Anti-tumor,Anti-allergy,Anti-angiogenesis and Hepatoprotective Effects of Deoxypodophyllotoxin and Its Molecular Mechanism

Deoxypodophyllotoxin not only has pharmacological effects such as anti-allergy,anti-angiogenesis and liver protection,but also has good anti-tumor activity.It can play an anti-tumor role by inhibiting cell viability,inducing apoptosis,blocking cell cycle and inhibiting cell migration.In this paper,the related research on pharmacological effect and mechanism of deoxypodophyllotoxin is reviewed,to lay a foundation for the follow-up study of deoxypodophyllotoxin and drug development.

Efficacy and safety of anlotinib combined with the STUPP regimen in patients with newly diagnosed glioblastoma: a multicenter, single-arm, phase Ⅱ trial

Objective:Glioblastomas are highly vascularized malignant tumors.We determined the efficacy and safety of the anti-angiogenic multi-kinase inhibitor,anlotinib,for a newly diagnosed glioblastoma.Methods:This multicenter,single-arm trial(NCT04119674)enrolled 33 treatment-naïve patients with histologically proven glioblastomas between March 2019 and November 2020.Patients underwent treatment with the standard STUPP regimen[fractionated focal irradiation in daily fractions of 1.8-2 Gy given 5 d/w×6 w(total=54-60 Gy)]or radiotherapy plus continuous daily temozolomide(TMZ)(75 mg/m^(2)of body surface area/d,7 d/w from the first to the last day of radiotherapy),followed by 6 cycles of adjuvant TMZ(150-200 mg/m^(2)×5 d during each 28-d cycle)plus anlotinib(8 mg/d on d 1-14 of each 3-w cycle for 2 cycles during concomitant chemoradiotherapy,8 maximal cycles as adjuvant therapy,followed by maintenance at 8 mg/d.The primary endpoint was progression-free survival(PFS).Secondary endpoints included overall survival(OS)and adverse events(AEs).Results:Thirty-three patients received the planned treatment.The median PFS was 10.9 months(95%CI,9.9-18.7 months)and the 12-month PFS rate was 48.5%.The median OS was 17.4 months(95%CI,14.5-21.1 months)and the 12-month OS rate was 81.8%.The most common AEs included hypertriglyceridemia[58%(n=19)],hypoalbuminemia[46%(n=15)],and hypercholesterolemia[46%(n=15)]during concurrent chemoradiotherapy and leukopenia[73%(n=24)],hypertriglyceridemia[67%(n=22)],and neutropenia[52%(n=17)]during adjuvant therapy.Five patients discontinued treatment due to AEs.HEG1(HR,5.6;95%CI,1.3-23.7;P=0.021)and RP1L1 alterations(HR,11.1;95%CI,2.2-57.2;P=0.004)were associated with a significantly shorter PFS.Conclusions:Anlotinib plus the STUPP regimen has promising anti-tumor activity against glioblastoma and manageable toxicity.HEG1 and RP1L1 alterations might be novel predictive biomarkers of the response to anlotinib.

Targeted anti-cancer therapy: Co-delivery of VEGF siRNA and Phenethyl isothiocyanate (PEITC) via cRGD-modified lipid nanoparticles for enhanced anti-angiogenic efficacy

Anti-tumor angiogenesis therapy, targeting the suppression of blood vessel growth in tumors, presents a potent approach in the battle against cancer. Traditional therapies have primarily concentrated on single-target techniques, with a specific emphasis on targeting the vascular endothelial growth factor, but have not reached ideal therapeutic efficacy. In response to this issue, our study introduced a novel nanoparticle system known as CS-siRNA/PEITC&L-cRGD NPs. These chitosan-based nanoparticles have been recognized for their excellent biocompatibility and ability to deliver genes. To enhance their targeted delivery capability, they were combined with a cyclic RGD peptide (cRGD). Targeted co-delivery of gene and chemotherapeutic agents was achieved through the use of a negatively charged lipid shell and cRGD, which possesses high affinity for integrin αvβ3 overexpressed in tumor cells and neovasculature. In this multifaceted approach, co-delivery of VEGF siRNA and phenethyl isothiocyanate (PEITC) was employed to target both tumor vascular endothelial cells and tumor cells simultaneously. The co-delivery of VEGF siRNA and PEITC could achieve precise silencing of VEGF, inhibit the accumulation of HIF-1α under hypoxic conditions, and induce apoptosis in tumor cells. In summary, we have successfully developed a nanoparticle delivery platform that utilizes a dual mechanism of action of anti-tumor angiogenesis and pro-tumor apoptosis, which provides a robust and potent strategy for the delivery of anti-cancer therapeutics.

