Bioreductive drugs can cause retinal toxicity, mediated by extensive apoptosis in the outer retina of rodents and monkeys. In the present study, we have investigated whether or not the novel and promising hypoxia-selective cytotoxin 4-[3-(2-nitro-1-imidazolyl)-propylamino]-7-chloroquinoline hydrochloride (NLCQ-1, NSC 709257) can cause hypoxia-dependent retinal toxicity in BALB/c mice alone or in combination with cyclophosphamide (CPM), one of the anti-cancer agents that acts synergistically with NLCQ-1 against mouse tumours and human xenografts. The bioreductive agent tirapazamine (TPZ) was included for comparison purposes. Retinal damage was quantified by morphometric analysis of histological sections following IP treatment of female BALB/c mice. No retinal toxicity was observed with 10 or 22 mg/kg of NLCQ-1 or 23 mg/kg TPZ alone, whereas statistically significant retinal toxicity was observed with the higher TPZ dose of 52 mg/kg (p < 0.001). Thus, a normalized photoreceptor layer thickness (NPT) value of 0.50 ± 0.04, 0.48 ± 0.03 and 0.33 ± 0.06 was determined for untreated, NLCQ-1 and TPZ-treated mice at the highest dose, respectively. Marginal retinal toxicity was observed with the lower dose of TPZ in combination with CPM.

01 Jul 2010·British Journal of CancerQ1 · MEDICINE

The hypoxia-selective cytotoxin NLCQ-1 (NSC 709257) controls metastatic disease when used as an adjuvant to radiotherapy

Q1 · MEDICINE

Article

Author: Peter J Julyan ; Christopher Cawthorne ; B Telfer ; A Smigova ; I Stratford ; K Williams ; S Lunt ; Patricia M Price ; W Bloomer ; M Papadopoulou ; M Ali ; M Babur

BACKGROUNDMetastases cause most cancer-related deaths. We investigated the use of hypoxia-selective cytotoxins as adjuvants to radiotherapy in the control of metastatic tumour growth.METHODSThe NLCQ-1, RB6145 and tirapazamine were assessed against the spontaneously metastasising KHT model. Subcutaneous KHT tumours (250 mm(3)) were irradiated with 25 Gy (single fraction) to control primary growth. Equitoxic drug treatments (NLCQ-1 (10 mg kg(-1)) once daily; RB6145 (75 mg kg(-1)) and tirapazamine (13 mg kg(-1)) twice daily) were administered 3-6 days post-radiotherapy when hypoxic cells were evident in lung micrometastases. Mice were culled when 50% of controls exhibited detrimental signs of lung metastases.RESULTSIn total, 95% of control mice presented with lung disease. This was significantly reduced by NLCQ-1 (33%; P=0.0002) and RB6145 (60%; P=0.02). Semi-quantitative grading of lung disease revealed a significant improvement with all treatments, with NLCQ-1 proving most efficacious (median grades: control, 4; NLCQ, 0 (P<0.0001); RB6145, 1 (P<0.001), tirapazamine, 3 (P=0.007)). Positron emission tomography (PET) was evaluated as a non-invasive means of assessing metastatic development. Primary and metastatic KHT tumours showed robust uptake of [(18)F]fluorodeoxyglucose ([(18)F]FDG). Metastatic burden discernable by [(18)F]FDG PET correlated well with macroscopic and histological lung analysis.CONCLUSIONThe hypoxia-selective cytotoxin NLCQ-1 controls metastatic disease and may be a successful adjuvant to radiotherapy in the clinical setting.

01 Jun 2010·Basic & Clinical Pharmacology & ToxicologyQ3 · MEDICINE

Investigational New Drug‐Directed, 5‐Day Repeat Dose Toxicity Study of 4‐[3‐(2‐Nitro‐1‐Imidazolyl)‐Propylamino]‐7‐Chloroquinoline Hydrochloride (NLCQ‐1, NSC 709257) Administered with or without Taxol^® in Sprague–Dawley Rats

Q3 · MEDICINE

Article

Author: Maria V. Papadopoulou ; William D. Bloomer ; John G. Page ; Vincent R. Torti

Abstract: In pre‐clinical studies, 4‐[3‐(2‐nitro‐1‐imidazolyl)‐propylamino]‐7‐chloroquinoline hydrochloride (NLCQ‐1, NSC 709257) is a weak DNA‐intercalating, hypoxia‐selective cytotoxin with a promising profile as an adjuvant to radio/chemotherapy and it is about to enter phase I clinical trials. The present investigation was undertaken to further evaluate potential systemic toxicity induced by i.v. doses of NLCQ‐1 alone or in combination with Taxol® in Sprague–Dawley rats, in support of an investigational new drug application. Doses of NLCQ‐1 were based on previous range‐finding studies. In the present study, NLCQ‐1 was administered either alone, at 0, 6, 9 or 12 mg/kg/dose to male rats and 8, 12 or 16 mg/kg/dose to female rats or, at 9 (male rats) and 12 (female rats) mg/kg/dose, in combination with Taxol®, on a qd × 5 schedule. Taxol® was administered i.v. at 3.5 mg/kg/dose 1 hr before NLCQ‐1. Observations were recorded for mortality/moribundity, clinical signs of toxicity, body weights, food consumption, haematology, clinical chemistry, gross lesions at necropsy and histopathology. Blood samples were taken from 10 animals from each dose group on each of 2 days (days 8 and prior to scheduled necropsy on day 33). Administration of i.v. doses of NLCQ‐1 alone, on a qdx5 schedule, resulted in no signs of toxicity over the 33‐day study. Taxol®‐induced toxicity included minimal decreases in the group mean RBC, haemoglobin and haematocrit values, minimal increases in group mean reticulocyte counts (females), marked decreases in group mean neutrophil counts and minimal decreases in group mean monocyte and eosinophil counts. Lymphoid atrophy of thymus, atrophy of bone marrow and atrophy of the germinal epithelium of the testis were also associated with the administration of Taxol®. There was no additional toxicity associated with the co‐administration of NLCQ‐1 and Taxol®. In the present study, the ‘no observable adverse effect level’ for NLCQ‐1, when administered on a qdx5 schedule, was >12 and >16 mg/kg/dose in male and female rats respectively. Daily administration of 9 (male rats) or 12 (female rats) mg/kg of NLCQ‐1 1 hr after i.v. administration of Taxol® (3.5 mg/kg) had no effect on Taxol®‐induced toxicity.

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Neoplasms	Discovery	US	Evanston Hospital Corp.	-

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