DNA damage measured by the comet assay in head and neck cancer patients treated with tirapazamine.
Tirapazamine (TPZ) [3-amino-1,2,4-benzotriazine 1,4-dioxide, SR4233, WIN 59075, and Tirazone] is a novel anticancer drug that is selectively activated by the low oxygen environment in solid tumors. By killing the radioresistant hypoxic cells, TPZ potentiates the antitumor efficacy of fractionated irradiation of transplanted tumors in mice. As this cell kill is closely correlated with TPZ-induced DNA damage, we investigated whether human head and neck cancers would show DNA damage similar to that seen in mouse tumors following TPZ administration. TPZ-induced DNA damage in both transplanted tumors in mice and in neck nodes of 13 patients with head and neck cancer was assessed using the alkaline comet assay on cells obtained from fine-needle aspirates. The oxygen levels of the patients' tumors were also measured using a polarographic oxygen electrode. Cells from the patients' tumors showed DNA damage immediately following TPZ administration that was comparable to, or greater than, that seen with transplanted mouse tumors. The heterogeneity of DNA damage in the patients' tumors was greater than that of individual mouse tumors and correlated with tumor hypoxia. The similarity of TPZ-induced DNA damage in human and rodent tumors suggests that tirapazamine should be effective when added to radiotherapy or to cisplatin-based chemotherapy in head and neck cancers.
Dorie
M J
MJ
Department of Radiation Oncology, Stanford University School of Medicine, CA 94305-5468, USA.
Kovacs
M S
MS
Gabalski
E C
EC
Adam
M
M
Le
Q T
QT
Bloch
D A
DA
Pinto
H A
HA
Terris
D J
DJ
Brown
J M
JM
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use*; D020552:Comet Assay / Q000379:methods*; D004249:DNA Damage / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D006801:Humans; D051379:Mice; D008809:Mice, Inbred C3H; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D010100:Oxygen / Q000378:metabolism; D013997:Time Factors; D000077704:Tirapazamine; D014227:Triazines / Q000494:pharmacology* / Q000627:therapeutic use*; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D014227:Triazines; D000077704:Tirapazamine; D010100:Oxygen