Preclinical and clinical studies of docetaxel and exisulind in the treatment of human lung cancer

Bunn, Paul A.; Chan, Daniel C.; Earle, Keith A.; Zhao, Tom; Helfrich, Barbara A.; Kelly, Karen; Piazza, Gary A.; Whitehead, Clark M.; Pamukcu, Rifat; Thompson, W. J.; Alila, Hector W.

doi:10.1053/sonc.2002.31529

Cited by 19 publications

(10 citation statements)

References 13 publications

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“…Lymph node invasion and spread into contralateral lung through lymphatic routes presented in this model represent common clinical features of lung cancer progression (31,32). The orthotopic A549 transplantation nude mice model used in this study, wherein tumor cells are directly injected into normal lung parenchyma resulting in solitary tumor in situ and metastases in lung and/or mediastinal lymph nodes, provides a stringent test of vasostatin gene therapy in a pathologic environment.…”

Section: Discussionmentioning

confidence: 99%

Suppression of Lung Tumor Growth and Metastasis in Mice by Adeno-Associated Virus-Mediated Expression of Vasostatin

Cai

Tse

Leung

et al. 2008

Clinical Cancer Research

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Purpose: Angiogenesis inhibitors have strong therapeutic potential as antitumor agents in suppressing tumor growth and metastatic progression. Vasostatin, the N-terminal domain of calreticulin, is a potent angiogenesis inhibitor. In this study, we determined the effectiveness of vasostatin delivered by recombinant pseudotype adeno-associated virus 2/5 (rAAV2/5-VAS) as a gene therapy approach for lung cancer treatment. Experimental Design: We used rAAV2/5 to deliver vasostatin intratumorally or systemically in different mouse lung tumor models ö subcutaneous, orthotopic xenograft, and spontaneous metastasis lung tumor models.The therapeutic efficacy of rAAV2/5-VAS was determined by monitoringtumor volume, survivalrate, and degreeof neovascularizationafter treatmentinthese models. Results: Mice bearing subcutaneous tumor of rAAV2/5-VAS pretreated Lewis lung carcinoma cells showed >50% reduction in primary tumor volume and reduced spontaneous pulmonary metastases. The tumor-suppressive action of rAAV2/5-VAS in subcutaneous human lung tumor A549 xenograft correlated with a reduced number of capillary vessels in tumors. In the orthotopic xenograft model, rAAV2/5-VAS suppressed metastasis of A549 tumors to mediastinal lymph nodes and contralateral lung. Furthermore, treatment of immunocompetent mice in the spontaneous lung metastases model with rAAV2/5-VAS after primary tumor excision prolonged their median survival from 21to 51.5 days. Conclusion: Our results show the effectiveness of rAAV2/5-VAS as an angiogenesis inhibitor in suppressing tumor growth during different stages of tumor progression, validating the application of rAAV2/5-VAS gene therapy in treatment against lung cancer.

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Section: Discussionmentioning

confidence: 99%

Suppression of Lung Tumor Growth and Metastasis in Mice by Adeno-Associated Virus-Mediated Expression of Vasostatin

Cai

Tse

Leung

et al. 2008

Clinical Cancer Research

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“…These drugs reduce β-Catenin activity and block Cyclin D1 followed by an induction of apoptosis and inhibition of tumor cell growth [164,172,173]. Currently, Exisulind is in Phase III clinical trials in combination with several chemotherapeutic agents [174,175]. Imatinib (Gleevec), originally identified as an inhibitor of platelet-derived growth factor (PDGF) receptor, has been used in treating chronic myelogenous leukemia (CML), gastrointestinal stromal tumors (GISTs) and a number of other malignancies.…”

Section: Metastasis Promotersmentioning

confidence: 99%

Drug development against metastasis-related genes and their pathways: A rationale for cancer therapy

