Noninvasive Magnetic Resonance Imaging of Transport and Interstitial Fluid Pressure in Ectopic Human Lung Tumors

Hassid, Yaron; Furman‐Haran, Edna; Margalit, Raanan; Eilam, Raya; Degani, Hadassa

doi:10.1158/0008-5472.can-05-3289

Cited by 68 publications

(73 citation statements)

References 27 publications

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“…However, the present study showed clearly that convection is the dominant transport mechanism for Gd-DTPA in the tumor periphery. Our observations are consistent with data reported by Hassid and colleagues (15). They administered Gd-DTPA slowly to tumor-bearing mice and showed that the steady-state concentration of Gd-DTPA was high in the tumor center and decreased steeply at the tumor surface, an observation that led them to conclude that Gd-DTPA is transported primarily by convection in the periphery of tumors with high IFP.…”

Section: Discussionsupporting

confidence: 93%

“…The possibility of using dynamic contrast-enhanced MRI (DCE-MRI) has been explored in a limited number of studies. Using a protocol based on slow infusion of gadolinium diethylene-triamine penta-acetic acid (Gd-DTPA), Hassid and colleagues showed that parametric images of the steady-state concentration of Gd-DTPA reflected the spatial distribution of the IFP of xenografted tumors, but correlations between steady-state Gd-DTPA concentration and IFP were not reported (15). Gulliksrud and colleagues reported significant correlations between EÁF (E is the initial extraction fraction of Gd-DTPA and F is blood perfusion) and IFP in melanoma xenografts, but EÁF decreased with increasing IFP in intradermal tumors and increased with increasing IFP in intramuscular tumors (16,17).…”

Section: Introductionmentioning

confidence: 99%

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Interstitial Fluid Pressure and Associated Lymph Node Metastasis Revealed in Tumors by Dynamic Contrast-Enhanced MRI

et al. 2012

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Elevated interstitial fluid pressure (IFP) in tumors can cause metastatic dissemination and treatment resistance, but its study poses a challenge because of a paucity of noninvasive imaging strategies. In this study, we address this issue by reporting the development of a noninvasive tool to assess tumor IFP and interstitial hypertension-induced lymph node metastasis. Using mouse xenograft models of several types of human cancer, we used gadolinium diethylene-triamine penta-acetic acid (Gd-DTPA) as a contrast agent for dynamic contrastenhanced MRI (DCE-MRI). Immediately after Gd-DTPA administration, a high-signal-intensity rim was observed in the tumor periphery, which moved outward with time. Assuming the velocity of Gd-DTPA to be equal to the fluid flow velocity, we used a simple model of peritumoral interstitial fluid flow to calculate the fluid flow velocity at the tumor surface (v 0 ) based on the rim movement. Significant positive correlations were found between v 0 and IFP in all tumor xenografts. Moreover, the primary tumors of metastasis-positive mice displayed higher IFP and v 0 than the primary tumors of metastasis-negative mice. Findings were confirmed in cervical cancer patients with pelvic lymph node metastases, where we found v 0 to be higher compared with patients without lymph node involvement (P < 0.00001). Together, these findings establish that Gd-DTPA-based DCE-MRI can noninvasively visualize tumor IFP, and they reveal the potential for v 0 determined by this method to serve as a novel general biomarker of tumor aggressiveness. Cancer Res; 72(19); 4899-908. Ó2012 AACR.

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Section: Discussionsupporting

confidence: 93%

Section: Introductionmentioning

confidence: 99%

Interstitial Fluid Pressure and Associated Lymph Node Metastasis Revealed in Tumors by Dynamic Contrast-Enhanced MRI

et al. 2012

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“…For example, MRI and BLI have been used in recent years for evaluating the antitumor (36) and antivascular effects of targeted therapies against solid tumors (39,40). In this study, we show that BLI and MRI are viable real-time, noninvasive, quantitative, and qualitative methods for monitoring the response to VTA therapy.…”

Section: Discussionmentioning

confidence: 71%

Enhanced Antitumor Efficacy of Clinical-Grade Vasculature-Targeted Liposomal Doxorubicin

Pastorino

Paolo

Piccardi³

et al. 2008

Clinical Cancer Research

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Purpose: In vivo evaluation of good manufacturing practice-grade targeted liposomal doxorubicin (TVT-DOX), bound to a CD13 isoform expressed on the vasculature of solid tumors, in human tumor xenografts of neuroblastoma, ovarian cancer, and lung cancer. Experimental Design: Mice were implanted with lung, ovarian, or neuroblastoma tumor cells via the pulmonary, peritoneal, or orthotopic (adrenal gland) routes, respectively, and treated, at different days post inoculation, with multiple doses of doxorubicin, administered either free or encapsulated in untargeted liposomes (Caelyx) or inTVT-DOX. The effect of TVT-DOX treatment on tumor cell proliferation, viability, apoptosis, and angiogenesis was studied by immunohistochemical analyses of neoplastic tissues and using the chick embryo chorioallantoic membrane assay. Results: Compared with the three control groups (no doxorubicin, free doxorubicin, or Caelyx), statistically significant improvements in survival was seen in all three animal models following treatment with 5 mg/kg (maximum tolerated dose) of TVT-DOX, with long-term survivors occurring in the neuroblastoma group; increased survival was also seen at a dose of 1.7 mg/kg in mice bearing neuroblastoma or ovarian cancer. Minimal residual disease after surgical removal of neuroblastoma primary mass, and the enhanced response toTVT-DOX, was visualized and quantified by bioluminescence imaging and with magnetic resonance imaging.When treated withTVT-DOX, compared with Caelyx, all three tumor models, as assayed by immunohistochemistry and chorioallantoic membrane, showed statistically significant reductions in cell proliferation, blood vessel density, and microvessel area, showing increased cell apoptosis. Conclusion: TVT-DOX should be evaluated as a novel angiostatic strategy for adjuvant therapy of solid tumors.

