic cells are often resistant to conventional radiotherapy and chemotherapy, targeting their cellular macromolecules provides a strategy to eliminate the most aggressive and treatment-resistant parts of a tumor (Brown & Wilson, 2004). Key drugs in this class include Tirapazamine, which generates DNA-damaging radicals, and Evofosfamide, which releases a DNA-alkylating mustard moiety specifically in hypoxic conditions (Weiss et al., 2011).

Other names

Hypoxic cell macromoleculesBioreductive drug targetsHypoxia-activated prodrug targetsIntracellular macromolecules in hypoxia

Bioreductive activation by intracellular reductases under low oxygen conditions to generate reactive radicals or alkylating species that covalently modify or damage DNA and proteins.