Iiizumi

Pai

et al. 2008

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer

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It is well recognized that the majority of cancer related deaths is caused by metastatic disease. Therefore, there is an urgent need for the development of therapeutic intervention specifically targeted to the metastatic process. In the last decade, significant progress has been made in this research field, and many new concepts have emerged that shed light on the molecular mechanism of metastasis cascade which is often portrayed as a succession of six distinct steps; localized invasion, intravasation, translocation, extravasation, micrometastasis and colonization. Successful metastasis is dependent on the balance and complex interplay of both the metastasis promoters and suppressors in each step. Therefore, the basic strategy of our interventions is aimed at either blocking the promoters or potentiating the suppressors in this disease process. Toward this goal, various kinds of antibodies and small molecules have been designed. These include agents that block the ligandrecepter interaction of metastasis promoters (HGF/c-Met), antagonize the metastasis promoting enzymes (AMF,uPA and MMP) and inhibit the transcriptional activity of metastasis promoter (β-Catenin). On the other hand, the intriguing roles of metastasis suppressors and their signal pathways have been extensively studied and various attempts have been made to potentiate these factors. Small molecules have been developed to restore the expression or mimic the function of metastasis suppressor genes such as NM23, E-cadherin, Kiss-1, MKK4 and NDRG1, and some of them are under clinical trials. This review summarizes our current understanding of the molecular pathway of tumor metastasis and discusses strategies and recent development of anti-metastatic drugs.

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“…Because of this complexity and also due to its highly conserved nature in biology, various PDEs have been useful targets for developing drugs. Such drugs have more recently found use in the treatment of human diseases, including erectile dysfunction [2][3][4], pulmonary hypertension [5][6][7][8][9] and cancer [10][11][12][13][14][15][16][17][18][19][20]. The side effects of many PDE inhibitors are also attributable to the effects on enzymes other than the primary target [21,22].…”

Section: Introductionmentioning

confidence: 99%

The Novel Functions of cGMP-Specific Phosphodiesterase 5 and its Inhibitors in Carcinoma Cells and Pulmonary/Cardiovascular Vessels

Zhu¹,

Strada²

2007

CTMC

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PDE5 is a key enzyme involved in the regulation of cGMP-specific signaling pathways in normal physiological processes such as smooth muscle contraction and relaxation. For this reason, inhibition of the enzyme can alter those pathophysiological conditions associated with a lowering cGMP level in tissues. For example, selective PDE5 inhibitors, such as sildenafil (Viagra, Pfizer), tadalafil (Cialis, Lilly-ICOS), and vardenafil (Levitra, Bayer), have been successfully used to treat the condition of human erectile dysfunction. More recently, the involvement of this enzyme has been proposed to influence antiproliferation and proapoptotic mechanism in multiple carcinomas. The data supporting this idea is based on increases in PDE5 activities in many carcinomas and the ability of PDE5 inhibitors such as exisulind and its analogs related to anticancer activities. Inhibition of PDE5 that results in sustained increases in [cGMP](i) are required to modify the process of apoptosis and mitotic arrest in those carcinoma cells with enhanced PDE5 expressions. Increases in PDE5 are also involved in contributing to the pathological changes in the pulmonary system resulting in hyper-proliferative remodeling of both smooth muscle and endothelium in models of pulmonary hypertension. For this reason, the use of PDE5 inhibitors in the treatment of human pulmonary hypertension has met with some success. The differences that we have previously noted in PDE isoenzymes in pulmonary arterial and microvascular endothelial cells may provide a more selective cellular strategy for use of such inhibitor. Additional studies on structure biology of these enzymes should lead to the development of agents with better cellular specificity than currently available drugs. Considering the enormous progress that has been made in the last few years, the future looks promising for agents affecting this enzyme and related systems.

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Preclinical and clinical studies of docetaxel and exisulind in the treatment of human lung cancer

Cited by 19 publications

References 13 publications

Suppression of Lung Tumor Growth and Metastasis in Mice by Adeno-Associated Virus-Mediated Expression of Vasostatin

Suppression of Lung Tumor Growth and Metastasis in Mice by Adeno-Associated Virus-Mediated Expression of Vasostatin

Drug development against metastasis-related genes and their pathways: A rationale for cancer therapy

The Novel Functions of cGMP-Specific Phosphodiesterase 5 and its Inhibitors in Carcinoma Cells and Pulmonary/Cardiovascular Vessels

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