Randomized, Double-Blind, Phase II Trial Comparing Gemcitabine-Cisplatin plus the LTB4 Antagonist LY293111 versus Gemcitabine-Cisplatin plus Placebo in First-Line Non–Small-Cell Lung Cancer

Paz‐Ares, Luis; Oh, Yun; Eschbach, C.; Hirsh, Vera; Enas, Nathan; Brail, Les; Pawel, Joachim von

doi:10.1097/jto.0000000000000037

Cited by 26 publications

(23 citation statements)

References 12 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, these studies have been criticized for using non-physiologically-relevant doses and inducing off-target effects (reviewed in (7)). In contrast, clinical data so far do not support a pro-tumorigenic role of 5-LO (9–11). In particular, a trial in advanced non-small cell lung cancer demonstrated a statistically significant decrease in the overall survival of patients treated with an LTB4 receptor antagonist plus chemotherapy compared to patients treated with chemotherapy alone.…”

Section: Discussionmentioning

confidence: 83%

“…In particular, a trial in advanced non-small cell lung cancer demonstrated a statistically significant decrease in the overall survival of patients treated with an LTB4 receptor antagonist plus chemotherapy compared to patients treated with chemotherapy alone. This implies, unexpectedly, that 5-LO products were protective in this setting (11). …”

Section: Discussionmentioning

confidence: 90%

“…There has also been significant interest in exploring the role of the 5-lipoxygenase pathway in cancer, however the results have been conflicting. While pharmacological inhibitors have shown anti-proliferative and pro-apoptotic effects in studies on cancer cells, clinical trials using these agents have not shown efficacy (9–11). In addition, these agents appear to have significant “off-target” effects (7).…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Deletion of 5-Lipoxygenase in the Tumor Microenvironment Promotes Lung Cancer Progression and Metastasis through Regulating T Cell Recruitment

Poczobutt

Nguyen

Hanson

et al. 2016

The Journal of Immunology

View full text Add to dashboard Cite

Eicosanoids, including prostaglandins, produced by cyclooxygenases (COX), and leukotrienes, produced by 5-lipoxygenase (5-LO) have been implicated in cancer progression. These molecules are produced by both cancer cells and the tumor microenvironment (TME). We previously reported that both COX and 5-LO metabolites increase during progression in an orthotopic immunocompetent model of lung cancer. While prostaglandins in the TME have been well studied, less is known regarding 5-LO products produced by the TME. We examined the role of 5-LO in the TME, using a model in which Lewis Lung Carcinoma cells are directly implanted into the lungs of syngeneic WT or 5-LO knockout (5-LO-KO) mice. Unexpectedly, primary tumor volume and liver metastases were increased in 5LO-KO mice. This was associated with an ablation of leukotriene production, consistent with production mainly mediated by the microenvironment. Increased tumor progression was partially reproduced in global LTC4 synthase knockout or mice transplanted with LTA4 hydrolase-deficient bone-marrow. Tumor bearing lungs of 5-LO-KO had decreased numbers of CD4 and CD8 T cells compared to WT controls, as well as fewer dendritic cells. This was associated with lower levels of CCL20 and CXL9, which have been implicated in dendritic and T cell recruitment. Depletion of CD8 cells increased tumor growth, and eliminated the differences between WT and 5-LO mice. These data reveal an anti-tumorigenic role for 5-LO products in the microenvironment during lung cancer progression through regulation of T cells, and suggest that caution should be used in targeting this pathway in lung cancer.

show abstract

Section: Discussionmentioning

confidence: 83%

Section: Discussionmentioning

confidence: 90%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Deletion of 5-Lipoxygenase in the Tumor Microenvironment Promotes Lung Cancer Progression and Metastasis through Regulating T Cell Recruitment

Poczobutt

Nguyen

Hanson

et al. 2016

The Journal of Immunology

View full text Add to dashboard Cite

show abstract

“…In a phase II study, treatment of stage-III/IV NSCLC patients with LY293111 along with cisplatin-gemcitabine did not increase median progression-free survival over placebo plus cisplatingemcitabine group [69]. Two key confounding factors might be effecting the efficacy of these treatments.…”

