NLCQ-1 (NSC 709257) in combination with radiation against human glioma U251 xenografts.
BACKGROUND
The efficacy of the weak DNA-intercalative hypoxia-selective cytotoxin NLCQ-1 (NSC 709257) was investigated in combination with single or fractionated doses of radiation against human glioma U251 xenografts. Two "advanced stage" experiments were performed in female athymic nude mice.


METHODS
Tumor-bearing mice were allocated in groups of 8-10 (treated) or 10-20 (control) and irradiated in the presence or absence of NLCQ-1. Fractionated radiation was administered either qd x 4 or qd x 2, followed by a 9-day rest and repeated dosing. NLCQ-1 was administered i.p. 45 min before each radiation dose.


RESULTS
NLCQ-1 alone did not show antitumor activity or toxicity. Radiation at the highest single dose used (5.0 Gy) showed antitumor activity without weight loss (optimal T/C = -45). Lower single radiation doses (2.0 or 3.0 Gy) were marginally effective (optimal T/C of 34 and 40, respectively). The addition of NLCQ-1 to the treatment with each single radiation dose provided better optimal T/C values (e.g., -64 with 5.0 Gy). Fractionated radiation at 1.0 Gy qd x 4 showed minimal effectiveness (T/C = 27) but, in combination with NLCQ-1, the T/C value was improved to 19. Radiation alone, given on a 3.0 Gy qd x 2, 9-day rest and repeat schedule was very effective (T/C = -57) without toxicity and resulted in 5 out of 10 complete regressions up to 42 days. When NLCQ-1 was added to the above protocol an optimal TIC value of -100 and 9 out of 10 complete regressions were obtained with a follow-up of 52 days.


CONCLUSIONS
The above results suggest a significant advantage in combining radiation with NLCQ-1 against glioma tumors.
Papadopoulou
Maria V
MV
Evanston Northwestern Healthcare, Department of Radiation Medicine, Evanston, IL 60201, USA. m-papadopoulou@northwestern.edu
Bloomer
William D
WD
Hollingshead
Melinda G
MG
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D015687:Cell Hypoxia / Q000187:drug effects; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D019583:Dose Fractionation, Radiation; D004307:Dose-Response Relationship, Radiation; D005260:Female; D005910:Glioma / Q000188:drug therapy* / Q000532:radiotherapy*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D051379:Mice; D008819:Mice, Nude; D011804:Quinolines / Q000494:pharmacology*; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
C434187:4-(3-(2-nitro-1-imidazolyl)-propylamino)-7-chloroquinoline hydrochloride; D000970:Antineoplastic Agents; D007093:Imidazoles; D011804:Quinolines; D011838:Radiation-Sensitizing Agents