Tumor Interstitial Fluid Pressure Research Articles

Magnetic resonance imaging identifies early effects of sunitinib treatment in human melanoma xenografts

BackgroundAntiangiogenic treatment may change the tumor microenvironment and hence influence the effect of conventional therapies. The potential of diffusion weighted magnetic resonance imaging (DW-MRI) and dynamic contrast enhanced MRI (DCE-MRI) in assessing microenvironmental effects of sunitinib treatment was investigated in this preclinical study.MethodsSunitinib-treated and untreated A-07 tumors were subjected to DW-MRI and DCE-MRI, and parametric images of ADC and Ktrans were produced. Microvascular density, hypoxic fraction, and necrotic fraction were assessed from immunohistochemical preparations, and tumor interstitial fluid pressure (IFP) was assessed with probe measurement.ResultsSunitinib-treated tumors showed reduced microvascular density, increased hypoxic fraction, increased necrotic fraction, increased ADC, and reduced Ktrans, but did not differ from untreated tumors in growth rate and IFP.ConclusionsSunitinib treatment affected the tumor microenvironment without affecting tumor size. DW-MRI and DCE-MRI were sensitive to the sunitinib-induced changes in the tumor microenvironment.

The Microenvironment of Cervical Carcinoma Xenografts: Associations with Lymph Node Metastasis and Its Assessment by DCE-MRI

Poor disease-free and overall survival rates in locally advanced cervical cancer are associated with a tumor micro-environment characterized by extensive hypoxia, interstitial hypertension, and high lactate concentrations. The potential of gadolinium diethylenetriamine pentaacetic acid-based dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) in assessing the microenvironment and microenvironment-associated aggressiveness of cervical carcinomas was investigated in this preclinical study. CK-160 and TS-415 cervical carcinoma xenografts were used as tumor models. DCE-MRI was carried out at 1.5 T, and parametric images of Ktrans and ve were produced by pharmacokinetic analysis of the DCE-MRI series. Pimonidazole was used as a marker of hypoxia. A Millar catheter was used to measure tumor interstitial fluid pressure (IFP). The concentrations of glucose, adenosine triphosphate (ATP), and lactate were measured by induced metabolic bioluminescence imaging. High incidence of lymph node metastases was associated with high hypoxic fraction and high lactate concentration in CK-160 tumors and with high IFP and high lactate concentration in TS-415 tumors. Low Ktrans was associated with high hypoxic fraction, low glucose concentration, and high lactate concentration in tumors of both lines and with high incidence of metastases in CK-160 tumors. Associations between ve and microenvironmental parameters or metastatic propensity were not detected in any of the tumor lines. Taken together, this preclinical study suggests that Ktrans is a potentially useful biomarker for poor outcome of treatment in advanced cervical carcinoma. The possibility that Ktrans may be used to identify patients with cervical cancer who are likely to benefit from particularly aggressive treatment merits thorough clinical investigations.

Corticotropin-releasing factor reduces tumor volume, halts further growth, and enhances the effect of chemotherapy in 4T1 mammary carcinoma in mice

The present study examines the effect of the endogenous neuroendocrine factor, corticotropin-releasing factor (CRF), alone or in combination with 5-fluorouracil (5-FU), on 4T1 mammary tumor cells in vitro and in vivo. CRF has been detected in breast cancer tissues; however, the biological effects reported in the literature are sparse and variable. We found that exogenously administered CRF significantly reduced tumor growth without influencing angiogenesis or cell death. Furthermore, CRF reduced tumor interstitial fluid pressure (Pif) and potentiated the effect of 5-FU. These results show that CRF has antitumor effect on mammary carcinoma in mice.

High interstitial fluid pressure promotes tumor cell proliferation and invasion in oral squamous cell carcinoma

It has been shown that interstitial fluid pressure (IFP) is elevated in many solid tumors. The elevated IFP in tumors is responsible, at least in part, for the poor blood supply, inadequate delivery of therapeutic agents to solid tumors and poor treatment response in patients. The present study was carried out to examine alterations in malignant phenotypes in oral squamous cell carcinoma cells subjected to conditions mimicking IFP and to identify the relevant molecular mechanisms. We investigated tumor cell proliferation and invasion using SCC-4 and SCC-9 cells subjected to an increased extracellular pressure of 0, 15 and 30 mmHg in vitro. The results revealed that the increased IFP resulted in a marked increase in cancer cell proliferation, survival and invasion in vitro and altered the expression of >1,800 genes involved in invasion and metastasis, the heat shock pathway, the p38 and JNK signaling pathway, apoptosis and the cell growth and differentiation signaling pathway. These results suggest the important potential clinical application of measuring IFP, which can be used as a generic marker of prognosis and response to therapy.