Anlotinib in combination with Envolizumab plus Etoposide for the treatment of EX-SCLC:a case report

Background:Small cell lung cancer(SCLC)is an aggressive malignant tumor with strong immunosuppressive effects,characterized by rapid doubling time and poor prognosis.Currently,effective therapeutic options are urgently needed for Extensive-stage small-cell lung Cancer.Case description:In the present case,a combination therapy of anlotinib,envolizumab,and etoposide was administered to treat an 80-year-old female patient with extensive-stage SCLC accompanied by mediastinal lymph node and bone metastasis.After two cycles of treatment,the tumor lesions in the right lungs decreased from 5.04*3.44 cm to 1.65*1.42 cm.As of now,no significant mass is seen there and no serious adverse reactions in this patient.Until September 2023,she has survived for 18 months with no disease progression.Conclusions:Research shows that Alectinib,in combination with evolocumab plus etoposide,could be an original,viable therapeutic option for the treatment option of patients with extensive-stage SCLC.

Nanoscale coordination polymer Fe-DMY downregulating Poldip2-Nox4-H2O2 pathway and alleviating diabetic retinopathy

Diabetic retinopathy(DR)is a prevalent microvascular complication of diabetes and the leading cause of blindness and severe visual impairment in adults.The high levels of glucose trigger multiple intracellular oxidative stress pathways,such as POLDIP2,resulting in excessive reactive oxygen species(ROS)production and increased expression of vascular cell adhesion molecule-1(VCAM-1),hypoxia-inducible factor 1a(HIF-1a),and vascular endothelial growth factor(VEGF),causing microvascular dysfunction.Dihydromyricetin(DMY)is a natural flavonoid small molecule antioxidant.However,it exhibits poor solubility in physiological environments,has a short half-life in vivo,and has low oral bioavailability.In this study,we present,for the first time,the synthesis of ultra-small Fe-DMY nano-coordinated polymer particles(Fe-DMY NCPs),formed by combining DMY with low-toxicity iron ions.In vitro and in vivo experiments confirm that Fe-DMY NCPs alleviate oxidative stress-induced damage to vascular endothelial cells by high glucose,scavenge excess ROS,and improve pathological features of DR,such as retinal vascular leakage and neovascularization.Mechanistic validation indicates that Fe-DMY NCPs can inhibit the activation of the Poldip2-Nox4-H_(2)O_(2) signaling pathway and downregulate vital vascular function indicators such as VCAM-1,HIF-1a,and VEGF.These findings suggest that Fe-DMY NCPs could serve as a safe and effective antioxidant and microangio-protective agent,with the potential as a novel multimeric drug for DR therapy.

Research Progress of Anti-Angiogenic Drugs in First-Line Treatment of Small Cell Lung Cancer

Small Cell Lung Cancer (SCLC) is a low-differentiated neuroendocrine tumor with rapid growth, early metastasis and sensitivity to radiotherapy and chemotherapy. It is highly recurrence rate. And there is lacking effective treatment now. As an active research direction at present, anti-angiogenic drugs are not only widely used in non-small cell lung cancer and other tumors, but also have certain effects in small cell lung cancer combined with chemotherapy. As one of the effective treatment methods for small cell lung cancer, related research is not rare, but there is still inadequacy, such as side effects can not be tolerated, and the timing of treatment can not be accurately assessed. This article will briefly describe the research progress of anti-angiogenic drugs combined with chemotherapy in the first-line treatment of extensive small cell lung cancer.