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“…Several strategies are currently under investigation, and approaches based on magnetic resonance imaging (MRI) seem to be particularly promising. Thus, by using a protocol based on the slow infusion of gadoliniumdiethylenetriaminepentaacetic acid, Hassid et al (29) were able to show that parametric images of the steady-state concentration of gadolinium-diethylenetriaminepentaacetic acid reflected the spatial distribution of IFP in nonsmall cell carcinoma and breast carcinoma xenografts. Haider et al (30) subjected patients with cervical cancer to gadolinium-diethylenetriaminepentaacetic acid-based dynamic contrast-enhanced MRI and measurement of IFP, and found weak but significant correlations between global parameters derived from the dynamic contrast-enhanced MRI series and IFP.…”

Section: Discussionmentioning

confidence: 99%

Associations between Radiocurability and Interstitial Fluid Pressure in Human Tumor Xenografts without Hypoxic Tissue

Rofstad

Ruud

Mathiesen

et al. 2010

Clinical Cancer Research

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Purpose: The interstitial fluid pressure (IFP) of the primary tumor is an independent prognostic parameter for cervical cancer patients treated with radiation therapy. The aim of this preclinical study was to investigate whether tumor radiocurability may be associated with IFP through hypoxia-independent mechanisms.Experimental Design: Small A-07 and R-18 melanoma xenografts without hypoxic tissue were used as preclinical tumor models. IFP was measured by using the wick-in-needle method. Radiation dose resulting in 50% local tumor control (TCD 50 ), cell density, cell tumorigenicity, plating efficiency in vitro, mitotic index, fraction of Ki67-positive cells, vascular endothelial growth factor-A (VEGF-A) concentration, and radiation-induced endothelial cell apoptosis were assessed in tumors with low and high IFP.Results: TCD 50 was found to be higher for tumors with high IFP than for tumors with low IFP by factors of 1.13 ± 0.03 (A-07; P < 0.0001) and 1.10 ± 0.03 (R-18; P < 0.0001). In the A-07 line, tumors with high IFP showed a larger number of clonogenic cells and a higher rate of cell proliferation than tumors with low IFP. In the R-18 line, tumors with high IFP showed a higher concentration of VEGF-A and a lower endothelial cell apoptotic index after irradiation than tumors with low IFP.Conclusions: The radiation resistance of normoxic tumor tissue with highly elevated IFP may be an indirect consequence of increased tumor cell clonogenicity as well as increased VEGF-A expression, possibly caused by hypertension-induced modifications of signaling pathways regulating cell proliferation, cell survival, and/or angiogenesis. Clin Cancer Res; 16(3); 936-45. ©2010 AACR.Clinical investigations have shown that the interstitial fluid pressure (IFP) is elevated in several tumor types, including lymphoma, breast carcinoma, head and neck carcinoma, cervical carcinoma, and cutaneous melanoma (1-3). Tumor tissues typically show IFP values within the range of 5 to 40 mmHg, whereas the IFP values of most normal tissues range from −3 to +3 mmHg. The IFP may be particularly high in malignant melanomas, where IFP values of up to 100 mmHg have been recorded (4). Only one large prospective clinical study of the association between IFP and patient outcome has been reported thus far (5, 6). The study was carried out at Princess Margaret Hospital in Toronto and involved 107 eligible patients with locally advanced cervical carcinoma. The patients were treated with radiation therapy alone, and IFP and oxygen tension were measured in the primary tumor before treatment. High IFP was found to be associated with poor disease-free survival independent of conventional prognostic factors, such as tumor size, stage, and lymph node status. Patients with tumors with high IFP showed an increased probability of developing recurrences both locally within the irradiated pelvic region and at distant nonirradiated sites. Interestingly, the independent prognostic effect of IFP for recurrence and survival was strong, whereas the independent pr...

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Noninvasive Magnetic Resonance Imaging of Transport and Interstitial Fluid Pressure in Ectopic Human Lung Tumors

Cited by 68 publications

References 27 publications

Interstitial Fluid Pressure and Associated Lymph Node Metastasis Revealed in Tumors by Dynamic Contrast-Enhanced MRI

Interstitial Fluid Pressure and Associated Lymph Node Metastasis Revealed in Tumors by Dynamic Contrast-Enhanced MRI

Enhanced Antitumor Efficacy of Clinical-Grade Vasculature-Targeted Liposomal Doxorubicin

Associations between Radiocurability and Interstitial Fluid Pressure in Human Tumor Xenografts without Hypoxic Tissue

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