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

Abstract

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. Introductionhyperthermia is a heat treatment that directly targets cancer cells or the environment surrounding them (1). according to the tenets of hyperthermic oncology, significant tumor cell killing could theoretically be achieved if cells or tissues were heated to over 42˚C for 1 h or more (2). It is speculated that such heat treatment would induce radio-and chemosensitization, in part by inhibiting dna damage repair (1). however, clinical experience over the past 25 years has shown that it is not possible to routinely achieve thermal doses of over 42˚C for 1 h or more. it is now known that, during typical hyperthermia treatments with currently available heating technologies (except for thermal ablation), cytotoxic temperatures are only achieved in small sub-volumes of tumors (3). meanwhile, until recently the effects of mild temperature hyperthermia (MTH) (39-42˚C for 1-2 h) on tissue have largely been ignored. however, mth has subtle effects, including heat-mediated tumor reoxygenation (4) and the inhibition of sublethal and potentially lethal damage repair (5), which provide a very strong rationale for using mth in combination with radiotherapy. in addition, the physiological and cellular effects of mth can improve the delivery of drug vehicles (6), activate promoters for heat-mediated gene therapy (7) and increase immune response to tumors through a variety ...

Methenamine's journey of 160 years: Repurposal of an old urinary antiseptic for treatment and hypoxic radiosensitization of cancers and glioblastoma

“…In squamous cell carcinoma (SCC)VII‐bearing mice, Masunaga et al also showed that methenamine enhanced the antitumor efficacy of cisplatin greater than the hypoxic sensitizer, tirapazamine . In regard to total tumour cell cytocidal effects, including elimination of quiescent cells, combining methenamine with radiotherapy or cisplatin demonstrated promising therapeutic potential, especially when methenamine was administered continuously . In subsequent studies, Masunaga et al subcutaneously injected mutantor empty vector transfected human head and neck squamous carcinoma cells into the hind legs of nude mice.…”

“…Hyperthermia is a heat‐treatment modality that targets malignant cells or their microenvironment; it is generally assumed that significant cancer cell death could be induced if malignant tissues were heated to over 42°C for 1 hour or longer . It is also presumed that hyperthermia would induce radiation and chemotherapy sensitization, partly through inhibition of the DNA damage repair machinery . For cancer treatment protocols, standard whole body hyperthermia (WBH) systemic temperatures of 41–42°C can be obtained and sustained for 60–120 minutes .…”

“…While Masunaga et al showed that mild hyperthermia (40°C, 60 minutes) may reduce the efficacy of methenamine's radiotherapy and cisplatin‐sensitization, İsmail‐zade showed great potential of high dose hyperthermia (42.5–43.0°C) and methenamine combination both in an animal cancer model (rats bearing Sarcoma 45/Sa45) and in 13 paediatric cancer patients (42 procedures in total) with advanced, refractory, or recurrent malignant tumours . He showed 5‐fold increase in the survival of rats during the first 2 days of extreme WBH treatment and simultaneous exposure to methenamine.…”