title: Evaluation of the potential of hexamethylenetetramine, compared with tirapazamine, as a combined agent with {gamma}-irradiation and cisplatin treatment in vivo.
abstract: The purpose of this investigation was to compare the effect on intratumour quiescent (Q) cells in vivo of hexamethylenetetramine (HMTA) or tirapazamine (TPZ) in combination with gamma-irradiation and cisplatin treatment. Squamous cell carcinoma (SCC) VII tumour-bearing mice were administered 5-bromo-2'-deoxyuridine (BrdU) continuously to label all intratumour proliferating (P) cells. The mice then received HMTA or TPZ intraperitoneally or continuously with or without gamma-irradiation or cisplatin treatment. Other tumour-bearing mice received HMTA or TPZ intraperitoneally immediately after gamma-irradiation. Immediately after gamma-irradiation or cisplatin treatment following HMTA or TPZ, or 24 h after gamma-irradiation followed by HMTA or TPZ, the response of Q cells was assessed in terms of the micronucleus frequency using immunofluorescence staining for BrdU. The response of all tumour cells (P + Q) was determined from the BrdU-non-treated tumours. HMTA was more toxic to the subset of Q cells than to the population of tumour cells as a whole, similar to the findings for TPZ. The radiosensitising effect of HMTA was similar to that of TPZ in both all cells and Q cells. The recovery-inhibiting effect of HMTA was reliable, but not as great as that of TPZ. The cisplatin sensitivity-enhancing effect of HMTA was similar to or slightly greater than that of TPZ. Continuous administration of both HMTA and TPZ resulted in higher radiosensitivity- and cisplatin sensitivity-enhancing effects than did a single i.p. administration. We concluded that, in terms of the total tumour cell killing effect, including killing of Q cells, gamma-irradiation and cisplatin treatment combined with continuous HMTA administration is a promising strategy given that HMTA is used in clinics.
authors.affiliation: Particle Radiation Oncology Research Center, Kyoto University, Kumatori, Osaka, Japan. smasuna@rri.kyoto-u.ac.jp
authors.forename: S
authors.initials: S
authors.lastname: Masunaga
authors.forename: K
authors.initials: K
authors.lastname: Tano
authors.forename: M
authors.initials: M
authors.lastname: Watanabe
authors.forename: G
authors.initials: G
authors.lastname: Kashino
authors.forename: M
authors.initials: M
authors.lastname: Suzuki
authors.forename: Y
authors.initials: Y
authors.lastname: Kinashi
authors.forename: K
authors.initials: K
authors.lastname: Ono
authors.forename: J
authors.initials: J
authors.lastname: Nakamura
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000532:radiotherapy; D015687:Cell Hypoxia / Q000502:physiology; D002945:Cisplatin / Q000627:therapeutic use; D003131:Combined Modality Therapy / Q000379:methods; D005260:Female; D005720:Gamma Rays / Q000627:therapeutic use*; D055104:Infusions, Subcutaneous; D008709:Methenamine / Q000008:administration & dosage*; D051379:Mice; D008809:Mice, Inbred C3H; D011838:Radiation-Sensitizing Agents / Q000008:administration & dosage*; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000532:radiotherapy; D000077704:Tirapazamine; D016896:Treatment Outcome; D014227:Triazines / Q000008:administration & dosage*; D014407:Tumor Cells, Cultured / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D011838:Radiation-Sensitizing Agents; D014227:Triazines; D000077704:Tirapazamine; D008709:Methenamine; D002945:Cisplatin