Interstitial Fluid Flow and Drug Delivery in Vascularized Tumors: A Computational Model

Interstitial fluid is a solution that bathes and surrounds the human cells and provides them with nutrients and a way of waste removal. It is generally believed that elevated tumor interstitial fluid pressure (IFP) is partly responsible for the poor penetration and distribution of therapeutic agents in solid tumors, but the complex interplay of extravasation, permeabilities, vascular heterogeneities and diffusive and convective drug transport remains poorly understood. Here we consider–with the help of a theoretical model–the tumor IFP, interstitial fluid flow (IFF) and its impact upon drug delivery within tumor depending on biophysical determinants such as vessel network morphology, permeabilities and diffusive vs. convective transport. We developed a vascular tumor growth model, including vessel co-option, regression, and angiogenesis, that we extend here by the interstitium (represented by a porous medium obeying Darcy's law) and sources (vessels) and sinks (lymphatics) for IFF. With it we compute the spatial variation of the IFP and IFF and determine its correlation with the vascular network morphology and physiological parameters like vessel wall permeability, tissue conductivity, distribution of lymphatics etc. We find that an increased vascular wall conductivity together with a reduction of lymph function leads to increased tumor IFP, but also that the latter does not necessarily imply a decreased extravasation rate: Generally the IF flow rate is positively correlated with the various conductivities in the system. The IFF field is then used to determine the drug distribution after an injection via a convection diffusion reaction equation for intra- and extracellular concentrations with parameters guided by experimental data for the drug Doxorubicin. We observe that the interplay of convective and diffusive drug transport can lead to quite unexpected effects in the presence of a heterogeneous, compartmentalized vasculature. Finally we discuss various strategies to increase drug exposure time of tumor cells.

Vascular Endothelial Growth Factor C-Induced Lymphangiogenesis Decreases Tumor Interstitial Fluid Pressure and Tumor

Characteristically, most solid tumors exhibit an increased tumor interstitial fluid pressure (TIFP) that directly contributes to the lowered uptake of macromolecular therapeutics into the tumor interstitium. Abnormalities in the tumor-associated lymph vessels are a central brick in the development and prolonged sustaining of an increased TIFP. In the current study, vascular endothelial growth factor C (VEGF-C) was used to enhance tumor-associated lymphangiogenesis as a new mechanism to actively reduce the TIFP by increased lymphatic drainage of the tumor tissue. Human A431 epidermoid vulva carcinoma cells were inoculated in NMRI nu/nu mice to generate a xenograft mouse model. Seven days after tumor cell injection, VEGF-C was peritumorally injected to induce lymphangiogenesis. Tumor growth and TIFP was lowered significantly over time in VEGF-C-treated tumors in comparison to control or VEGF-A-treated animals. These data demonstrate for the first time that actively induced lymphangiogenesis can lower the TIFP in a xenograft tumor model and apparently reduce tumor growth. This model represents a novel approach to modulate biomechanical properties of the tumor interstitium enabling a lowering of TIFP in vivo.

Docetaxel Conjugate Nanoparticles That Target α-Smooth Muscle Actin–Expressing Stromal Cells Suppress Breast Cancer Metastasis