Extraordinary response of metastatic pancreatic cancer to apatinib after failed chemotherapy: A case report and literature review

Chemotherapy has limited efficacy in the treatment of advanced and metastatic pancreatic cancer(PC), and has serious side effects. The development of novel effective agents, especially targeted therapy, is essential for patients with PC. We present a 58-year-old Chinese woman initially diagnosed with locally advanced PC. As the disease progressed to Stage Ⅳ, the patient was unable to tolerate chemotherapy after the fourth-line treatment. She was then treated with apatinib, a novel and highly selective tyrosine kinase inhibitor of vascular endothelial growth factor receptor-2 and achieved a progression-free-survival of 7 mo. All drug-related side effects were well controlled with medication. To the best of our knowledge, this is the first case of PC which responded to apatinib. Considering this remarkable response, apatinib may be a promising agent in the treatment of PC. We also reviewed the literature on chemotherapy and targeted therapy, especially the anti-angiogenesis therapy for patients with PC, and investigated the effect of apatinib in other solid tumors as well.

Influence of bioactive sulphated polysaccharide-protein complexes on hepatocarcinogenesis, angiogenesis and immunomodulatory activities

Objective:To explore the in vivo anticancer,anti-angiogenesis and immunomodulatory efficacies of the bioactive polysaccharide isolated from cold aqueous extract of Jania rubens(JCEM) and Pterocladia capillacea(PCEM) as well as hot aqueous extract of Enteromorpha intestinalis(EHEM) against hepatocellular carcinoma rat model(HCC) and to study their chemical composition.Methods:The sugars and amino acids composition of the bioactive polysaccharides of JCEM,PCEM and EHEM were determined using gas liquid chromatography and amino acid analyzer,respectively.These polysaccharide extracts(20 mg/kg b.wt.for 5 weeks) were assessed on hepatocarcinogenesis in rats and α-fetoprotein(AFP),carcinoembryonic antigen(CEA),glypican-3(GPC-3),hepatocyte growth factor(HGF) and vascular endothelial growth factor(VEGF) and Ig G levels were evaluated.Results:The GLC analysis of JCEM,PCEM and EHEM polysaccharide revealed the presence of 10,9 and10 sugars,in addition the amino acid analyser enable identification of 16,15 and 15 amino acids,respectively.These polysaccharide extracts of JCEM,PCEM and EHEM produced significant decrease in serum AFP,CEA,GPC-3,HGF and VEGF compared with untreated HCC group.JCEM,PCEM and EHEM had an immunostimulatory responses by increasing the IgG levels as compared by naive value(1.23,1.53 and 1.17 folds),respectively.The bioactive polysaccharides in HCC induced rats improved the humoral immune response.The photomicrographs of liver tissue sections of the groups of HCC treated with polysaccharide extracts of Jania rubens and Enteromorpha intestinalis showed intact histological structure.Moreover,fractions HE1,HE4,HE7 obtained from polysaccharide of EHEM showed moderate cytotoxic activity against Hep G2 in vitro with IC_(50) 73.1,42.6,76.2 μg/mL.However,fractions of PCEM and JCEM show no or weak cytotoxicity against Hep G2 in vitro where the cytotoxic activity of their crude polysaccharide extract proved synergetic effect.Conclusions:The pronounced antitumor activity of sulphated polysaccharide-protein complexes of JCEM and EHEM is due to direct cytotoxic activity,anti-hepatocarcinogensis,and anti-angiogenesis.In addition,JCEM,PCEM and EHEM had an immunostimulatory response and improved the humoral immune response in HCC induced rats.

Tumor progression-dependent angiogenesis in gastric cancer and its potential application

Despite improvements in the early diagnosis,prognosis and therapeutic strategies for gastric cancer(GC),human GC remains one of the most frequently diagnosed malignant tumors in the world,and the survival rate of GC patients remains very poor.Thus,a suitable therapeutic strategy for GC is important for prolonging survival.Both tumor cells themselves and the tumor microenvironment play an important role in tumorigenesis,including angiogenesis,inflammation,immunosuppression and metastasis.Importantly,these cells contribute to gastric carcinogenesis by altering the angiogenic phenotype switch.The development,relapse and spreading of tumors depend on new vessels that provide the nutrition,growth factors and oxygen required for continuous tumor growth.Therefore,a state of tumor dormancy could be induced by blocking tumor-associated angiogenesis.Recently,several antiangiogenic agents have been identified,and their potential for the clinical management of GC has been tested.Here,we provide an up-to-date summary of angiogenesis and the angiogenic factors associated with tumor progression in GC.We also review antiangiogenic agents with a focus on the anti-vascular endothelial growth factor receptor(VEGFR)-mediated pathway for endothelial cell growth and their angiogenesis ability in GC.However,most antiangiogenic agents have reported no benefit to overall survival(OS)compared to chemotherapy alone in local or advanced GC.In phase III clinical trials,only ramucirumab(anti-VEGFR blocker)and apatinib(VEGFR-TKI blocker)have reported an improved median overall response rate and prolonged OS and progression-free survival outcomes as a 2 nd-line agent combined with chemotherapy treatment in advanced GC.By providing insights into the molecular mechanisms of angiogenesis associated with tumor progression in GC,this review will hopefully aid the optimization of antiangiogenesis strategies for GC therapy in combination with chemotherapy and adjuvant treatment.

