Magnetic resonance imaging in an experimental model of human ovarian cancer demonstrating altered microvascular permeability after inhibition of vascular endothelial growth factor

Goßmann, Axel; Helbich, Thomas H.; Mesiano, Sam; Shames, David M.; Wendland, Michael F.; Roberts, Timothy P.L.; Ferrara, N; Jaffe, Robert B.; Brasch, Robert C.

doi:10.1067/mob.2000.107092

Cited by 58 publications

(46 citation statements)

References 15 publications

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“…Previous dynamic MR imaging studies to examine the effects of anti-vascular endothelial growth factor treatment in athymic rats with human breast carcinoma xenografts have revealed decreases in fractional leak rates and reflux rates, compared with these rates in control animals, as early as 24 hours after treatment (10). Similar results were obtained with other preclinical models of ovarian cancer assessed with dynamic MR imaging (11).…”

Section: Introductionsupporting

confidence: 77%

Inflammatory Breast Cancer: Dynamic Contrast-enhanced MR in Patients Receiving Bevacizumab—Initial Experience

Su¹

2008

Breast Diseases: A Year Book Quarterly

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PURPOSETo retrospectively compare three dynamic contrast material-enhanced magnetic resonance (MR) imaging (dynamic MR imaging) analytic methods to determine the parameter or combination of parameters most strongly associated with changes in tumor microvasculature during treatment with bevacizumab alone and bevacizumab plus chemotherapy in patients with inflammatory or locally advanced breast cancer. MATERIALS AND METHODSThis study was conducted in accordance with the institutional review board of the National Cancer Institute and was compliant with the Privacy Act of 1974. Informed consent was obtained from all patients. Patients with inflammatory or locally advanced breast cancer were treated with one cycle of bevacizumab alone (cycle 1) followed by six cycles of combination bevacizumab and chemotherapy (cycles 2-7). Serial dynamic MR images were obtained, and the kinetic parameters measured by using three dynamic analytic MR methods (heuristic, Brix, and general kinetic models) and two region-ofinterest strategies were compared by using two-sided statistical tests. A P value of .01 was required for significance. RESULTSIn 19 patients, with use of a whole-tumor region of interest, the authors observed a significant decrease in the median values of three parameters measured from baseline to cycle 1: forward transfer rate constant (K trans ) (_34% relative change, P = .003), backflow compartmental rate constant extravascular and extracellular to plasma (K ep ) (-15% relative change, P < .001), and integrated area under the gadolinium concentration curve (IAUGC) at 180 seconds (-23% relative change, P = .009). A trend toward differences in the heuristic slope of the washout curve between responders and nonresponders to therapy was observed after cycle 1 (bevacizumab alone, P = .02). The median relative change in slope of the wash-in curve from baseline to cycle 4 was significantly different between responders and nonresponders (P = .009). CONCLUSIONThe dynamic contrast-enhanced MR parameters K trans , K ep , and IAUGC at 180 seconds appear to have the strongest association with early physiologic response to bevacizumab. INTRODUCTIONDynamic contrast material-enhanced magnetic resonance (MR) imaging (dynamic MR imaging) can depict changes in the physiologic characteristics of tumors after a therapeutic intervention. Dynamic MR imaging has been used to monitor response to chemotherapy and for drug development; therefore, it may be clinically useful for determining prognoses (1-3). Bevacizumab (Avastin; Genentech, South San Francisco, Calif) is a recombinant humanized monoclonal antibody that binds specifically to and inhibits vascular endothelial growth factor (4,5). Because vascular endothelial growth factor is involved in the proliferation and differentiation of endothelial cells, it is an attractive intervention target that could be monitored with dynamic MR imaging.Conventional anatomic imaging depicts the physical size of tumors and is therefore considered a delayed indicator that might not enable reliable pred...

