Antitumour action of 5,6-dimethylxanthenone-4-acetic acid in rats bearing chemically induced primary mammary tumours

Liu, JJ; Li, Ching; Goldthorpe, Michael A.; Sutherland, Robert M.; Baguley, Bruce C.; Kirker, James A.; McKeage, Mark J.

doi:10.1007/s00280-006-0321-7

Cited by 19 publications

(25 citation statements)

References 24 publications

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“…Interestingly, however, we found that the vascular disrupting effects of DMXAA on subcutaneous tumors did not extend to either the 344SQ-ELuc metastases obtained following intracardiac injection of these cells, or to the spontaneously arising tumors in the K-ras LA1/+ GEMM model of NSCLC. Indeed, the majority of successful pre-clinical studies evaluating the utility of DMXAA were carried out in subcutaneous tumor models, with relatively few studies examining the effects of DMXAA on tumors in other anatomical sites [37], [38]. Echoing our results, experiments employing a different vascular disrupting drug, flavone acetic acid (FAA), vessel disruption was seen in subcutaneous tumors, but not systemic tumors [39].…”

Section: Discussionsupporting

confidence: 55%

DMXAA Causes Tumor Site-Specific Vascular Disruption in Murine Non-Small Cell Lung Cancer, and like the Endogenous Non-Canonical Cyclic Dinucleotide STING Agonist, 2′3′-cGAMP, Induces M2 Macrophage Repolarization

et al. 2014

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The vascular disrupting agent 5,6-dimethylxanthenone-4-acetic acid (DMXAA), a murine agonist of the stimulator of interferon genes (STING), appears to target the tumor vasculature primarily as a result of stimulating pro-inflammatory cytokine production from tumor-associated macrophages (TAMs). Since there were relatively few reports of DMXAA effects in genetically-engineered mutant mice (GEMM), and models of non-small cell lung cancer (NSCLC) in particular, we examined both the effectiveness and macrophage dependence of DMXAA in various NSCLC models. The DMXAA responses of primary adenocarcinomas in K-rasLA1/+ transgenic mice, as well as syngeneic subcutaneous and metastatic tumors, generated by a p53R172HΔg/+; K-rasLA1/+ NSCLC line (344SQ-ELuc), were assessed both by in vivo bioluminescence imaging as well as by histopathology. Macrophage-dependence of DMXAA effects was explored by clodronate liposome-mediated TAM depletion. Furthermore, a comparison of the vascular structure between subcutaneous tumors and metastases was carried out using micro-computed tomography (micro-CT). Interestingly, in contrast to the characteristic hemorrhagic necrosis produced by DMXAA in 344SQ-ELuc subcutaneous tumors, this agent failed to cause hemorrhagic necrosis of either 344SQ-ELuc-derived metastases or autochthonous K-rasLA1/+ NSCLCs. In addition, we found that clodronate liposome-mediated depletion of TAMs in 344SQ-ELuc subcutaneous tumors led to non-hemorrhagic necrosis due to tumor feeding-vessel occlusion. Since NSCLC were comprised exclusively of TAMs with anti-inflammatory M2-like phenotype, the ability of DMXAA to re-educate M2-polarized macrophages was examined. Using various macrophage phenotypic markers, we found that the STING agonists, DMXAA and the non-canonical endogenous cyclic dinucleotide, 2′3′-cGAMP, were both capable of re-educating M2 cells towards an M1 phenotype. Our findings demonstrate that the choice of preclinical model and the anatomical site of a tumor can determine the vascular disrupting effectiveness of DMXAA, and they also support the idea of STING agonists having therapeutic utility as TAM repolarizing agents.

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Section: Discussionsupporting

confidence: 55%

DMXAA Causes Tumor Site-Specific Vascular Disruption in Murine Non-Small Cell Lung Cancer, and like the Endogenous Non-Canonical Cyclic Dinucleotide STING Agonist, 2′3′-cGAMP, Induces M2 Macrophage Repolarization

et al. 2014

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“…However this agent failed in a Phase I clinical trial and showed no activity in rat tumor models (42), raising the question of possible species-specificity. In an attempt to obtain similar drugs that produced tumor hemorrhagic necrosis, the molecular structure of FAA was modified, generating several compounds; 5,6-dimethyllxanthenone-4-acetic acid (DMXAA) was the compound with the highest potency and it also showed activity against a rat mammary carcinoma (43). Similar to FAA, DMXAA showed anti-tumor activity in different mouse models (44).…”

Section: Clinical-translational Advancesmentioning

confidence: 99%

Molecular Pathways: Targeting the Stimulator of Interferon Genes (STING) in the Immunotherapy of Cancer