Docetaxel-conjugate nanoparticles, known as Cellax, were synthesized by covalently conjugating docetaxel and polyethylene glycol to acetylated carboxymethylcellulose via ester linkages, yielding a polymeric conjugate that self-assembled into 120 nm particles suitable for intravenous administration. In 4T1 and MDA-MB-231 orthotopic breast tumor models, Cellax therapy reduced α-smooth muscle actin (α-SMA) content by 82% and 70%, respectively, whereas native docetaxel and nab-paclitaxel (albumin-paclitaxel nanoparticle, Abraxane) exerted no significant antistromal activity. In Cellax-treated mice, tumor perfusion was increased by approximately 70-fold (FITC-lectin binding), tumor vascular permeability was enhanced by more than 30% (dynamic contrast-enhanced magnetic resonance imaging), tumor matrix was decreased by 2.5-fold (immunohistochemistry), and tumor interstitial fluid pressure was suppressed by approximately 3-fold after Cellax therapy compared with the control, native docetaxel, and nab-paclitaxel groups. The antistromal effect of Cellax treatment corresponded to a significantly enhanced antimetastatic effect: lung nodules were reduced by 7- to 24-fold by Cellax treatment, whereas native docetaxel and nab-paclitaxel treatments were ineffective. Studies of the 4T1 tumor showed that more than 85% of the Cellax nanoparticles were delivered to the α-SMA+ stroma. Significant tumor stromal depletion occurred within 16 hours (∼50% depletion) postinjection, and the α-SMA+ stroma population was almost undetectable (∼3%) by 1 week. The 4T1 tumor epithelial cell population was not significantly reduced in the week after Cellax injection. These data suggest that Cellax targets tumor stroma and performs more efficaciously than docetaxel and nab-paclitaxel.

Coevolution of Solid Stress and Interstitial Fluid Pressure in Tumors During Progression: Implications for Vascular Collapse

The stress harbored by the solid phase of tumors is known as solid stress. Solid stress can be either applied externally by the surrounding normal tissue or induced by the tumor itself due to its growth. Fluid pressure is the isotropic stress exerted by the fluid phase. We recently showed that growth-induced solid stress is on the order of 1.3 to 13.0 kPa (10-100 mmHg)--high enough to cause compression of fragile blood vessels, resulting in poor perfusion and hypoxia. However, the evolution of growth-induced stress with tumor progression and its effect on cancer cell proliferation in vivo is not understood. To this end, we developed a mathematical model for tumor growth that takes into account all three types of stresses: growth-induced stress, externally applied stress, and fluid pressure. First, we conducted in vivo experiments and found that growth-induced stress is related to tumor volume through a biexponential relationship. Then, we incorporated this information into our mathematical model and showed that due to the evolution of growth-induced stress, total solid stress levels are higher in the tumor interior and lower in the periphery. Elevated compressive solid stress in the interior of the tumor is sufficient to cause the collapse of blood vessels and results in a lower growth rate of cancer cells compared with the periphery, independently from that caused by the lack of nutrients due to vessel collapse. Furthermore, solid stress in the periphery of the tumor causes blood vessels in the surrounding normal tissue to deform to elliptical shapes. We present histologic sections of human cancers that show such vessel deformations. Finally, we found that fluid pressure increases with tumor growth due to increased vascular permeability and lymphatic impairment, and is governed by the microvascular pressure. Crucially, fluid pressure does not cause vessel compression of tumor vessels.

Randomized phase II trial of gemcitabine versus gemcitabine and imatinib mesylate in patients with previously treated metastatic breast cancer.

