Practice question

HSV-1 thymidine kinase ganciclovir exemplifies enzyme-prodrug suicide paradigm. Viral kinase active site accommodates bulky acyclic guanosine analog ganciclovir monophosphorylating it rate far exceeding mammalian cytosolic thymidine kinase preferring thymidine. Subsequently host guanylate kinase GUK1 and NDP kinase NME1 sequentially phosphorylate di and triphosphate forms. Ganciclovir triphosphate acts dGTP analog incorporated DNA polymerases alpha and delta into nascent strand during S-phase proliferating tumor cells but not quiescent normal cells rarely synthesizing DNA. Lacking 3 prime hydroxyl due acyclic side chain, incorporation causes chain termination stalled replication forks double-strand breaks sensed ATR kinase activating checkpoint kinase 1 p53 phosphorylation caspase-9 intrinsic apoptosis via mitochondrial cytochrome c release. Phosphorylated ganciclovir transfers via gap junctions to adjacent cells extending killing beyond transduced population bystander effect. Clinical approaches deliver adenovirus bearing HSV-TK under CMV promoter intratumorally into glioblastoma resection cavity followed by intravenous ganciclovir causing local tumor regression combined with surgery enhancing local control and survival.