Advantage of Combining NLCQ-1 (NSC 709257) with Radiation in Treatment of Human Head and Neck Xenografts

Papadopoulou, Maria V.; Bloomer, William D.; Taylor, Alice P.; Hernandez, Marisol; Blumenthal, Rosalyn D.; Hollingshead, Melinda G.

doi:10.1667/rr0539.1

Cited by 7 publications

(8 citation statements)

References 29 publications

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“…Earlier studies have established that NLCQ-1 has a good hypoxia-selectivity ratio and combines well with radiotherapy and a range of chemotherapy approaches in vivo (Papadopoulou et al , 2001a, 2001b, 2002, 2005, 2006, 2007). Here, we show that NLCQ-1 is an excellent and well-tolerated adjuvant to radiotherapy in the control of metastatic tumour growth.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2010

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Background:Metastases cause most cancer-related deaths. We investigated the use of hypoxia-selective cytotoxins as adjuvants to radiotherapy in the control of metastatic tumour growth.Methods:The NLCQ-1, RB6145 and tirapazamine were assessed against the spontaneously metastasising KHT model. Subcutaneous KHT tumours (250 mm3) 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.Results:In 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 [18F]fluorodeoxyglucose ([18F]FDG). Metastatic burden discernable by [18F]FDG PET correlated well with macroscopic and histological lung analysis.Conclusion:The hypoxia-selective cytotoxin NLCQ-1 controls metastatic disease and may be a successful adjuvant to radiotherapy in the clinical setting.

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Section: Discussionmentioning

confidence: 99%

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

et al. 2010

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“…Multiple views containing >20 cells per × 400 microscopic field were captured at room temperature with Microfire software (Olympus America, Center Valley, PA, USA) with the exposure time, image-intensity gain, and enhancement held constant throughout to minimise intra- and inter-experimental variation. For each actin form, the number of pixels of a given fluorescence intensity was determined using Photoshop software (Adobe Systems, San Jose, CA, USA) at intensity values for AF-DNase I, 108±11; FITC-phalloidin, 159±10; non-cellular background, 7±4 (DNase I) or 15±4 (phalloidin) (Chan et al , 1998; Hirshman et al , 2001; Papadopoulou et al , 2007). …”

Section: Methodsmentioning

confidence: 99%

Placental growth factor (PlGF) enhances breast cancer cell motility by mobilising ERK1/2 phosphorylation and cytoskeletal rearrangement

2010

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Background:During metastasis, cancer cells migrate away from the primary tumour and invade the circulatory system and distal tissues. The stimulatory effect of growth factors has been implicated in the migration process. Placental growth factor (PlGF), expressed by 30–50% of primary breast cancers, stimulates measurable breast cancer cell motility in vitro within 3 h. This implies that PlGF activates intracellular signalling kinases and cytoskeletal remodelling necessary for cellular migration. The PlGF-mediated motility is prevented by an Flt-1-antagonising peptide, BP-1, and anti-PlGF antibody. The purpose of this study was to determine the intracellular effects of PlGF and the inhibiting peptide, BP-1.Methods:Anti-PlGF receptor (anti-Flt-1) antibody and inhibitors of intracellular kinases were used for analysis of PlGF-delivered intracellular signals that result in motility. The effects of PlGF and BP-1 on kinase activation, intermediate filament (IF) protein stability, and the actin cytoskeleton were determined by immunohistochemistry, cellular migration assays, and immunoblots.Results:Placental growth factor stimulated phosphorylation of extracellular-regulated kinase (ERK)1/2 (pERK) in breast cancer cell lines that also increased motility. In the presence of PlGF, BP-1 decreased cellular motility, reversed ERK1/2 phosphorylation, and decreased nuclear and peripheral pERK1/2. ERK1/2 kinases are associated with rearrangements of the actin and IF components of the cellular cytoskeleton. The PlGF caused rearrangements of the actin cytoskeleton, which were blocked by BP-1. The PlGF also stabilised cytokeratin 19 and vimentin expression in MDA-MB-231 human breast cancer cells in the absence of de novo transcription and translation.Conclusions:The PlGF activates ERK1/2 kinases, which are associated with cellular motility, in breast cancer cells. Several of these activating events are blocked by BP-1, which may explain its anti-tumour activity.