Mechanism of Wnt/β-catenin signaling pathway in enhanced malignant phenotype of non-small cell lung cancer induced by antiangiogenesis therapy

Objective:To study the mechanism of Wnt/β-catenin signaling pathway in the enhanced malignant phenotype of A549 cells of human non-small cell lung cancer induced by the antiangiogenesis therapy.Methods:The siRNA technique was employed to inhibit the expression of vascular endothelial growth factor(VEGF) in A549 cells and simulate the clinical course of anti-angiogencsis therapy.Real-time PCR and western-blot were used to study the change in the expression of Wnt/β-catenin signaling molecules at the mRNA and protein level respectively,as well as the effect on the epithelial mesenchymal transition in A549 cells.The proliferation and invasion abilities of tumor cells were detected to discuss the mechanism of Wnt/β-catenin signaling pathway in the enhanced malignant phenotype of non-small cell lung cancer induced by the anti-angiogenesis therapy.Results:The specific siRNA could significantly inhibit the expression of VEGF in cells to simulate the anti-angiogenesis therapy.Under the action of 50 nM VEGF siRNA,the proliferation ability of A549 significantly increased(P<0.05).After being treated with VEGF siRNA,the invasion ability of cells increased.Twenty-four hours after the transcription of 50 nM siRNA into cells,the number of cells that come through the membrane was278.3 ± 12.9.Compared with the Ctrl siRNA group,when VEGF was inhibited,the expression ofβ-catenin and Cyclin D1 increased by 86%and 55%respectively.Meanwhile,the expression of E-cadherin decreased,while the one of vimentin increased.Conclusions:siRNA can significantly inhibit the expression of VEGF.For the anti-angiogencsis therapy,the inhibited expression of VEGF can activate the Wnt/β-catenin signaling pathway to cause the epithelial mesenchymal transition and then the enhanced malignant phenotype of non-small cell lung cancer.

Clinical Observation of Bevacizumab Combined with S-1 in the Treatment of Pretreated Advanced Esophageal Carcinoma

Objective To investigate the clinical effects and safety of bevacizumab combined with S-1 as the second-line treatment of recurrent and/or metastatic esophageal cancer after chemoradiation. Methods Patients with recurrent or metastatic esophageal cancer after chemoradiation were treated with bevacizumab and S-1. Bevacizumab was used by intravenous infusion, 7.5mg/kg body weight on day 1; S-1 was used by oral at 80mg/m^2·d on day 1-14, 21 days as a cycle of treatment and repeated until either progressive disease or intolerable toxicity occurred. Chest CT were performed and RECIST 1.1 was used for response evaluation. Kaplan-Meier method was used for survival analysis. Side effects were recorded and analyzed. Results Totally 78 patients were enrolled in the study, including 67 squamous cell carcinoma and 11 adenocarcinoma histologically. The overall response(CR+PR) rate was 22.4%(17/76) and disease control(CR+PR+SD) rate was 61.8%(47/76) respectively. The median follow-up time was 20 months(range from 9 to 44 months). The median progression-free survival(PFS) was 4.9 months(95% CI 4.4-5.5) and the median overall survival(OS) was 8.1 months(95% CI 7.6-9.2). The median PFS and OS of patients with metastasis diseases were 6.2 months(95% CI 3.3 to 6.3) and 8.5 months(95% CI 5.8 to 11.2), where PFS was longer than that of patients with local regional recurrence(median 5.0 months, 95% CI 3.0 to 5.5, P=0.017) and OS was longer than that of patients with regional disease and metastasis(median 8.0 months, 95% CI 4.6 to 9.5, P=0.010). The common adverse effects were mild to moderate neutropenia(84.2%), grade Ⅰ -Ⅱ hand and foot syndrome(51.3%), grade Ⅰ -Ⅱ nausea(48.7%), mild epistaxis(30.1%) and mild vomiting(14.5%). Esophageal bleeding occurred in 7.9% of patients. One patient(1.3%) died from massive bleeding which was caused by esophageal perforation. Conclusion Bevacizumab combined with S-1 was effective and safe for esophageal cancer patients who had recurrent or metastatic diseases after chemoradiation.