1091 Background: Gemcitabine (GEM) as a standard 30-min infusion has activity as a single-agent in metastatic breast cancer (mbc). Prolonged infusion of GEM at a fixed dose rate (FDR) of 10 mg/m2/min is associated with greater formation of active metabolite and may result in improved antitumor activity. Imatinib mesylate (IM)-mediated inhibition of PDGFR reduces tumor interstitial fluid pressure allowing for improved chemotherapy penetration into tumors. We evaluated the addition of IM to FDR GEM in patients (pts) with previously treated mbc. Methods: This was a randomized phase II trial in mbc pts who progressed after 1 but no more than 2 prior cytotoxic regimens. Eligibility included measurable disease; no prior GEM or IM exposure. Group 1 received FDR GEM IV 1250 mg/m2 at 10 mg/m2/min (over 120 min) on days 3 and 10 every 21 days; Group 2 received the same FDR GEM dose and schedule plus IM 400 mg orally daily on days 1-5 and 8-12 every 21 days. Primary endpoint was time to progression (TTP). Sample size of 40 pts per group was needed to detect an 8 mo increase in TTP with the combination (80% power, α = .05, 2-sided). Secondary endpoints included ORR and safety. Results: Between 5/2006-4/2011, 44 pts were randomized (22 per group). Study closed early due to slow accrual. Median age 54 (31-75); median ECOG PS 1 (0-2); 52% were hormone receptor-positive and HER2-negative; 27% triple-negative, and 20% HER2-positive. Median number of cycles was 2 in Group 1 (range 1-12) and 3.5 in Group 2 (range 1-13). Most common adverse events (%) of any grade, Group 1 vs Group 2 were neutropenia (68 vs. 78), anemia (48 vs. 65), thrombocytopenia (24 vs. 47), nausea (40 vs. 52) and vomiting (24 vs. 21). One gr 4 thrombotic thrombocytopenic purpura occurred in Group 2. Median TTP were 2 mo (95% CI: 1-5 mo) in Group 1 and 2.5 mo (95% CI: 1-5 mo) in Group 2 (p = 0.3 log rank test). ORR was 9.1% in each group (95% CI: 1.6-30.6%), with 2 PRs in each group. Stable disease (≥ 3 mo) was 32% in Group 1 and 41% in Group 2. Conclusions: This study was underpowered to draw any conclusion regarding a difference in TTP between the two groups at the time it was prematurely closed. Combination of IM and FDR GEM showed a trend to increased toxicity compared to FDR GEM alone. Clinical trial information: NCT00323063.

Potentiation of radiotherapy by a localized antiangiogenic gene therapy

Background and purposeWe hypothesized that electrotransfer of a plasmid encoding an antiangiogenic factor, the recombinant disintegrin domain of ADAM-15, (pRDD) could modify the tumor microenvironment and radiosensitize tumor. Materials and methodspRDD was injected in the TLT tumor or FSaII fibrosarcomas before electroporation. pO2 in tumors and oxygen consumption in vitro were measured by electronic paramagnetic resonance (EPR) oximetry. Tumor perfusion was assessed by laser doppler imaging and patent blue assay. ResultspRDD electrotransfer caused a significant delay in TLT growth and an anti-angiogenic effect. It significantly increased tumor pO2 in TLT and FSaII for at least 4days. pRDD electrotransfer and radiotherapy were more effective than either treatment alone. Modifications of tumor microenvironment were evaluated: tumor perfusion and interstitial fluid pressure were not modified. Oxygen consumption by the cells was decreased resulting both from a decrease in oxygen consumption rate and from a decrease in cell viability. ConclusionThe combination of localized antiangiogenic gene therapy and radiotherapy applied in the time of maximal oxygenation could be a promising alternative for cancer treatment.

Connective tissue of cervical carcinoma xenografts: Associations with tumor hypoxia and interstitial fluid pressure and its assessment by DCE-MRI and DW-MRI

Background. A high fraction of stroma in malignant tissues is associated with tumor progression, metastasis, and poor prognosis. Possible correlations between the stromal and physiologic microenvironments of tumors and the potential of dynamic contrast-enhanced (DCE) and diffusion-weighted (DW) magnetic resonance imaging (MRI) in quantification of the stromal microenvironment were investigated in this study. Material and methods. CK-160 cervical carcinoma xenografts were used as preclinical tumor model. A total of 43 tumors were included in the study, and of these tumors, 17 were used to search for correlations between the stromal and physiologic microenvironments, 11 were subjected to DCE-MRI, and 15 were subjected to DW-MRI. DCE-MRI and DW-MRI were carried out at 1.5 T with a clinical MR scanner and a slotted tube resonator transceiver coil constructed for mice. Fraction of connective tissue (CTFCol) and fraction of hypoxic tissue (HFPim) were determined by immunohistochemistry. A Millar SPC 320 catheter was used to measure tumor interstitial fluid pressure (IFP). Results. CTFCol showed a positive correlation to IFP and an inverse correlation to HFPim. The apparent diffusion coefficient assessed by DW-MRI was inversely correlated to CTFCol, whereas no correlation was found between DCE-MRI-derived parameters and CTFCol. Conclusion. DW-MRI is a potentially useful method for characterizing the stromal microenvironment of tumors.

