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First published online August 17, 2006
British Journal of Radiology (2006) 79, 991-998
© 2006 British Institute of Radiology
doi: 10.1259/bjr/10893584
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Full paper

The usefulness of a continuous administration of tirapazamine combined with reduced dose-rate irradiation using {gamma}-rays or reactor thermal neutrons

S Masunaga, MD, PhD1, Y Sakurai, PhD4, K Nagata, MD, PhD1, M Suzuki, MD, PhD1, A Maruhashi, PhD2, Y Kinashi, MD, PhD3, H Nagasawa, PhD5, Y UTO, PhD6, H Hori, PhD6 and K Ono, MD, PhD1

1 Radiation Oncology Research Laboratory, 2 Division of Radiation Life Science, 3 Division of Radiation Safety, Research Reactor Institute, Kyoto University, Osaka, 4 Department of Physics, Faculty of Medicine, Sapporo Medical University, Sapporo, 5 Laboratory of Pharmaceutical Chemistry, Gifu Pharmaceutical University, Gifu, 6 Department of Biological Science and Technology, Faculty of Engineering, University of Tokushima, Tokushima, Japan

Correspondence: Shin-ichiro Masunaga, Radiation Oncology Research Laboratory, 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

We clarified the usefulness of the continuous administration of tirapazamine (TPZ) in combination with reduced dose-rate irradiation (RDRI) using {gamma}-rays or reactor thermal neutrons. Squamous cell carcinoma (SCC) VII tumour-bearing mice received a continuous administration of 5-bromo-2'-deoxyuridine (BrdU) to label all proliferating (P) cells. Then, they received a single intraperitoneal injection or 24 h continuous subcutaneous infusion of TPZ in combination with conventional dose-rate irradiation (CDRI) or RDRI using {gamma}-rays or thermal neutrons. After irradiation, the tumour cells were isolated and incubated with a cytokinesis blocker, and the micronucleus (MN) frequency in cells without BrdU labelling ( = quiescent (Q) cells) was determined using immunofluorescence staining for BrdU. The MN frequency in the total tumour cells was determined using tumours that were not pre-treated with BrdU. The sensitivity of both total and Q cells, especially of Q cells, was significantly reduced with RDRI compared with CDRI. Combination of TPZ increased the sensitivity of both populations, with a slightly more remarkable increase in Q cells. Furthermore, the continuous administration of TPZ raised the sensitivity of both total and Q cell populations, especially the former, more markedly than the single administration, whether combined with CDRI or RDRI using {gamma}-rays or thermal neutrons. From the viewpoint of solid tumour control as a whole, including intratumour Q-cell control, the use of TPZ, especially when administered continuously, combined with RDRI, is useful for suppressing the reduction in the sensitivity of tumour cells caused by the decrease in irradiation dose rate in vivo.






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