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“…administration of 10 mg ⁄ kg (30 mg ⁄ m 2 ) NLCQ-1. Importantly, 10 mg ⁄ kg is a therapeutic NLCQ-1 dose, required for effective combination with radiation [12][13][14] or chemotherapy in mice [16][17][18][19][20][21] and represents 33% of its MTD (in mice). On the other hand, the AUC of 410 lg ⁄ ml · min.…”

Section: Discussionmentioning

confidence: 99%

Investigational New Drug‐Directed Toxicology and Pharmacokinetic Study of 4‐[3‐(2‐Nitro‐1‐Imidazolyl)‐Propylamino]‐7‐Chloroquinoline Hydrochloride (NLCQ‐1, NSC 709257) in Beagle Dogs

Papadopoulou

Bloomer

Torti

et al. 2010

Basic Clin Pharma Tox

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4-[3-(2-Nitro-1-imidazolyl)-propylamino]-7-chloroquinoline hydrochloride (NLCQ-1), a 2-nitroimidazole-based hypoxia-selective cytotoxin has been shown to target hypoxic regions of solid tumours. The present study is one of several pre-clinical toxicology studies conducted in support of an 'investigational new drug' (IND) application to test this agent as an adjuvant to radio ⁄ chemotherapy for the treatment of cancer in humans. Twenty-four dogs were each assigned to one vehicle control group or to one of three test article-treated groups (three dogs ⁄ sex ⁄ treatment group). Intravenous (i.v.) doses of 0, 2.74, 5.48 and 10.95 mg ⁄ kg ⁄ day (54.8, 109.6 or 219 mg ⁄ m 2 ⁄ day) were administered on a per day · 5 days (qd · 5) schedule. NLCQ-1 was formulated as a solution in sterile saline at 1.5 mg ⁄ ml. None of the dogs died during this 33-day study. With few exceptions, most of the clinical signs of toxicity were noted within 2 hr following dosing in the 10.95 mg ⁄ kg ⁄ day dose group. These observations included aggressive behaviour, ataxia, tachypnea, emesis, hypoactivity, excessive salivation, tremors, and involuntary urination and defecation. Aggressive behaviour was judged to be dose-limiting. No clinical signs of toxicity were noted during the 28-day observation period that followed the 5-day dose period. Findings in a functional observation battery examination were consistent with the clinical observations. No drug-related effects were noted on the body weight or food consumption values, and no drug-related changes were noted during ocular examinations made on these animals prior to scheduled necropsy or during examination of electrocardiogram recordings made at 15 min. and 2 hr after dosing on days 1 and 5. No definitive changes in haematology, clinical chemistry or coagulation values were noted in dogs treated with NLCQ-1. NLCQ-1 was detected in the plasma of treated dogs on days 1 and 5, up to 60 min. after dosing (2.74 and 5.48 mg ⁄ kg ⁄ day) and up to 8 hr after dosing (10.95 mg ⁄ kg ⁄ day). There was a dose-related increase in maximum plasma concentration of NLCQ-1 at 5 min. after dosing; comparable concentrations were noted on days 1 and 5. No definitive test article-related lesions were noted during microscopic evaluation of tissues from dogs in this study, although lesions noted at the injection site and in the vascular tissue, lungs, thymus, prostate gland, muscle, adrenal cortex and tongue may have resulted from treatment with this drug. Any drug-related toxicity noted was readily reversible and not cumulative. No sex difference was detected in the susceptibility to NLCQ-1-induced toxicity.

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Advantage of Combining NLCQ-1 (NSC 709257) with Radiation in Treatment of Human Head and Neck Xenografts

Cited by 7 publications

References 29 publications

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

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

Placental growth factor (PlGF) enhances breast cancer cell motility by mobilising ERK1/2 phosphorylation and cytoskeletal rearrangement

Investigational New Drug‐Directed Toxicology and Pharmacokinetic Study of 4‐[3‐(2‐Nitro‐1‐Imidazolyl)‐Propylamino]‐7‐Chloroquinoline Hydrochloride (NLCQ‐1, NSC 709257) in Beagle Dogs

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