ARCON: accelerated radiotherapy with carbogen and nicotinamide in non small cell lung cancer: a phase I/II study by the EORTC

Bernier, Jacques; Denekamp, Juliana; Rojas, Á.; Trovò, M.; Horiot, J.C.; Hamers, Han; Antognoni, Paolo; Dahl, Olav; Richaud, Pierre; Kaanders, J.H.A.M.; Glabbeke, M. van; Piérart, M.

doi:10.1016/s0167-8140(99)00106-1

Cited by 45 publications

(27 citation statements)

References 12 publications

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“…However, it has largely been used in the clinic at pharmacological doses over many years with a low incidence of side effects and toxicity for diverse conditions including dermatological, metabolic and psychiatric disorders (19-22). In cancer, NAM has been used in clinical studies in combination with accelerated radiotherapy with carbogen and nicotinamide (ARCON) for radiosensitation (12,(16)(17)(18). In the present study, we demonstrate that NAM effectively inhibits PARP activity in vitro, results that are consistent with those of previous reports (13).…”

Section: Discussionsupporting

confidence: 92%

“…Preclinical studies have shown that NAM may exert antitumor effects and reverse chemotherapy resistance in some models (14). In addition, this drug is currently used as a component of accelerated radiotherapy with carbogen and nicotinamide (ARCON), a therapeutic strategy used in non-small cell lung cancer, head and neck and bladder cancer (15)(16)(17)(18). In the present study, the results showed that NAM increased the cytotoxic effects of cisplatin and radiation on breast cancer cells.…”

Section: Introductionmentioning

confidence: 51%

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Nicotinamide sensitizes human breast cancer cells to the cytotoxic effects of radiation and cisplatin

et al. 2014

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Abstract. Poly(ADP-ribose) polymerase (PARP) inhibitors enhance the effect of DNA alkylating agents on BRCA1-and BRCA2-deficient cell lines. The aim of this study was to analyze the effect of the PARP inhibitor nicotinamide (NAM) on breast cancer cells with different BRCA1 expression or function, such as BRCA1-deficient MDA-MB-436 cells, low expression BRCA1 MCF-7 cells, and the BRCA1 wild-type MDA-MB-231 cells, to demonstrate its effects as a chemoor radiosensitizing agent. PARP activity was analyzed in MDA-MB-436, MCF-7 and MDA-MB-231 breast cancer cells subjected or not to NAM. Inhibition of PARP by NAM in the presence of DNA damage was examined by Alexa Fluor 488 immunofluorescence. Crystal violet assays were used to test growth inhibition and the chemo-and radiosensitization effects of NAM were investigated using clonogenic assays. Significant differences among data sets were determined using two-tailed ANOVA and Bonferroni tests. We demonstrated that NAM reduces PARP activity in vitro, and in cells subjected or not to DNA damage, it also reduces the viability of breast cancer cell lines and synergyzes the cytotoxicity of cisplatin in MDA-MB-436 and MCF-7 cells. Downregulation of PARP1 with siRNA led to modest growth inhibition, which was further increased by cisplatin. Nicotinamide also induced radiosensitization in MDA-MB-436 and MDA-MB-231 cells. In conclusion, NAM may be used as a chemo-or radiosensitizing agent regardless of the BRCA1 status in breast cancer.

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Section: Discussionsupporting

confidence: 92%

Section: Introductionmentioning

confidence: 51%

Nicotinamide sensitizes human breast cancer cells to the cytotoxic effects of radiation and cisplatin

et al. 2014

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“…This means that all volumes of a tumor are currently treated to a uniform volume, despite the fact that subregions of the tumor associated with hypoxia are the regions most likely to recur. (31) Altered fractionation protocols and hypoxia modifiers can greatly impact effectiveness (32–34), yet the optimal regimen remains elusive. (35) While there are several direct imaging markers of hypoxia (36–38), their temporal resolution is relatively poor.…”

Section: Discussionmentioning

confidence: 99%

Acute Tumor Lactate Perturbations as a Biomarker of Genotoxic Stress: Development of a Biochemical Model

Sandulache

Chen

Skinner

et al. 2015

Molecular Cancer Therapeutics

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Ionizing radiation is the primary non-surgical treatment modality for solid tumors. Its effectiveness is impacted by temporal constraints such as fractionation, hypoxia and development of radioresistant clones. Biomarkers of acute radiation response are essential to developing more effective clinical algorithms. We hypothesized that acute perturbations in tumor lactate levels act as a surrogate marker of radiation response. In vitro experiments were carried out using validated human derived cell lines from 3 histologies: anaplastic thyroid carcinoma (ATC), head and neck squamous cell carcinoma (HNSCC) and papillary thyroid carcinoma (PTC). Cellular metabolic activity was measured using standard biochemical assays. In vivo validation was performed using both an orthotopic and a flank derivative of a previously established ATC xenograft murine model. Irradiation of cells and tumors triggered a rapid, dose-dependent, transient decrease in lactate levels which was reversed by free radical scavengers. Acute lactate perturbations following irradiation could identify hypoxic conditions and correlated with hypoxia-induced radioresistance. Mutant TP53 cells and cells in which p53 activity was abrogated (shRNA) demonstrated a blunted lactate response to irradiation, consistent with a radioresistant phenotype. Lactate measurements therefore rapidly detected both induced (i.e. hypoxia) and intrinsic (i.e. mutTP53 driven) radioresistance. We conclude that lactate is a quantitative biomarker of acute genotoxic stress, with a temporal resolution which can inform clinical decision-making. Combined with the spatial resolution of newly developed metabolic imaging platforms, this biomarker could lead to the development of truly individualized treatment strategies.

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“…However, the results obtained with ARCON in clinical studies have been disappointing. In non-smallcell lung cancer, there were no significant responses with ARCON [119]. Nevertheless, in bladder cancer, ARCON showed significant gains on local control, disease-free survival and overall survival compared with a group control [120].…”

Section: Hypoxia As a Therapeutic Target In Cancermentioning

confidence: 91%

The magic of the hypoxia-signaling cascade

Benizri

Ginouvès

Berra

2008

Cell. Mol. Life Sci.

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All organisms respond to changes in their environment by activating complex signaling cascades. The "hypoxia-signaling cascade" is activated in response to low oxygen availability and this activation is central to maintaining oxygen homeostasis and hence to survival. By regulating the transcriptional complex hypoxia-inducible factor, hypoxia is associated with several physiopathological processes. Several strategies, based on the targeting of the hypoxia-signaling cascade, have been developed to treat these pathologies. Our review summarize different aspects of the hypoxic pathway.

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ARCON: accelerated radiotherapy with carbogen and nicotinamide in non small cell lung cancer: a phase I/II study by the EORTC

Cited by 45 publications

References 12 publications

Nicotinamide sensitizes human breast cancer cells to the cytotoxic effects of radiation and cisplatin

Nicotinamide sensitizes human breast cancer cells to the cytotoxic effects of radiation and cisplatin

Acute Tumor Lactate Perturbations as a Biomarker of Genotoxic Stress: Development of a Biochemical Model

The magic of the hypoxia-signaling cascade

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