Abstract
Purpose
The effect of vascular disrupting agent ZD6126 with time on the sensitivity to the hypoxic cytotoxin tirapazamine (TPZ) and γ-rays was examined in large and small solid tumors.
Methods
Mice bearing SCC VII tumors 1 or 1.5 cm in diameter received 5-bromo-2′-deoxyuridine (BrdU) continuously to label all proliferating (P) cells, followed by injection with or without ZD6126. In the absence of ZD6126, or 1 or 24 h following ZD6126 injection, the response to TPZ or γ-ray irradiation in quiescent (Q) cells was assessed in terms of induced micronucleus (MN) frequency using immunofluorescence staining for BrdU. The MN frequency in the total cell population was determined from the tumors not pretreated with BrdU. Another group of tumor-bearing mice received a series of test doses of γ-rays while alive or after tumor clamping to obtain hypoxic fractions (HFs) in the tumors.
Results
One hour after ZD6126 injection, both small and large tumors showed lower and higher sensitivity, and 24 h after, higher and lower sensitivity, to γ-rays and TPZ, respectively, than the tumors not treated with ZD6126. Further, they showed larger and smaller HFs 1 and 24 h after ZD6126 injection, respectively. Without ZD6126 and 1 h after injection, small tumors were more sensitive to γ-rays and less sensitive to TPZ than large tumors, probably due to the smaller HFs than large tumors. In contrast, 24 h after the injection, these differences in sensitivity and the HF between small and large tumors were reversed. The changes in sensitivity and the size of the HF were more marked in the total cell population than in Q cells.
Conclusions
Following ZD6126 treatment, in terms of tumor control, especially large tumors and total tumor cell population, administering TPZ 1 h later and γ-ray irradiation 24 h later were effective. Intratumor physiologic factors such as the size of the HF, depending on the time after ZD6126 injection, have to be taken into account when combining another treatment with ZD6126.
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Acknowledgments
This study was supported, in part, by a Grant-in-Aid for Scientific Research (C) (18591380) from the Japan Society for the Promotion of Science.
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Masunaga, Si., Nagasawa, H., Nagata, K. et al. Dependency of the effect of a vascular disrupting agent on sensitivity to tirapazamine and γ-ray irradiation upon the timing of its administration and tumor size, with reference to the effect on intratumor quiescent cells. J Cancer Res Clin Oncol 133, 47–55 (2007). https://doi.org/10.1007/s00432-006-0145-1
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DOI: https://doi.org/10.1007/s00432-006-0145-1