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 intercalator, was studied in conjunction with radiation against V79 cultured cells and EMT6 or SCCVII tumors in their syngeneic mice and compared with tirapazamine (TPZ). NLCQ-1 was a very potent and efficient radiosensitizer of hypoxic V79 cells, providing SER values of 2.27-2.56 at 20-80 microM concentration (measured at 10% survival level). Its C1.6 (concentration for an SER of 1.6 to be obtained) was 7.2+/-0.2 microM. Its in vitro therapeutic index (ThI, defined as CT50(Air),/C1.6) varied by the exposure time from 57 (1-h exposure) to 145 (4.5-h exposure). The corresponding C1.6 value for TPZ was 16.9 microM whereas its in vitro therapeutic index was 49 (3-h exposure). A schedule-dependent synergistic interaction was observed between NLCQ-1 or TPZ and 20 Gy of radiation in both tumor models examined, by using the in vivo-in vitro assay as endpoint. Optimal synergism (> 1 log) was observed in EMT6 tumors when each bioreductive drug was given between 45 and 60 min before irradiation. 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 obtained with 10 mg/kg NLCQ-1 and 30 mg/kg TPZ, respectively, in EMT6 tumors. An SER value of 1.58 was obtained for both hypoxia-selective cytotoxins, at equitoxic doses, in SCCVII tumors, by using a fractionated regimen. These results suggest a possible use of NLCQ-1 or TPZ as adjuvants to radiotherapy.
Papadopoulou
M V
MV
The Radiation Medicine Institute at Evanston Northwestern Healthcare, Evanston, IL 60201, USA. m-papadopoulou@nwu.edu
Ji
M
M
Rao
M K
MK
Bloomer
W D
WD
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000378:metabolism / Q000633:toxicity*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000473:pathology / Q000532:radiotherapy; D015687:Cell Hypoxia; D002460:Cell Line; D002470:Cell Survival; D006224:Cricetinae; D003603:Cytotoxins / Q000008:administration & dosage / Q000009:adverse effects / Q000378:metabolism / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004307:Dose-Response Relationship, Radiation; D004334:Drug Administration Schedule; D005260:Female; D007093:Imidazoles / Q000008:administration & dosage / Q000378:metabolism / Q000633:toxicity*; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy / Q000473:pathology / Q000532:radiotherapy; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy*; D011804:Quinolines / Q000008:administration & dosage / Q000378:metabolism / Q000633:toxicity*; D011838:Radiation-Sensitizing Agents / Q000008:administration & dosage / Q000378:metabolism / Q000633:toxicity*; D000077704:Tirapazamine; D014227:Triazines / Q000008:administration & dosage / Q000378:metabolism / Q000633:toxicity; D014407:Tumor Cells, Cultured; D014410:Tumor Stem Cell Assay; D023041:Xenograft Model Antitumor Assays
C434187:4-(3-(2-nitro-1-imidazolyl)-propylamino)-7-chloroquinoline hydrochloride; D000970:Antineoplastic Agents; D003603:Cytotoxins; D007093:Imidazoles; D011804:Quinolines; D011838:Radiation-Sensitizing Agents; D014227:Triazines; D000077704:Tirapazamine