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Masunaga S.-I.,Particle Radiation Oncology Research Center | Tano K.,Particle Radiation Biology | Nakamura J.,University of North Carolina at Chapel Hill | Watanabe M.,Particle Radiation Biology | And 9 more authors.
Journal of Radiation Research | Year: 2010

The usefulness of hexamethylenetetramine as an adjuvant to radiation and cisplatin in the treatment of solid tumors and its dependency on the p53 status of tumor cells were examined. Human head and neck squamous cell carcinoma cells transfected with mutant TP53 (SAS/mp53), or with neo vector as a control (SAS/neo), were inoculated subcutaneously into both the hind legs of Balb/cA nude mice. The tumor-bearing mice received 5-bromo-2'-deoxyuridine (BrdU) continuously to label all proliferating (P) cells in the tumors. Then, they received hexamethylenetetramine (HMTA), intraperitoneally or continuously, combined with or without γ-ray irradiation or cisplatin treatment. Immediately after treatment following HMTA, the response of quiescent (Q) cells was assessed in terms of the micronucleus frequency using immunofluorescence staining for BrdU. The response of the total (= P + Q) tumor cells was determined from the BrdU non-treated tumors. A higher toxicity of HMTA to Q cells than total cells, especially in SAS/neo, was made less clear by continuous administration. There was no apparent difference in the radio-and cisplatin-sensitivity enhancing effects by HMTA combination between SAS/neo and SAS/mp53 tumors, with a slightly greater effect in SAS/mp53. In both SAS/neo and SAS/mp53 tumors, continuous HMTA administration produced higher radio-and cisplatin-sensitivity enhancing effects than intraperitoneal single administration. Therefore, the use of HMTA as an adjuvant to radiation or cisplatin might be promising in curing solid tumors with large fraction of hypoxic cells and also with frequent loss-of-function in p53.


PubMed | Particle Radiation Oncology Research Center
Type: Journal Article | Journal: Experimental and therapeutic medicine | Year: 2012

This study aimed to assess the effect on solid tumors of mild temperature hyperthermia (MTH) combined with hexamethylenetetramine (HMTA) or tirapazamine (TPZ). Squamous cell carcinoma (SCC VII) tumor-bearing mice were continuously administered 5-bromo-2-deoxyuridine (BrdU) to label intratumor proliferating (P) cells. Mice received HMTA or TPZ through intraperitoneal single or subcutaneous continuous administration, with or without MTH (40C, 60 min), followed or not by -ray irradiation or cisplatin treatment. After HMTA or TPZ administration without -ray irradiation or cisplatin treatment, immediately after -ray irradiation, or 1 h after cisplatin treatment, the response of quiescent (Q) cells was assessed in terms of micronucleus frequency using immunofluorescence staining for BrdU. The response of the total (P + Q) tumor cells was determined based on a comparison with non-BrdU-treated tumors. Without MTH, HMTA and TPZ had a nearly equal radiosensitizing and cisplatin sensitivity-enhancing effect on both total and Q cells. With MTH, radio- and cisplatin-sensitizing effects by HMTA were reduced, particularly in the Q cells. In contrast, the enhancing effects of TPZ were increased, particularly in the Q cells. Continuous administration of HMTA and TPZ resulted in higher radio- and cisplatin-sensitizing effects than intraperitoneal single administration. In terms of tumor cytotoxicity as a whole, including Q cells, the administration of -ray irradiation or cisplatin treatment combined with continuous HMTA administration is promising, taking into account the clinical use of HMTA. However, MTH should not be combined with HMTA administration.

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