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Section: Introductionsupporting

confidence: 77%

Inflammatory Breast Cancer: Dynamic Contrast-enhanced MR in Patients Receiving Bevacizumab—Initial Experience

Su¹

2008

Breast Diseases: A Year Book Quarterly

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“…xenograft model is the difficulty in monitoring disease progression, it is possible to visualize tumor burden by MRM (36). To examine the antitumor efficacy, we randomly selected five mice from each group for scanning with MRM, as described in Materials and Methods.…”

Section: Resultsmentioning

confidence: 99%

RAD001 Inhibits Human Ovarian Cancer Cell Proliferation, Enhances Cisplatin-Induced Apoptosis, and Prolongs Survival in an Ovarian Cancer Model

Mabuchi¹,

Altomare²,

Cheung³

et al. 2007

Clinical Cancer Research

204

147

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Purpose: mTOR (mammalian target of rapamycin) plays a central role in regulating cell growth and cell cycle progression and is regarded as a promising therapeutic target. We examined whether mTOR inhibition by RAD001 (everolimus) is therapeutically efficacious in the treatment of ovarian cancer as a single agent and in combination with cisplatin. Experimental Design: Using four human ovarian cancer cell lines, we determined the effect of RAD001 by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, Western blot, and apoptosis assays. We evaluated the association between phospho-AKT/mTOR activity and RAD001sensitivity. We also determined the effect of RAD001on tumor growth and malignancy using mice inoculated with human ovarian cancer cells. Results: RAD001markedly inhibited cell proliferation of human ovarian carcinoma cells with high AKT activity (OVCAR10 and SKOV-3), but the effect was minimal in cells with low AKT activity (OVCAR4 and OVCAR5). Sensitivity to RAD001was independent of p53 expression. RAD001 inhibited the phosphorylation of downstream 4E-BP1 and p70S6 kinase and attenuated the expression of Myc. RAD001 also attenuated the expression of HIF-1a and vascular endothelial growth factor, important factors in angiogenesis and tumor invasiveness. RAD001 enhanced cisplatin-induced apoptosis in cells with high AKT/mTOR activity, with minimal effect in cells with low AKT-mTOR activity. Mouse xenografts of SKOV-3 cells revealed that RAD001inhibits tumor growth, angiogenesis, and i.p. dissemination and ascites production and prolongs survival. Moreover, treatment with RAD001significantly enhanced the therapeutic efficacy of cisplatin in vivo. Conclusion: These results indicate that RAD001 could have therapeutic efficacy in human ovarian cancers with hyperactivated AKT/mTOR signaling.

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“…Elevated VEGF expression occurs in all stages of ovarian cancer and is associated with poor prognosis, including shorter survival 30 Clinical Development of Bevacizumab 0 6 12 18 24 30 36 0 6 12 18 24 30 36 [30][31][32][33]. In addition to its role in ovarian-cancer-associated angiogenesis [34,35], VEGF overexpression is directly associated with the production of ascitic fluid [36], a feature probably related to the ability of VEGF to induce endothelial hyperpermeability [37]. The parent murine antibody of bevacizumab, A.4.6.1, demonstrated promising antitumor activity in a subcutaneous SKOV-3 human ovarian cancer xenograft model [38].…”

Section: Gynecologic Cancersmentioning

confidence: 99%

Expanding the Clinical Development of Bevacizumab

Chen

2004

The Oncologist

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Magnetic resonance imaging in an experimental model of human ovarian cancer demonstrating altered microvascular permeability after inhibition of vascular endothelial growth factor

Cited by 58 publications

References 15 publications

Inflammatory Breast Cancer: Dynamic Contrast-enhanced MR in Patients Receiving Bevacizumab—Initial Experience

Inflammatory Breast Cancer: Dynamic Contrast-enhanced MR in Patients Receiving Bevacizumab—Initial Experience

RAD001 Inhibits Human Ovarian Cancer Cell Proliferation, Enhances Cisplatin-Induced Apoptosis, and Prolongs Survival in an Ovarian Cancer Model

Expanding the Clinical Development of Bevacizumab

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