Cytotoxic effect of RB 6145 in human tumour cell lines: dependence on hypoxia, extra- and intracellular pH and drug uptake

Abstract

Summary Low pH and hypoxia are a common feature of many solid tumours. This study examined the effect of these two conditions on the cytotoxic properties of the bifunctional agent RB 6145, the prodrug of RSU 1069. The effect of acidic pH on RB 6145 toxicity was examined in six human tumour (Coleman, 1988), much effort has been directed at finding ways to specifically target such cells in tumours. The use of hypoxic cell radiosensitisers such as the 2-nitroimidazole, misonidazole, has provided some therapeutic gain, though neurotoxicity limited its dose and thus its effectiveness. (Dische, 1985;Overgaard et al., 1989). RSU 1069 [x-(1-aziridinomethyl)-2-nitro-lH-imidazole-1-ethanol] was one of the newer generation nitroimidazoles developed by Adams et al. (1984a,b), and one which exhibited two functions: radiosensitisation due to the electron affinic properties of the molecule and alkylation by the aziridine moiety. It was very efficient both as a radiosensitiser and as a chemosensitiser, but also produced severe gastrointestinal toxicity (Horwich et al., 1986). RB 6145 [a-([(2-bromoethyl)-aminoJmethyl)-2-nitro-JH-imidazole-1-ethanol hydrobromide] was developed as an analogue (see Figure 1) and prodrug of RSU 1069 (Jenkins et al., 1990). It retained most of the radiosensitisation and bioreductive cytotoxicity of RSU 1069 but had much lower toxicity (Cole et al., 1990(Cole et al., , 1991(Cole et al., , 1992Bremner, 1993), and is currently awaiting clinical evaluation.The pharmacokinetics of RB 6145 and its metabolites have been carefully examined in mice (Binger and Workman, 1991). The major metabolites were shown to be RSU 1069 (the pharmacologically active aziridine ring metabolite) and an oxazolidinone metabolite, with much lower levels of at least two other analogues, RSU 1137 and RSU 1111 (see Figure 1)

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In vivo tumour extracellular pH monitoring using electron paramagnetic resonance: the effect of X‐ray irradiation

“…In addition, the excess carbon used in lactate production may result in the faster incorporation of carbon into biomass, thereby facilitating cell proliferation . The adverse microenvironment resulting from the reduction in extracellular pH (pH e ), together with increased levels of cellular hypoxia, has a profound effect on the effectiveness of cytotoxic anticancer drugs, and provides increased therapeutic resistance . Therefore, improvement in therapeutic outcome may depend on the effectiveness of treatment approaches that specifically target cells in low pH e environments, or those that can increase tumour pH e .…”

Anticancer Prodrugs for Application in Monotherapy Targeting Hypoxia, Tumor-Associated Enzymes, and Receptors

“…9) [60]) were originally developed as radiosensitizers, but have also been used as bioreductive drugs. These compounds have an increased reduction potential and compound 21 showed good hypoxia selectivity [61], but retinal toxicity was observed as a severe side effect [62].…”