Assessing the bioreductive effectiveness of the nitroimidazole RSU1069 and its prodrug RB6145: with particular reference to in vivo methods of evaluation.
The nitroimidazole, RSU1069, has been shown to have a very high differential toxicity towards hypoxic cells compared to oxic cells both in in vitro and in vivo experimental conditions. However, in the clinic it was found to cause severe emesis and had to be withdrawn. After an extensive drug development programme an analogue of RSU1069, RB6145, which acts as a pro-drug for RSU1069, was found to be the most suitable candidate for further investigation. In in vivo studies with murine tumour models, when RB6145 was used in combination with X-rays it was shown to produce a similar level of toxicity towards hypoxic cells as that observed for RSU1069. Its activity was the same whether it was administered interperitoneally or orally and the same level of anti-tumour effect was observed if the drug was given before or after X-rays. RB6145 is better tolerated systemically in mice than RSU1069 and canine studies have shown that it is less emetic than the parent drug. Bioreductive drugs can also be used in combination with treatments that preferentially increase tumour hypoxia. Photodynamic therapy (PDT) causes extensive vascular damage in tumours. If either RSU1069 or RB6145 are administered during PDT, very large increases in the growth delay induced by PDT alone are seen for the RIF-1 murine tumour. RB6145 has been accepted for clinical toxicity trials with the prospect of using it in combination with X-rays. In the future it may also be of clinical use with treatments such as PDT.
Bremner
J C
JC
MRC Radiobiology Unit, Chilton, Didcot, Oxon, United Kingdom.
D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D015687:Cell Hypoxia / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects*; D006801:Humans; D008920:Misonidazole / Q000031:analogs & derivatives* / Q000633:toxicity; D009374:Neoplasms, Experimental / Q000188:drug therapy; D009593:Nitroimidazoles / Q000633:toxicity*; D010084:Oxidation-Reduction; D011355:Prodrugs / Q000633:toxicity*; D011838:Radiation-Sensitizing Agents / Q000633:toxicity
D000970:Antineoplastic Agents; D009593:Nitroimidazoles; D011355:Prodrugs; D011838:Radiation-Sensitizing Agents; C067834:RB 6145; C041712:1-(2-nitro-1-imidazolyl)-3-aziridino-2-propanol; D008920:Misonidazole