THNLA-1 as radio/chemosensitiser of EMT-6 tumours in mice

THNLA-1 contains a 2-nitroimidazole tethered to 9-amino-1,2,3,4-tetrahydroacridine. Compared with its parent acridinic analogue, NLA-1, THNLA-1 is a weak DNA-affinic bioreductive compound with a greater mobility along the DNA backbone, decreased aerobic toxicity, greater hypoxic selectivity and a superior in vitro therapeutic index. Also, THNLA-1 behaves as a radio/chemosensitiser in vitro. In this report we have expanded our radio/chemosensitisation studies in vivo, using the EMT-6 mouse mammary tumour model in balb/c mice and the in vivo-in vitro assay. THNLA-1 was given i.p. ( < or = 0.5 ml in saline) at various time intervals before a single dose of 20 Gy whole-body irradiation. Tumours were excised immediately or 24 h after irradiation. Radiosensitisation studies with SR-2508 (i.v.) have been performed in a similar way for comparison purposes. THNLA-1 demonstrated the same radiosensitising effect as SR-2508 but with 19-fold less dose (mmol kg-1). The optimum effect was observed when THNLA-1 was given 1 h before irradiation and the tumours excised 24 h after irradiation. Chemosensitisation studies in the same tumour model and using cis DDP showed that the cytotoxic effect of cis-DDP (5 or 8 mg kg-1, i.p.) was significantly enhanced with 30 or 45 mg kg-1 THNLA-1 given approximately 3 h before cis-DDP. A similar potentiating effect was observed when NLA-1 (27 or 30 mg kg-1) was used, but toxicity was also observed at the higher dose. Limited toxicity studies showed that THNLA-1 is well tolerated up to at least 70 mg kg-1 as a single dose, for more than 40 days.