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First published online January 19, 2009
British Journal of Radiology (2009) 82, 392-400
© 2009 British Institute of Radiology
doi: 10.1259/bjr/54190057
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British Journal of Radiology 82 (2009),392-400 ©2009 The British Institute of Radiology

Evaluation of the potential of hexamethylenetetramine, compared with tirapazamine, as a combined agent with {gamma}-irradiation and cisplatin treatment in vivo

S MASUNAGA, MD, PhD 1 K TANO, PhD 2 M WATANABE, PhD 2 G KASHINO, PhD 1 M SUZUKI, MD, PhD 1 Y KINASHI, MD, PhD 3 K ONO, MD, PhD 1 and J NAKAMURA, PhD 4

1 Particle Radiation Oncology Research Center, 2 Particle Radiation Biology and, 3 Radiation Safety and Control, Research Reactor Institute, Kyoto University, Kumatori, Osaka, Japan, 4 Department of Environmental Sciences and Engineering, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

Correspondence: Shin-ichiro Masunaga, Particle Radiation Oncology Research Center, Research Reactor Institute, Kyoto University, 2-1010, Asashiro-nishi, Kumatori-cho, Sennan-gun, Osaka 590-0494, Japan. E-mail: smasuna{at}rri.kyoto-u.ac.jp

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.






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