The reduction of tumor interstitial fluid pressure by liposomal imatinib and its effect on combination therapy with liposomal doxorubicin

Interstitial fluid pressure (IFP) in tumor is much higher than that in normal tissue and it constitutes a great obstacle for the delivery of chemodrugs, which makes it a potential target for cancer therapy. In this study, imatinib, a molecular targeting drug, was loaded in sterically stabilized liposomes (SSL-IMA) to reduce the tumor IFP, in an attempt to deliver more liposomal doxorubicin (SSL-DOX) into tumor tissue. In a mouse B16 melanoma model, intravenous injection of 20 mg/kg SSL-IMA achieved the most reduction of tumor IFP and the effect lasted for at least 50 h with the least hematotoxicity. However, intragastric administration of 100 mg/kg free IMA did not decrease the tumor IFP significantly. Mechanisms of the reduction of tumor IFP by SSL-IMA were proved to be the inhibition of PDGF receptor beta, the inhibition of tumor fibroblasts as well as the anti-angiogenesis effect of SSL-IMA. Then it was demonstrated by in vivo imaging that the decrease of tumor IFP by SSL-IMA led to a more and longer intratumoral distribution of the lipid vehicles. The improved delivery was proved again in the anti-tumor study. The combination of SSL-IMA and SSL-DOX inhibited tumor growth and induced apoptosis of tumor cells the most, at a low dose in which neither SSL-DOX nor SSL-IMA showed obvious anti-tumor efficacy. Since no synergy against B16 cells was found between SSL-IMA and SSL-DOX, it was clear that the improved combinational therapy was basically due to the decrease of tumor IFP by SSL-IMA. In conclusion, reducing tumor IFP by SSL-IMA seems to be a promising strategy to potentiate chemotherapies.

Preclinical evaluation of Gd-DTPA and gadomelitol as contrast agents in DCE-MRI of cervical carcinoma interstitial fluid pressure

BackgroundHigh interstitial fluid pressure (IFP) in the primary tumor is associated with poor disease-free survival in locally advanced cervical carcinoma. A noninvasive assay is needed to identify cervical cancer patients with highly elevated tumor IFP because these patients may benefit from particularly aggressive treatment. It has been suggested that dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) with gadolinium diethylene-triamine penta-acetic acid (Gd-DTPA) as contrast agent may provide useful information on the IFP of cervical carcinomas. In this preclinical study, we investigated whether DCE-MRI with contrast agents with higher molecular weights (MW) than Gd-DTPA would be superior to Gd-DTPA-based DCE-MRI.MethodsCK-160 human cervical carcinoma xenografts were subjected to DCE-MRI with Gd-DTPA (MW of 0.55 kDa) or gadomelitol (MW of 6.5 kDa) as contrast agent before tumor IFP was measured invasively with a Millar SPC 320 catheter. The DCE-MRI was carried out at a spatial resolution of 0.23 × 0.23 × 2.0 mm3 and a time resolution of 14 s by using a 1.5-T whole-body scanner and a slotted tube resonator transceiver coil constructed for mice. Parametric images were derived from the DCE-MRI recordings by using the Tofts iso-directional transport model and the Patlak uni-directional transport model.ResultsWhen gadomelitol was used as contrast agent, significant positive correlations were found between the parameters of both pharmacokinetic models and tumor IFP. On the other hand, significant correlations between DCE-MRI-derived parameters and IFP could not be detected with Gd-DTPA as contrast agent.ConclusionGadomelitol is a superior contrast agent to Gd-DTPA in DCE-MRI of the IFP of CK-160 cervical carcinoma xenografts. Clinical studies attempting to develop DCE-MRI-based assays of the IFP of cervical carcinomas should involve contrast agents with higher MW than Gd-DTPA.