Corrales

Gajewski

2015

Clinical Cancer Research

152

113

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Novel immunotherapy approaches are transforming the treatment of cancer, yet many patients remain refractory to these agents. One hypothesis is that immunotherapy fails because of a tumor microenvironment that fails to support recruitment of immune cells including CD8+ T cells. Therefore, new approaches designed to initiate a de novo anti-tumor immune response from within the tumor microenvironment are being pursued. Recent evidence has indicated that spontaneous activation of the Stimulator of Interferon Genes (STING) pathway within tumor-resident dendritic cells leads to type I interferon (IFN) production and adaptive immune responses against tumors. This pathway is activated in the presence of cytosolic DNA, that is detected by the sensor cyclic-GMP-AMP synthase (cGAS), and generates cyclic GMP-AMP (cGAMP), which binds and activates STING. As a therapeutic approach, intratumoral injection of STING agonists has demonstrated profound therapeutic effects in multiple mouse tumor models, including melanoma, colon, breast, prostate, and fibrosarcoma. Better characterization of the STING pathway in human tumor recognition, and the development of new pharmacologic approaches to engage this pathway within the tumor microenvironment in patients, are important areas for clinical translation.

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“…For examples, they can be categorized by locations such as subcutaneous [51,59] , intramuscular [60][61][62] or visceral organ [57] tumors; by destination relative to source graft such as orthotopic [63][64][65] or ectopic tumors; by carcinogenesis such as primary [26,48,65,66] or secondary tumors; by graft origins such as allograft [63] or xenograft human [61,67,68] or animal [69] tumors; and by immune status of tumor recipient such as the tumors growing in immunocompetent or immunodeficient [64,68] animals. A wide range of diverse VDA effects have been observed in various tumor models [70,71] .…”

Section: Animal Tumor Modelsmentioning

confidence: 99%

Multiparametric MRI biomarkers for measuring vascular disrupting effect on cancer

Marchal¹,

2011

WJR

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Solid malignancies have to develop their own blood supply for their aggressive growth and metastasis; a process known as tumor angiogenesis. Angiogenesis is largely involved in tumor survival, progression and spread, which are known to be significantly attributed to treatment failures. Over the past decades, efforts have been made to understand the difference between normal and tumor vessels. It has been demonstrated that tumor vasculature is structurally immature with chaotic and leaky phenotypes, which provides opportunities for developing novel anticancer strategies. Targeting tumor vasculature is not only a unique therapeutic intervention to starve neoplastic cells, but also enhances the efficacy of conventional cancer treatments. Vascular disrupting agents (VDAs) have been developed to disrupt the already existing neovasculature in actively growing tumors, cause catastrophic vascular shutdown within short time, and induce secondary tumor necrosis. VDAs are cytostatic; they can only inhibit tumor growth, but not eradicate the tumor. This novel drug mechanism has urged us to develop multiparametric imaging biomarkers to monitor early hemodynamic alterations, cellular dysfunctions and metabolic impairments before tumor dimensional changes can be detected. In this article, we review the characteristics of tumor vessels, tubulindestabilizing mechanisms of VDAs, and in vivo effects of the VDAs that have been mostly studied in preclinical studies and clinical trials. We also compare the different tumor models adopted in the preclinical studies on VDAs. Multiparametric imaging biomarkers, mainly diffusion-weighted imaging and dynamic contrast-enhanced imaging from magnetic resonance imaging, are evaluated for their potential as morphological and functional imaging biomarkers for monitoring therapeutic effects of VDAs.

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Antitumour action of 5,6-dimethylxanthenone-4-acetic acid in rats bearing chemically induced primary mammary tumours

Abstract: This study shows for the first time that DMXAA has significant in vivo antitumour activity against non-transplanted autochthonous tumours and in a host species other than the mouse.

Cited by 19 publications

References 24 publications

DMXAA Causes Tumor Site-Specific Vascular Disruption in Murine Non-Small Cell Lung Cancer, and like the Endogenous Non-Canonical Cyclic Dinucleotide STING Agonist, 2′3′-cGAMP, Induces M2 Macrophage Repolarization

DMXAA Causes Tumor Site-Specific Vascular Disruption in Murine Non-Small Cell Lung Cancer, and like the Endogenous Non-Canonical Cyclic Dinucleotide STING Agonist, 2′3′-cGAMP, Induces M2 Macrophage Repolarization

Molecular Pathways: Targeting the Stimulator of Interferon Genes (STING) in the Immunotherapy of Cancer

Multiparametric MRI biomarkers for measuring vascular disrupting effect on cancer

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