Targeting tumor interstitial fluid pressure: will it yield novel successful therapies for solid tumors?

Böckelmann, Lukas Clemens; Schumacher, Udo

doi:10.1080/14728222.2019.1702974

Cited by 50 publications

(34 citation statements)

References 94 publications

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“…When taken into consideration with the in vitro results, particularly the clonogenic assay which also found the duration of vandetanib exposure to be an important factor for achieving radiosensitisation, it would appear the radiosensitisation occurs at a stage after the initial binding and inhibition of the receptor. The dynamics of in vivo treatment with vandetanib have been shown to alter the physical properties of the tumour microenvironment, by increasing oxygenation immediately following vandetanib treatment [ 25 ] and the anti-angiogenic class of drugs in general have been shown to decrease tumour vessel permeability and interstitial fluid pressure [ 45 , 48 ]. Interestingly, when combined with radiotherapy this period of increased oxygenation would coincide with increased tumour perfusion leading to fluid extravasation from the tumour and a reduction in interstitial pressure and hypoxia in the tumour microenvironment [ 45 , 48 , 49 , 50 , 51 ] due to radiation.…”

Section: Discussionmentioning

confidence: 99%

“…The dynamics of in vivo treatment with vandetanib have been shown to alter the physical properties of the tumour microenvironment, by increasing oxygenation immediately following vandetanib treatment [ 25 ] and the anti-angiogenic class of drugs in general have been shown to decrease tumour vessel permeability and interstitial fluid pressure [ 45 , 48 ]. Interestingly, when combined with radiotherapy this period of increased oxygenation would coincide with increased tumour perfusion leading to fluid extravasation from the tumour and a reduction in interstitial pressure and hypoxia in the tumour microenvironment [ 45 , 48 , 49 , 50 , 51 ] due to radiation. Additionally, the well documented [ 23 , 24 ] vascular normalisation effect of angiogenic therapy is another means of anti-tumour effect due to vandetanib therapy.…”

Section: Discussionmentioning

confidence: 99%

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Radiosensitisation of Hepatocellular Carcinoma Cells by Vandetanib

Znati

Carter

Vásquez

et al. 2020

Cancers

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Hepatocellular Carcinoma (HCC) is increasing in incidence worldwide and requires new approaches to therapy. The combination of anti-angiogenic drug therapy and radiotherapy is one promising new approach. The anti-angiogenic drug vandetanib is a tyrosine kinase inhibitor of vascular endothelial growth factor receptor-2 (VEGFR-2) and RET proto-oncogene with radio-enhancement potential. To explore the benefit of combined vandetanib and radiotherapy treatment for HCC, we studied outcomes following combined treatment in pre-clinical models. Methods: Vandetanib and radiation treatment were combined in HCC cell lines grown in vitro and in vivo. In addition to 2D migration and clonogenic assays, the combination was studied in 3D spheroids and a syngeneic mouse model of HCC. Results: Vandetanib IC 50 s were measured in 20 cell lines and the drug was found to significantly enhance radiation cell kill and to inhibit both cell migration and invasion in vitro. In vivo, combination therapy significantly reduced cancer growth and improved overall survival, an effect that persisted for the duration of vandetanib treatment. Conclusion: In 2D and 3D studies in vitro and in a syngeneic model in vivo, the combination of vandetanib plus radiotherapy was more efficacious than either treatment alone. This new combination therapy for HCC merits evaluation in clinical trials.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Radiosensitisation of Hepatocellular Carcinoma Cells by Vandetanib

Znati

Carter

Vásquez

et al. 2020

Cancers

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“…The stroma separates cancer cells from the vasculature (14)(15)(16). Before diffusion into cancer cells, oxygen, nutrition, and antitumor drugs should cross the stiff stroma and overcome the hamper by increasing interstitial fluid pressure and lengthening transport distance (9,17,18). The inadequate supply of oxygen and antineoplastic agents may induce hypoxia and chemoresistance, ultimately driving tumor progression (19)(20)(21)(22).…”

Section: Introductionmentioning

confidence: 99%

Long Distance From Microvessel to Cancer Cell Predicts Poor Prognosis in Non-Small Cell Lung Cancer Patients

