Improved potency of the hypoxic cytotoxin tirapazamine by DNA-targeting.
To improve the potency of the hypoxic cytotoxin tirapazamine (TPZ), we have constructed an analog, SN26955, with the TPZ moiety attached to an acridine chromophore to target the drug to DNA. The underlying reason for this is our previous finding that the hypoxic cytotoxicity of TPZ is a result of its ability to produce DNA double-strand breaks, whereas many of the toxicities of the drug in clinical use are likely the result of its metabolism in the cytoplasm and effects on mitochondria. We found that the DNA-targeted TPZ analog was more potent than TPZ in killing hypoxic cells by 1-2 orders of magnitude, yet it retained the hypoxic selectivity for cell killing of TPZ. We show that SN26955 is only active in producing DNA damage when it is enzymatically reduced while bound to, or in close association with, the DNA. We also show that it has a different cofactor dependence than TPZ for reduction leading to DNA double-strand breaks, suggesting the involvement of a different reductase for production of the lethal lesion than for TPZ. These results show the promise of DNA-targeting of TPZ to produce a DNA compound with greater clinical efficacy than TPZ itself.
Delahoussaye
Yvette M
YM
Department of Radiation Oncology, Stanford University School of Medicine, 269 Campus Drive, CCSR 1255, Stanford, CA 94305-5152, USA.
Hay
Michael P
MP
Pruijn
Frederik B
FB
Denny
William A
WA
Brown
J Martin
JM
D000166:Acridines / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D004249:DNA Damage; D004273:DNA, Neoplasm / Q000187:drug effects* / Q000378:metabolism; D004354:Drug Screening Assays, Antitumor; D005609:Free Radicals / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D000860:Hypoxia; D010100:Oxygen / Q000378:metabolism; D000077704:Tirapazamine; D014227:Triazines / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D000166:Acridines; D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D005609:Free Radicals; C475278:N(1)-(9-acridinyl)-N(6)-(1,4-dioxido-1,2,4-benzotriazin-3-yl)-1,6-hexanediamine; D014227:Triazines; D000077704:Tirapazamine; D010100:Oxygen