Radiosensitization by Reaction with DNA Radicals

The principal mechanism of cell killing by ionizing radiation is the formation of clustered DNA lesions (386,392,393) by a combination of direct ionizations in the DNA molecule (the direct effect) and reaction of DNA with free radicals produced in the vicinity of DNA (the indirect effect). The reactions that produce the DNA radicals that are the precursors cf these clustered lesions are complete within nanoseconds (387). However, the chemical reactions of these free radicals that result in damage fixation are not complete until 10 ms after irradiation (394), and there is an opportunity to alter the outcome of these reactions (Fig. 4.2). Damage fixation is a process that renders the damage nonrestorable by chemical protectors.

Reaction of DNA radicals with molecular oxygen results in damage fixation. This reaction occurs in competition with the restorative

Thiol radioprotectors, oxygen-mirnetic: -radiosensitizers

Modifiers cf

DNA repair nanoseconds

DNA radicals

10 milliseconds

DNA lesions hours

Chromosome aberrations

Figure 4.2. Time frame for radiochemical events. In living cells, dna radicals are formed within nanoseconds by a combination of direct ionization of DNA and reaction of dna with HO' produced by the radiolysis of water. Protectors and sensitizers that modify initial lesion formation act in a millisecond time frame by reaction with these dna radicals. Biological processes that can lead to repair or mis-repair of the lesions take place over a period of hours.

reaction of DNA radicals with endogenous protectors (395). In experiments using chemical model systems (dilute solutions of macro-molecules), sensitization by oxygen was observed only when radioprotectors were also present (395,396).Thus, damage fixation will occur without a sensitizer (by internal bond rearrangement) if protective reactions are not fast enough. Either an increase in the concentration of oxygen-mimetic sensitizer or a decrease in the concentration of endogenous protector can result in radiosensitization.

The chemical property of oxygen that is the basis for oxygen mimetic radiosensitization is the one-electron redox potential, or electron affinity (397). Electron affinity correlates with hypoxic cell radiosensitization, for agents that sensitize by this mechanism, over a range of different chemical structures, with some exceptions (397, 398). Radiosensitization by an oxygen-mimetic mechanism occurs within milliseconds of irradiation, and techniques have been developed to distinguish between this mechanism and other mechanisms of sensitization by determining the time frame for the effect (399). For example, a rapid-mix ex periment was used to show that AT-ethylmale-imide (48)can sensitize by an oxygen-mimetic mechanism, even though it can also sensitize

by reacting with cellular thiols (399). Whillans and Hunt (400) used a rapid-mix experiment to demonstrate that radiosensitization by mi-sonidazole (53)does not occur if misonidazole is mixed with hypoxic cells more than 10 ms after irradiation. Some of the first compounds that were found to be radiosensitizers, such as AT-ethylmaleimide (401) and menadione (402), are electron affinic, but were too toxic, too complicated mechanistically, or not sufficiently effective to be thoroughly developed for clinical use.

Attention in recent years has been concentrated on two general classes of electron-af-finic radiosensitizers: quinones and nitroimid-azoles (403). Highly electron affinic agents are effective in vitro, but not in vivo, presumably because they are so reactive they are depleted before they reach the target cells. The first nitro compounds that were found to be effective electron-affinic sensitizers in vitro, p-ni-tro-acetophenone (49) (404), p-nitro-3-di-methylamino-propiophenone (50) (405), and nitrofurazone (51) (406), were too toxic and

too metabolically unstable to be useful in vivo. Similarly, many quinones are effective in vitro but have been disappointing in vivo (407).

(50)

The first electron-affinic sensitizer based on the nitro functional group to be tested clinically (407) was metronidazole (1-13-hydroxy-ethyl-2-methyl-5-nitro-imidazole; Flagyl, 52),

a 5-nitroimidazole that was already in clinical use as an antitrichimonal agent. The trial, conducted with patients with glioblastoma multiforme using nonstandard fractionation, was positive, in that the median survival for the sensitizer group (7 months) was superior to the median survival for the controls (3 months). However, the long-term survival of the sensitizer group was not superior to that of historical controls given standard fractionated radiotherapy. The 2-nitroimidazole, mi-

sonidazole (53), was tested more extensively f=\

NO, in clinical trials. Only 5 of 33 trials showed some possible benefit (408). The most promising result came from a large randomized trial of patients with pharyngeal cancer (409), with an overall disease-free survival of 46% for the misonidazole group vs. 26% for the controls.

The dose of misonidazole that can be administered is-limited by peripheral neuropathy (410).In an effort to reduce this side effect, less lipophilic 2-nitroimidazoles were synthesized (411, 462). Desmethylmisonidazole (54) and etanidazole (55) are less neurotoxic than misonidazole, in keeping with their lower li-pophilicity. In a phase I clinical trial (413), it was determined that 30% more desmethylmisonidazole than misonidazole could be administered, but this compound was not tested further. Etanidazole can be administered at about 4 times the dose of misonidazole (414), and peripheral neuropathy can be almost completely avoided by determination of individual patient pharmacokinetics and adjustment cf the dosage accordingly (415). Efficacy data for etanidazole are not yet available, although several trials are nearing completion (415-418).

Nimorazole (56) (419), a 5-nitroimidazole, is less effective on a molar basis than the 2-ni-troimidazoles, but its dose-limiting toxicity is different. The dose-limiting toxicity for nimorazole is nausea and vomiting, whereas it is peripheral neuropathy for the 2-nitroimidaz-oles. The toxicity of nimorazole is not cumulative, and it can therefore be given with each radiation fraction. A phase III trial of nimora-

zole with 422 patients with squamous cell cancer of the larynx and pharynx (420, 421) showed an improvement in local control. Pimonidazole (Ro 03-8799) (57) is a 2-ni-

moiety on the side chain, of which KIN-804 (59) (429) and KIH-802 (60) (430) appear most promising, suggest that this functional /=\

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