Assessment of the interstitial fluid pressure of tumors by dynamic contrast-enhanced magnetic resonance imaging with contrast agents of different molecular weights

Background. Cancer patients showing highly elevated interstitial fluid pressure (IFP) in the primary tumor may benefit from particularly aggressive treatment. There is some evidence that gadolinium diethylene-triamine penta-acetic acid (Gd-DTPA)-based dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) may be a useful non-invasive method for providing information on the IFP of tumors. The purpose of this preclinical study was to investigate whether any association between DCE-MRI-derived parametric images and tumor IFP can be strengthened by using MR contrast agents with higher molecular weights than that of Gd-DTPA. Material and methods. A-07 human melanoma xenografts were used as preclinical models of human cancer. Three contrast agents were compared: Gd-DTPA (0.55 kDa), P846 (3.5 kDa), and gadomelitol (6.5 kDa). A total of 46 tumors were subjected to DCE-MRI and subsequent measurement of IFP. Parametric images of Ktrans (the volume transfer constant of the contrast agent) and ve (the fractional distribution volume of the contrast agent) were produced by pharmacokinetic analysis of the DCE-MRI series. Results. Significant inverse correlations were found between median Ktrans and IFP for Gd-DTPA (p = 0.0076; R2 = 0.46; n = 14) and P846 (p = 0.0042; R2 = 0.45; n = 16), whereas there was no correlation between median Ktrans and IFP for gadomelitol (p > 0.05; n = 16). Significant correlation between median ve and IFP was not found for any of the contrast agents (p > 0.05 for Gd-DTPA, P846, and gadomelitol). Conclusion. Ktrans images, but not ve images, derived by pharmacokinetic analysis of DCE-MRI data for low-molecular-weight contrast agents may provide information on the IFP of tumors. Any association between Ktrans and IFP cannot be expected to be improved by using contrast agents with higher molecular weights than those of Gd-DTPA and P846.

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

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 contrast-enhanced 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.

Therapeutic Targeting of Hyaluronan in the Tumor Stroma

The tumor stroma, consisting of non-malignant cells and the extracellular matrix, undergoes significant quantitative and qualitative changes throughout malignant transformation and tumor progression. With increasing recognition of the role of the tumor microenvironment in disease progression, stromal components of the tumor have become attractive targets for therapeutic intervention. Stromal accumulation of the glycosaminoglycan hyaluronan occurs in many tumor types and is frequently associated with a negative disease prognosis. Hyaluronan interacts with other extracellular molecules as well as cellular receptors to form a complex interaction network influencing physicochemical properties, signal transduction, and biological behavior of cancer cells. In preclinical animal models, enzymatic removal of hyaluronan is associated with remodeling of the tumor stroma, reduction of tumor interstitial fluid pressure, expansion of tumor blood vessels and facilitated delivery of chemotherapy. This leads to inhibition of tumor growth and increased survival. Current evidence shows that abnormal accumulation of hyaluronan may be an important stromal target for cancer therapy. In this review we highlight the role of hyaluronan and hyaluronan-mediated interactions in cancer, and discuss historical and recent data on hyaluronidase-based therapies and the effect of hyaluronan removal on tumor growth.

High Payload Dual Therapeutic‐Imaging Nanocarriers for Triggered Tumor Delivery

The in vitro and in vivo characterization of an optimized formulation of nanoparticles (NPs) loaded with a high content of dexamethasone palmitate (DEX-P), a chemotherapeutic adjuvant that decreases interstitial fluid pressure in tumors, and (111) In, a signaling agent, is described. These NPs are uniform in size and composition. Single photon emission computed tomography imaging demonstrates significant tumor uptake of (111) In-labeled DEX-P NPs in tumor-bearing mice. As with many nanoparticle-based drug delivery systems, significant liver accumulation is observed. Assessment of liver histology and blood tests show no apparent hepatic or renal toxicity of the DEX-P NPs. Conversion of DEX-P to DEX occurs when DEX-P NPs are incubated with mouse plasma, human tumor homogenate and ascites from tumor bearing mice, but not with human plasma. This conversion is slower in plasma from Es1(e) ((-/-)) /SCID mice, a potential alternative animal model that better mimics humans; however, plasma from these mice are not completely devoid of esterase activity. The difference between blood and tumor esterase activity in humans facilitates the delivery of DEX-P NPs to tumors and the release of dexamethasone by an esterase trigger.

