Usefulness of Hexamethylenetetramine as an Adjuvant to Radiation and Cisplatin in the Treatment of Solid Tumors: its Independency of p53 Status

Abstract

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 gamma-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.

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“…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. They revealed that methenamine equally sensitized mutant TP53 or wild‐type tumours to chemoradiation, indicating that this agent has a great potential for chemo‐radiosensitization, as a great percentage of human cancers possess TP53 mutations …”

“…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. They revealed that methenamine equally sensitized mutant TP53 or wild‐type tumours to chemoradiation, indicating that this agent has a great potential for chemo‐radiosensitization, as a great percentage of human cancers possess TP53 mutations …”

Synthesis of mesoporous titanium oxide for release control and high efficiency drug delivery of vinorelbine bitartrate

“…8(a) and (b) display stained sections of both tumors, control and treated by HMTA and show undamaged periphery of tissues. Some cells died in the case of HMTA, as it released formaldehyde and ammonia, [30][31][32][33] whereas the tumor that was treated by VB showed a greater inimical effect, as it damaged more tissue, which can be observed as a dark spot inside the tissue section (Fig. 7(c)).…”

“…Under acidic conditions, its clinical efficacy has been proven in a combinatorial therapy with radiotherapy for a synergistic response to induce death in cancer cells. [29][30][31][32][33] The impact of formaldehyde was found to be enormous when combined with HMTA. The results were veried using HeLa cells and a histological study (H&A staining) performed on tumor bearing mice.…”

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“…For example, methenamine (HMTA), methenamine anhydromethylene-citrate, methenamine hippurate, methenamine mandelate and methenamine sulfosalicylate have all been reported as synthetic antibacterials [20] and as anti-infectives [21]. HMTA has also been applied in the treatment of ear canal infections in combination with anti-inflammatory and antiseptic agents [22], and as an adjuvant to radiation and cisplatin in the treatment of solid tumors [23]. In recent years HMTA has been used as base catalyst in the synthesis of phenolic gel and most recently Garci 9 a et al published a report on the use of HMTA as a base catalyst to control the porosity and pore size of resorcinol furaldehyde cryogels synthesized in t-butanol [24].…”