Section: Leukotriene B4 In Cancermentioning

confidence: 99%

The yin and yang of leukotriene B 4 mediated inflammation in cancer

Jala

Bodduluri

Satpathy

et al. 2017

Seminars in Immunology

View full text Add to dashboard Cite

The high affinity leukotriene B4 receptor, BLT1 mediates chemotaxis of diverse leukocyte subsets to the sites of infection or inflammation. Whereas the pathological functions of LTB4/BLT1 axis in allergy, autoimmunity and cardiovascular disorders are well established; its role in cancer is only beginning to emerge. In this review, we summarize recent findings on LTB4/BLT1 axis enabling distinct outcomes toward tumor progression. In a mouse lung tumor model promoted by silicosis-induced inflammation, genetic deletion of BLT1 attenuated neutrophilic inflammation and tumor promotion. In contrast, in a spontaneous model of intestinal tumorigenesis, absence of BLT1 led to defective mucosal host response, altered microbiota and bacteria dependent colon tumor progression. Furthermore, BLT1 mediated CD8+ T cell recruitment was shown to be essential for initiating anti-tumor immunity in number of xenograft models and is critical for effective PD1 based immunotherapy. BLT2 mediated chemotherapy resistance, tumor promotion and metastasis are also discussed. This new information points to a paradigm shift in our understanding of the LTB4 pathways in cancer.

show abstract

“…Hence, they are forced to accept chemotherapy, radiotherapy or immunotherapy because losing the chance of surgery [3–4]. Gemcitabine and cisplatin (GP) is the first line chemotherapy and it can increase the overall response rate (ORR) of NSCLC patients [5–7]. But its clinical efficacy is often limited by the acute or subacute toxicity including leucopenia, anemia and thrombocytopenia, et.al [8–9].…”

Section: Introductionmentioning

confidence: 99%

Has aidi injection the attenuation and synergistic efficacy to gemcitabine and cisplatin in non-small cell lung cancer? A meta-analysis of 36 randomized controlled trials

et al. 2016

View full text Add to dashboard Cite

Gemcitabine and cisplatin is the first line chemotherapy for non-small cell lung cancer with high toxicity. Aidi injection is a cantharidin and astragalu-based Chinese herbs injection in China. Has Aidi injection attenuation and synergistic efficacy to GP in NSCLC? There is lack of strong evidence to prove it. To further reveal it, we systematically evaluated all related studies. We collected all studies about Aidi injection plus GP for NSCLC in Medline, Embase, Web of Science, CNKI, VIP, Wanfang Database, CBM, CCRCT, Chi-CTR, and US-clinical trials (established to June 2015). We evaluated their quality according to the Cochrane evaluation handbook of randomized controlled trials (5.1.0), extracted data following the PICO principles and synthesized the data by Meta analysis. Thirty six RCTs with 2582 NSCLC patients were included, with general methodological quality in most trials. The RR values and their 95% CI of Meta-analysis for ORR, DCR and QOL were as following: 1.28 (1.17, 1.39), 1.11(1.07, 1.15) and 1.81 (1.61, 2.03). The merged RD values and their 95% CI of Meta-analysis for myelosuppression, neutropenia, thrombocytopenia, neurotoxicity and nausea and vomiting were as following: -0.23(-0.29, -0.17), -0.17(-0.22, -0.11), -0.13(-0.18, -0.08), -0.06(-0.17, 0.05) and -0.15(-0.21, -0.10). To compare with GP alone, all differences were statistically significant. The available evidence indicates that Aidi injection plus GP can significantly increase the clinical efficacy and improve the QOL of patients with NSCLC. Aidi injection can reduce myelosuppression, neutropenia, thrombocytopenia neurotoxicity and nausea/vomiting. These indirectly reveal that Aidi injection has the attenuation and synergistic efficacy to GP chemotherapy in NSCLC.

show abstract

Randomized, Double-Blind, Phase II Trial Comparing Gemcitabine-Cisplatin plus the LTB4 Antagonist LY293111 versus Gemcitabine-Cisplatin plus Placebo in First-Line Non–Small-Cell Lung Cancer

Cited by 26 publications

References 12 publications

Deletion of 5-Lipoxygenase in the Tumor Microenvironment Promotes Lung Cancer Progression and Metastasis through Regulating T Cell Recruitment

Deletion of 5-Lipoxygenase in the Tumor Microenvironment Promotes Lung Cancer Progression and Metastasis through Regulating T Cell Recruitment

The yin and yang of leukotriene B 4 mediated inflammation in cancer

Has aidi injection the attenuation and synergistic efficacy to gemcitabine and cisplatin in non-small cell lung cancer? A meta-analysis of 36 randomized controlled trials

Contact Info

Product

Resources

About