Adverse effect of mild temperature hyperthermia combined with hexamethylenetetramine compared to its effect combined with tirapazamine in the treatment of solid tumors

Masunaga,Shin-Ichiro; Tano,Keizo; Nakamura,Jun; Watanabe,Masami; Kashino,Genro; Suzuki,Minoru; Kinashi,Yuko; Ono,Koji

doi:10.3892/etm_00000027

Adverse effect of mild temperature hyperthermia combined with hexamethylenetetramine compared to its effect combined with tirapazamine in the treatment of solid tumors

Authors:
- Shin-Ichiro Masunaga
- Keizo Tano
- Jun Nakamura
- Masami Watanabe
- Genro Kashino
- Minoru Suzuki
- Yuko Kinashi
- Koji Ono
View Affiliations

Affiliations: Particle Radiation Oncology Research Center, Research Reactor Institute, Kyoto University, Osaka 590-0494, Japan. smasuna@rri.kyoto-u.ac.jp
Published online on: January 1, 2010 https://doi.org/10.3892/etm_00000027
Pages: 169-174

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

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 (40°C, 60 min), followed or not by γ-ray irradiation or cisplatin treatment. After HMTA or TPZ administration without γ-ray irradiation or cisplatin treatment, immediately after γ-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 γ-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.

View Figures

View References

1.	Hall EJ and Roizin-Towle L: Biological effects of heat. Cancer Res. 44:4708–4713. 1984.PubMed/NCBI
2.	Sapareto SA and Dewey WC: Thermal dose determination in cancer therapy. Int J Radiat Oncol Biol Phys. 10:787–800. 1984. View Article : Google Scholar : PubMed/NCBI
3.	Oleson JR, Samulski TV, Leopold KA, et al: Sensitivity of hyperthermia trial outcomes to temperature and time: Implications for thermal goals of treatment. Int J Radiat Oncol Biol Phys. 25:289–297. 1993. View Article : Google Scholar : PubMed/NCBI
4.	Song CW, Park HJ, Lee CK and Griffin R: Implications of increased tumour blood flow and oxygenation caused by mild temperature hyperthermia in tumor treatment. Int J Hyperthermia. 21:761–767. 2005. View Article : Google Scholar : PubMed/NCBI
5.	Armour EP and Raaphorst GP: Long duration mild temperature hyperthermia and brachytherapy. Int J Hyperthermia. 20:175–189. 2004. View Article : Google Scholar : PubMed/NCBI
6.	Kong G, Braun RD and Dewhirst MW: Hyperthermia enables tumor-specific nanoparticle delivery: effect of particle size. Cancer Res. 60:4440–4445. 2000.PubMed/NCBI
7.	Li CY and Dewhirst MW: Hyperthermia-regulated immunogene therapy. Int J Hyperthermia. 18:586–596. 2002.PubMed/NCBI
8.	Kinuya S, Yokoyama K, Michigishi T and Tonami N: Optimization of radioimmunotherapy interactions with hyperthermia. Int J Hyperthermia. 20:190–200. 2004. View Article : Google Scholar : PubMed/NCBI
9.	Masunaga S, Nagasawa H, Uto Y, et al: The usefulness of continuous administration of hypoxic cytotoxin combined with mild temperature hyperthermia, with reference to effects on quiescent tumour cell populations. Int J Hyperthermia. 21:305–318. 2005. View Article : Google Scholar : PubMed/NCBI
10.	Brown JM: Evidence of acutely hypoxic cells in mouse tumours and a possible mechanism of reoxygenation. Br J Radiol. 52:650–656. 1979. View Article : Google Scholar : PubMed/NCBI
11.	McKeown SR, Cowen RL and Williams KJ: Bioreductive drugs: from concept to clinic. Clin Oncol. 19:427–442. 2007. View Article : Google Scholar : PubMed/NCBI
12.	Adam M, Bayer C, Henke J, Grosu A, Molls M and Nieder C: Tirapazamine plus cisplatin and irradiation in a mouse model: improved tumor control at the cost of increased toxicity. J Cancer Res Clin Oncol. 134:137–146. 2008. View Article : Google Scholar : PubMed/NCBI
13.	Ridpath JR, Nakamura J, Tano K, et al: Cells deficient in the Fanc/Brac pathway are hypersensitive to plasma levels of formaldehyde. Cancer Res. 67:11117–11122. 2007. View Article : Google Scholar : PubMed/NCBI
14.	Swift LP, Cutts SM, Rephaeli A, Nudelman A and Phillips DR: Activation of adriamycin by the pH-dependent formaldehyde-releasing prodrug hexamethylenetetramine. Mol Cancer Therapeut. 2:189–198. 2003.PubMed/NCBI
15.	Masunaga S and Ono K: Significance of the response of quiescent cell populations within solid tumors in cancer therapy. J Radiat Res. 43:11–25. 2002. View Article : Google Scholar : PubMed/NCBI
16.	Masunaga S, Tano K, Watanabe M, et al: Evaluation of the potential of hexamethylenetetramine, compared with tirapazamine, as a combined agent with γ-irradiation and cisplatin treatment in vivo. Br J Radiol. 82:392–400. 2009.PubMed/NCBI
17.	Nishimura Y, Ono K, Hiraoka M, et al: Treatment of murine SCC VII tumors with localized hyperthermia and temperature-sensitive liposomes containing cisplatin. Radiat Res. 122:161–167. 1990. View Article : Google Scholar : PubMed/NCBI
18.	Hubal EA, Schlosser PM, Conolly RB and Kimbell JS: Comparison of inhaled formaldehyde dosimetry predictions with DNA-protein cross-link measurements in the rat nasal passages. Toxicol Appl Pharmacol. 143:47–55. 1997. View Article : Google Scholar : PubMed/NCBI
19.	Kim JW and Dang CV: Cancer's molecular sweet tooth and the Warburg effect. Cancer Res. 66:8927–8930. 2006.
20.	Iskandarova GT: Hygienic rationale for maximum permissible concentration of hexamethylenetetramine salt of 2-chloroethyl-phosphonic acid. Gig Sanit. 10:14–17. 1993.PubMed/NCBI
21.	Wouters BG and Brown JM: Cells at intermediate oxygen levels can be more important than the ‘hypoxic fraction’ in determining tumor response to fractionated radiotherapy. Radiat Res. 147:541–550. 1997.
22.	Bertram JS: The molecular biology of cancer. Mol Aspects Med. 21:167–223. 2000. View Article : Google Scholar
23.	Vaupel P: Tumor microenvironmental physiology and its implications for radiation oncology. Semin Radiat Oncol. 14:197–275. 2004. View Article : Google Scholar : PubMed/NCBI