et al. 2021

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BackgroundBlood supply, which is crucial for nutrition and drug delivery, was determined by microvessel density as well as the diffusion distance between vessels and cancer cells. Therefore, we evaluated the distance from microvessels to cancer cells (Dmvcc) and its role in the prognosis of non-small cell lung cancer (NSCLC) patients.MethodsPatients with primary NSCLC were retrospectively analyzed. The tumor samples were immunochemically stained with CD31 to visualize the microvessels. The Dmvcc was defined as the mean distance from each microvessel to its nearest cancer cell in the “hot-spot” of an individual patient. The patients were stratified into short- and long-distance groups using five strategies, including dichotomy by the median value, optimal cutoff, trichotomy, quartation and per-10 µm increase. The correlation between the Dmvcc and survival was evaluated by using univariate and multivariate analyses with various Dmvcc strategies.ResultsIn total, 100 patients were analyzed. The median value of Dmvcc was 13.1 μm (ranged, 1.6 to 269.7 μm; mean value, 24.4 ± 33.5 μm). The optimal cutoff value of Dmvcc for predicting survival outcome was 20 μm. Dmvcc was significantly related to overall survival (OS) with all the five categories (p = 0.001–0.000004) and progression-free survival (PFS) categorized by optimal cutoff value (p = 0.024), trichotomy (p = 0.041) and per-10 µm increase (p = 0.040) after adjusting for other factors. Patients with longer Dmvcc (≥20 μm) were observed to have poor survival outcomes (OS: HR = 13.5, 95CI: 4.42–41.18, p = 0.000005; PFS: 3.26, 95CI: 1.56–6.81, p = 0.002). A high Dmvcc per-10 µm was associated with a significantly increased risk of cancer-related death and progression by 98% (p = 0.0001) and 30% (p = 0.044), respectively.ConclusionThe NSCLC tissues had varying distances from microvessels to cancer cells, and long distances were strongly associated with poor survival.

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“…Cancer chemotherapy obviously spares some malignant cells even in the absence of resistance mutations. Therefore, several non-genomic factors that might trigger resistance were in focus during recent investigations, including: drug gradients in relation to blood vessels [8], regions of hypoxia [9], abnormalities of tumor vascularization [10], interstitial pressure [11], abundance of cellular debris [12] and some other phenomena. All these studies theoretically imply that higher injected doses must result in better therapeutic outcomes.…”

Section: Introductionmentioning

confidence: 99%

Doxorubicin uptake in ascitic lymphoma model: resistance or curability is governed by tumor cell density and prolonged drug retention

et al. 2020

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Background/Aims: Chemotherapy resistance of malignancies is a universal phenomenon which unfavorably affects therapeutic results. Genetic adaptations as well as epigenetic factors can play an important role in the development of multidrug resistance. Cytotoxic drug content in plasma of cancer patients is known to variate up to one hundred-fold regardless of the same dose injected per m 2 body surface. The relationship between plasma concentrations, tissue uptake, and chemotherapy response is not completely understood. The main objective of this study was to investigate how the identical dose of Doxorubicin (Dox) can result in a different therapeutic response pattern depending on tumor size. Study Design: The study was performed on ascitic EL4 lymphoma in an exponential growth phase focusing on the rapidly changing tumor susceptibility to the Dox treatment. Well distinguishable tumor response patterns (curability, remission-relapse, resistance) were selected to unveil Dox intratumoral uptake and drug tissue persistence. Intratumoral Dox content within peritoneal cavity (PerC) in conjunction with systemic toxicity and plasma pharmacokinetics, were monitored at several time points following Dox injection in tumor bearing mice (TBM) with differing patterns of response. Results: Following intraperitoneal (i.p.) transplantation of 5x10 4 EL4 lymphoma cells rapid exponential proliferation with ascites volume and animal mass increase resulted in median survival of 14.5 days. The increase in tumor cell mass in PerC between day 3 and day 9 was 112.5-fold (0.2±0.03 mg vs 22.5±0.31 mg respectively). However, tumors at this time interval (day 3 to day 9 post-transplantation) were relatively small and constituted less than 0.05% of animal weight. An identical dose of Dox (15 mg/kg) injected intravenously (i.v.) on Day 3 lead to a cure whereas a TBM injected on day 9 exhibited resistance with a median survival time no different from the untreated TBM control. Injection of Dox resulted in noticeable differences of cellular uptake in PerC between all three groups of TBM ("cure", relapse", "resistance"). Larger tumors were consistently taking up less Dox 60 min after the 15 mg/kg i.v. bolus injection. Higher initial uptake resulted also in longer retention of drug in PerC cells. The area under the concentration curve in PerC cells AUC0-10d was 8.2+0.57 µg/g x h, 4.6+0.27 µg/g x h and 1.6+0.02 µg/g x h in "cure", "relapse" and "resistance" TBM respectively (p<0.05 "relapse" vs "cure" and p<0.001 "resistance" vs "cure"). No differences in plasma Dox pharmacokinetics or systemic hematological effects were observed in TBM following a single i.v. Dox push. Hematologic nadir was tested on day 2 and subsequent hematologic recovery was evaluated on day 10 following Dox administration. Hematologic recovery on day 10 coincided with complete drug efflux from PerC and rising tumor cell numbers in PerC of "relapse" TBM. Myelosuppression and hematological recovery patterns were identical in all surviving animal groups regardless of the tumor si...

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Targeting tumor interstitial fluid pressure: will it yield novel successful therapies for solid tumors?

Cited by 50 publications

References 94 publications

Radiosensitisation of Hepatocellular Carcinoma Cells by Vandetanib

Radiosensitisation of Hepatocellular Carcinoma Cells by Vandetanib

Long Distance From Microvessel to Cancer Cell Predicts Poor Prognosis in Non-Small Cell Lung Cancer Patients

Doxorubicin uptake in ascitic lymphoma model: resistance or curability is governed by tumor cell density and prolonged drug retention

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