Construction of lentivirus vectors carrying alphastatin gene and its secretion expression in human umbilical vein endothelia cells

Objective To construct lentivirus vectors carrying alphastatin gene,test its secretion expression in human umbilical vein endothelia cells(HUVECs)and observe its effects on growth,migration and tube formation of HUVECs.Methods We constructed recombinant lentivirus vectors of NT4-alphastatin fusion gene containing neurotrophin-4 signal peptide,pro-region sequences and alphastatin,then transfected the recombinant lentivirus vectors into HUVECs to obtain secretory protein alphastatin and test its anti-angiogenic activities in vitro.Results Our data showed that recombinant self-inactivating lentivirus vectors of NT4-alphastatin were successfully constructed,and stable NT4-alphastatin transduced HUVECs were capable of sustainably secreting alphastatin which significantly suppressed HUVECs migration and differentiation but not VEGF-induced proliferation.Conclusion This report represents the first time on the use of lentivirus-based vectors to deliver alphastatin,the endogenous angiogenesis inhibitor,and reveals the potential utility of anti-angiogenic gene therapy with lentivirus vectors for treating cancer.

Inhibitory Effect of Recombinant Endostatin on Angiogenesis and Tumor Growth of Hepatoma

To study the influence of recombinant endostatin on angiogenesis and tumor growth of mice H22 hepatoma, tumor models were constructed by injecting H22 hepatoma cells into the leg muscle of mice Recombinant endostatin was produced by gene engineering in E coli The recombinant protein was injected subcutaneously to treat transplanted hepatoma faraway The weight of tumors was measured, and the changes of necrosis of tumor cells and vessel density were observed by immunohistochemistry The results suggested that the growth of hepatoma models transplanted in the muscle of legs was suppressed by recombinant endostatin The density of vacularity was decreased, but the necrosis of tumor cells increased The inhibitory effect of recombinant endostatin on angiogenesis and tumor growth of hepatoma was not affected after chemotherapy

Novel therapeutic agents in the treatment of metastatic colorectal cancer

Over the past couple of decades considerable progress has been made in the management of metastatic colorectal cancers(mCRC) leading to a significant improvement in five-year survival. Although part of this success has been rightly attributed to aggressive surgical management and advances in other adjunct treatments, our understanding of the pathogenesis of cancer and emergence of newer molecular targets for colon cancer has created a powerful impact. In this review article we will discuss various targeted therapies in the management of mCRC. Newer agents on the horizon soon to be incorporated in clinical practice will be briefly reviewed as well.

Anti-angiogeneic Target Therapy for Cancer with Vaccine Based on the Recombinant Chicken FGFR-1 in Tumor-bearing Mice

To explore the anti-tumor effect of immunotherapy with recombinant protein vaccine based on FGFR-1 of chicken （cFR-1） in a mouse Meth A fibrosarcoma model, tumor volume and survival rate of the mice were observed at a 3-day interval. Microvessel density （MVD） was detected by immunohistochemistry. Auto-antibodies against self-FGFR-1 were detected by Western blotting and ELISA, respectively. The anti-FGFR-1 antibody-producing B cells （APBCs） were detected by enzyme-linked immunospot （ELISPOT） assay. Eighteen days after inoculation of tumor cells, the tumor volume was significantly smaller in cFR-l-immunized group than in mouse FGFR-1 （mFR-1） immunized group and normal saline （NS） control group （P〈0.05）, and the survival time was significantly longer in cFR-l-immunized group than in the control groups （P〈0.01）. MVD was significantly lower in cFR-l-immunized group than in mFR-1-immunized group and NS group （16.8 ±5.6 vs 64.6±1.8 and 59.6±8.7, P〈0.01）. Antibodies against self-FGFR-1 were found in mFR-1-immunized group, the major antibody subclasses were IgG1 and IgG2b. Compared with the two control groups, the numbers of APBCs in cFR-l-immunized group were significantly increased （P〈0.01） These results demonstrated that the cFR-1-related anti-angiogenesis protein vaccine could induce the production of auto-antibodies against self-FGFR-1, which futher inhibit angiogenesis and growth of solid tumor.