397 Non-invasive Measurement of Tumour Interstitial Fluid Pressure Using Magnetic Resonance Imaging

397 Non-invasive Measurement of Tumour Interstitial Fluid Pressure Using Magnetic Resonance Imaging

High Interstitial Fluid Pressure Is Associated with Tumor-Line Specific Vascular Abnormalities in Human Melanoma Xenografts

PurposeInterstitial fluid pressure (IFP) is highly elevated in many solid tumors. High IFP has been associated with low radiocurability and high metastatic frequency in human melanoma xenografts and with poor survival after radiation therapy in cervical cancer patients. Abnormalities in tumor vascular networks have been identified as an important cause of elevated tumor IFP. The aim of this study was to investigate the relationship between tumor IFP and the functional and morphological properties of tumor vascular networks.Materials and MethodsA-07-GFP and R-18-GFP human melanomas growing in dorsal window chambers in BALB/c nu/nu mice were used as preclinical tumor models. Functional and morphological parameters of the vascular network were assessed from first-pass imaging movies and vascular maps recorded after intravenous bolus injection of 155-kDa tetramethylrhodamine isothiocyanate-labeled dextran. IFP was measured in the center of the tumors using a Millar catheter. Angiogenic profiles of A-07-GFP and R-18-GFP cells were obtained with a quantitative PCR array.ResultsHigh IFP was associated with low growth rate and low vascular density in A-07-GFP tumors, and with high growth rate and high vascular density in R-18-GFP tumors. A-07-GFP tumors showed chaotic and highly disorganized vascular networks, while R-18-GFP tumors showed more organized vascular networks with supplying arterioles in the tumor center and draining venules in the tumor periphery. Furthermore, A-07-GFP and R-18-GFP cells differed substantially in angiogenic profiles. A-07-GFP tumors with high IFP showed high geometric resistance to blood flow due to high vessel tortuosity. R-18-GFP tumors with high IFP showed high geometric resistance to blood flow due to a large number of narrow tumor capillaries.ConclusionsHigh IFP in A-07-GFP and R-18-GFP human melanoma xenografts was primarily a consequence of high blood flow resistance caused by tumor-line specific vascular abnormalities.

Abstract 3743: NVP-BYL719, a selective inhibitor of the class Ia PI3K isoform alpha impairs angiogenesis and microvascular permeability.

Abstract Tumor blood vessels are distinctly abnormal in structure and function. When compared to normal vessels, they are enlarged, tortuous, leaky, poorly covered by pericytes and with a defective basement membrane. VEGF is a prominent cytokine responsible for the hyperpermeable state of tumor microvasculature to plasma macromolecules. The phosphatidylinositol 3-kinase (PI3K)-Akt signaling pathway functions downstream of VEGF and can activate the production of the free radical gas nitric oxide (NO) through the enzyme endothelial NO synthase (eNOS), a key player for the in vivo biological activity of VEGF. In the present study, we investigated the effect of NVP-BYL719, a novel, synthetic low molecular mass compound, which potently and selectively inhibits class I PI3K isoform alpha activity, on vascular leakage in tumors and its impact on tumor progression in an orthotopic breast cancer model (BN472) in syngeneic rats. Effects on the vasculature were investigated in normal and tumor tissues via tumor interstitial fluid pressure (IFP) measurements in conscious animals via radio-telemetry and a modified Miles assay. The antiangiogenic effect of NVP-BYL719 and its impact on tumor progression was also assessed in an U87MG glioblastoma subcutaneous xenograft tumor model. Pathway inhibition was confirmed using tumor histology and Reverse Phase Protein Array (RPPA) approaches. NVP-BYL719 inhibits VEGF driven tissue formation as well as neo-vascularization of the newly formed tissue. Moreover, the compound strongly inhibited microvessel permeability in normal tissue as determined in the modified miles assay. Similarly, tumor interstitial fluid pressure (IFP), a phenomenon that is directly dependent on tumor vessel permeability, was significantly reduced (up to 43%) by NVP-BYL719 in a dose-dependent manner, upon oral administration in BN472 mammary carcinoma grown orthotopically in syngeneic rats. Concomitantly, tumor growth was significantly inhibited in BN472 mammary carcinoma and U87MG xenografts. The compound was well tolerated with no significant body weight loss at any tested dose. In conclusion, our data suggest that NVP-BYL719, a Class I PI3K selective inhibitor of p110 alpha, interferes with the tumor vasculature system. Thus, the anti-angiogenic proprieties of NVP-BYL719 might participate to the antitumor activity (or efficacy) of the compound. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3743. doi:1538-7445.AM2012-3743