A toxicity and pharmacokinetic study in man of the hypoxic-cell radiosensitiser RSU-1069

Horwich, A.; Holliday, Steve; Deacon, Judith; Peckham, M. J.

doi:10.1259/0007-1285-59-708-1238

Cited by 50 publications

(20 citation statements)

References 3 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This aziridine function was believed to be responsible for the toxicity seen in humans. 40 While more potent than misonidazole, 7 was also characterized by relatively low potency under hypoxic conditions, with a reported IC 50 value under N 2 of 15 µM in V79-379A cells. 39 A prodrug of 7, 41 1-(2-bromoethylamino)-3-(2-nitro-1H-imidazol-1-yl)propan-2-ol hydrobromide (RB-6145, 8, Figure 9), 42 has shown reduced toxicity but without significant improvement in efficacy.…”

mentioning

confidence: 99%

Potent and Highly Selective Hypoxia-Activated Achiral Phosphoramidate Mustards as Anticancer Drugs

et al. 2008

View full text Add to dashboard Cite

A series of achiral hypoxia-activated prodrugs were synthesized on the basis of the DNA cross-linking toxin of the prodrug, ifosfamide. The hypoxia-selective cytotoxicity of several of the compounds was improved over previously reported racemic mixtures of chiral bioreductive phosphoramidate prodrugs. Prodrugs activated by 2-nitroimidazole reduction demonstrated up to 400-fold enhanced cytotoxicity toward H460 cells in culture under hypoxia versus their potency under aerobic conditions. Compounds were further assessed for their stability to cytochrome P450 metabolism using a liver microsome assay. The 2-nitroimidazole containing lead compound 3b (TH-302) was selectively potent under hypoxia and stable to liver microsomes. It was active in an in ViVo MIA PaCa-2 pancreatic cancer orthotopic xenograft model as a monotherapy and demonstrated dramatic efficacy when used in combination with gemcitabine, extending survival with one of eight animals tumor free at day-44. Compound 3b has emerged as a promising antitumor agent that shows excellent in ViVo efficacy and is currently being evaluated in the clinic.

show abstract

mentioning

confidence: 99%

Potent and Highly Selective Hypoxia-Activated Achiral Phosphoramidate Mustards as Anticancer Drugs

et al. 2008

View full text Add to dashboard Cite

show abstract

“…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).…”

mentioning

confidence: 99%

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

Acheson²,

Vinczan³

et al. 1995

Br J Cancer

View full text Add to dashboard Cite

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)

show abstract

“…As a hypoxic-cell cytotoxin it is 100 times more toxic to anoxic than to normoxic cells in vitro (Ahmed et al, 1986;Stratford et al, 1986). In a limited clinical trial it has been found to cause the side-effects of nausea and vomiting (Horwich et al, 1986).…”

mentioning

confidence: 99%

Distribution of pimonidazole and RSU 1069 in tumour and normal tissues

Cobb¹,

Nolan²,

Butler³

1990

Br J Cancer

View full text Add to dashboard Cite

Summary The tritium-labelled analogues of pimonidazole and RSU 1069 were injected into mice bearing the KHT murine sarcoma which has a hypoxic cell fraction of 1-0%. The distribution of activity at 24 h was recorded using autoradiography and measurement of tissue activity. Autoradiographs with both drugs showed high activity in particular cells within tumour, eye (melanin-associated cells), eyelid (Meibomian gland), liver (centrilobular area), skin (sebaceous gland and melanin), stomach (squamous area), footpad, oesophagus, labial gland, Zymbal's gland, preputial gland, parotid gland (intralobular ducts) and airway epithelium. These tissues had previously been identified as sites of binding of misonidazole. The measurement of total tissue radioactivity showed significantly higher activity in liver, eyelid (Meibomian gland), oesophageal lining, kidney and labial gland than was found in the tumour.Misonidazole (1-(2-nitro-1-imidazolyl)-3-methoxy-2-propanol; MISO) sensitises hypoxic tumour cells to ionising radiation (Asquith et al., 1974). This radiosensitisation is associated with the electron affinity of, MISO and is a fast (subsecond) free-radical process. MISO can also be involved in a separate, slower, enzyme dependent process in which, in the presence of the appropriate reductase(s), the nitro group is reduced yielding cytotoxic species (Varghese et al., 1976;Rauth, 1984). This second process is favoured by a hypoxic environment -such as occurs in parts of many tumoursand this leads to locally enhanced retention. The concept of the preferential retention of reactive bioreduced metabolites in tumours has generated two lines of research. One is directed towards tumour therapy (bioreductive drug therapy). In this, drugs are being developed which, as with MISO, on reduction in the hypoxic milieu of the tumour, form cytotoxic metabolites(s) that bind to critical macromolecules such as DNA. The other line of research is in the field of imaging and spectroscopy.

show abstract

A toxicity and pharmacokinetic study in man of the hypoxic-cell radiosensitiser RSU-1069

Cited by 50 publications

References 3 publications

Potent and Highly Selective Hypoxia-Activated Achiral Phosphoramidate Mustards as Anticancer Drugs

Potent and Highly Selective Hypoxia-Activated Achiral Phosphoramidate Mustards as Anticancer Drugs

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

Distribution of pimonidazole and RSU 1069 in tumour and normal tissues

Contact Info

Product

Resources

About