Reactions in the Radiosensitizer Misonidazole Induced by Low-Energy (0–10 eV) Electrons

Abstract

Misonidazole (MISO) was considered as radiosensitizer for the treatment of hypoxic tumors. A prerequisite for entering a hypoxic cell is reduction of the drug, which may occur in the early physical-chemical stage of radiation damage. Here we study electron attachment to MISO and find that it very effectively captures low energy electrons to form the non-decomposed molecular anion. This associative attachment (AA) process is exclusively operative within a very narrow resonance right at threshold (zero electron energy). In addition, a variety of negatively charged fragments are observed in the electron energy range 0–10 eV arising from dissociative electron attachment (DEA) processes. The observed DEA reactions include single bond cleavages (formation of NO2−), multiple bond cleavages (excision of CN−) as well as complex reactions associated with rearrangement in the transitory anion and formation of new molecules (loss of a neutral H2O unit). While any of these AA and DEA processes represent a reduction of the MISO molecule, the radicals formed in the course of the DEA reactions may play an important role in the action of MISO as radiosensitizer inside the hypoxic cell. The present results may thus reveal details of the molecular description of the action of MISO in hypoxic cells.

Ring Formation and Hydration Effects in Electron Attachment to Misonidazole

“…The top panel of Figure 1 represents “dry” conditions when pure He, without humidification, was used as a buffer gas. These data may be compared to the results for isolated MISO [21] (see Table 1). Isolated MISO fragments primarily to m/z=46 (NO2−; 100), m/z=201 (M−; 50) and m/z=141 (25) anions, with numbers in parentheses representing the integrated yield of the anion.…”

“…Second, the electron source in Ref. [21] is dedicated to electron attachment spectroscopy, with excellent performance at low electron energies. The simple electron gun at the CLUB setup cannot produce reliable results at electron energies below ∼1.2 eV [33], this region is therefore hatched in Figure 2.…”

“…The study is a continuation of our systematic exploration of low-energy electron induced chemistry of nitro-imidazolic radiosensitizers [19,20]. In the present issue, we also report on the electron induced chemistry of isolated MISO [21].…”

A formula constituted by arsenic trioxide and dimercaprol enhances sensitivity of pancreatic cancer xenografts to radiotherapy

“…Hypoxia occurs in most solid tumor tissues and is de ned as an essential cause of resistance of tumors to radiotherapy [27,28]. At present, most radiosensitizers consist of compounds containing nitro groups, such as misonidazole and RRx-001 [29][30][31]. These drugs could result in greater anticancer effects in radiation treatments than radiotherapy alone; however, their toxicity and adverse effects are obvious, which leads to limitation in clinical application.…”

Electron Transfer Induced Decomposition in Potassium–Nitroimidazoles Collisions: An Experimental and Theoretical Work

“…The recent work of Meißner et al [8] has demonstrated that low-energy electrons are responsible for reduction of nimorazole via associative electron attachment, which corroborates the rationale that the radiosensitization process of this molecule in tumour cells is a result of reduction inside the cells. In contrast, Meißner and co-workers [9] have also investigated the role of low-energy electrons in misonidazole, showing that this molecule does not undergo reduction but rather dissociates in several anionic species leading to formation of radicals which are highly reactive to the hypoxic cell. Tanzer and co-workers [10,11] showed that low-energy electrons (0 to 8 eV) successfully decompose 4-nitroimidazole and two methylated isomers via DEA pointing out the significant importance of the study on the molecular mechanisms involved in these reactions (including detailed knowledge on the electronic and molecular structure) and emphasises the implications of that in tumour radiation therapy.…”