4-[3-(2-nitro-1-imidazolyl)propylamino]-7-chloroquinoline hydrochloride (NLCQ-1), a novel bioreductive agent as radiosensitizer in vitro and in vivo:Comparison with tirapazamine

The novel hypoxia-selective cytotoxin NLCQ-1, which is a weak DNA intercala tor, was studied in conjunction with radiation against V79 cultured cells a nd EMT6 or SCCVII tumors in their syngeneic mice and compared with tirapaza mine (TPZ) NLCQ-1 was a very potent and efficient radiosensitizer of hypoxi c V79 cells, providing SER values of 2.27-2.56 at 20-80 muM concentration ( measured at 10% survival level). Its C-1.6 (concentration for an SER of 1.6 to be obtained) was 7.2 +/- 0.2 muM. Its in vitro therapeutic index (ThI, defined as CT50(Air)/C-1.6) varied by the exposure time from 57 (1-h exposu re) to 145 (4.5-h exposure). The corresponding Cl. value for TPZ was 16.9 m uM whereas its in vitro therapeutic index was 49 (3-h exposure). A schedule -dependent synergistic interaction was observed between NLCQ-1 or TPZ and 2 0 Gy of radiation in both tumor models examined, by using the in vivo-in vi tro assay as endpoint. Optimal synergism (> 1 log) was observed in EMT6 tum ors when each bioreductive drug was given between 45 and 60 min before irra diation. NLCQ-1 alone had no significant antitumor activity at 10 mg/kg (28 % of its single LD50), whereas a 0.4 surviving fraction was obtained by TPZ at 30 mg/kg (38% of its single LD50). SER values of 1.52 and 1.25 were obt ained with 10 mg/kg NLCQ- I and 30 mg/kg TPZ, respectively, in EMT6 tumors. An SER value of 1.58 was obtained for both hypoxia-selective cytotoxins, a t equitoxic doses, in SCCVII tumors, by using a fractionated regimen. These results suggest a possible use of NLCQ-1 or TPZ as adjuvants to radiothera py.