Numerical simulation of solid tumor angiogenesis with Endostatin treatment:a combined analysis of inhibiting effect of anti-angiogenic factor and micro mechanical environment of extracellular matrix

To investigate the influence of anti-angiogenesis drug Endostatin on solid tumor angiogenesis, a mathematical model of tumor angiogenesis was developed with combined influences of local extra-cellular matrix mechanical environment, and the inhibiting effects of Angiostatin and Endostatin. Simulation results show that Angiostatin and Endostatin can effectively inhibit the process of tumor angiogenesis, and decrease the number of blood vessels in the tumor. The present model could be used as a valid theoretical method in the investigation of anti-angiogenic therapy of tumors.

Modeling and Numerical Solution of a Cancer Therapy Optimal Control Problem

A mathematical optimal-control tumor therapy framework consisting of radio- and anti-angiogenesis control strategies that are included in a tumor growth model is investigated. The governing system, resulting from the combination of two well established models, represents the differential constraint of a non-smooth optimal control problem that aims at reducing the volume of the tumor while keeping the radio- and anti-angiogenesis chemical dosage to a minimum. Existence of optimal solutions is proved and necessary conditions are formulated in terms of the Pontryagin maximum principle. Based on this principle, a so-called sequential quadratic Hamiltonian (SQH) method is discussed and benchmarked with an “interior point optimizer—a mathematical programming language” (IPOPT-AMPL) algorithm. Results of numerical experiments are presented that successfully validate the SQH solution scheme. Further, it is shown how to choose the optimisation weights in order to obtain treatment functions that successfully reduce the tumor volume to zero.

Future options of anti-angiogenic cancer therapy

In human patients,drugs that block tumor vessel growth are widely used to treat a variety of cancer types.Many rigorous phase 3 clinical trials have demonstrated significant survival benefits;however,the addition of an anti-angiogenic component to conventional therapeutic modalities has generally produced modest survival benefits for cancer patients.Currently,it is unclear why these clinically available drugs targeting the same angiogenic pathways produce dissimilar effects in preclinical models and human patients.In this article,we discuss possible mechanisms of various anti-angiogenic drugs and the future development of optimized treatment regimens.

Angiogenesis and immune checkpoint dual blockade:Opportunities and challenges for hepatocellular carcinoma therapy

The disease burden related to hepatocellular carcinoma(HCC) is increasing. Most HCC patients are diagnosed at the advanced stage and multikinase inhibitors have been the only treatment choice for them. Recently, the approval of immune checkpoint inhibitors(ICIs) has provided a new therapeutic strategy for HCC. It is noteworthy that the positive outcomes of the phase Ⅲ clinical trial IMBrave150 [atezolizumab(anti-programmed cell death ligand 1 antibody) combined with bevacizumab(anti-vascular endothelial growth factor monoclonal antibody)],showed that overall survival and progression-free survival were significantly better with sorafenib. This combination therapy has become the new standard therapy for advanced HCC and has also attracted more attention in the treatment of HCC with anti-angiogenesis-immune combination therapy. Currently, the synergistic antitumor efficacy of this combination has been shown in many preclinical and clinical studies. In this review, we discuss the mechanism and clinical application of anti-angiogenics and immunotherapy in HCC, outline the relevant mechanism and rationality of the combined application of antiangiogenics and ICIs, and point out the existing challenges of the combination therapy.

Simulation of tumor microvasculature and microenvironment response to anti-angiogenic treatment by angiostatin and endostatin

The effects of anti-angiogenesis treatment by angiostatin and endostatin on normalization of tumor microvasculature and microenvironment are investigated, based on mathematical modeling and numerical simulation of tumor anti-angiogenesis and tumor haemodynamics. The results show that after anti-angiogenesis treatment： （i） the proliferation, growth, and branching of neo-vessels are effectively inhibited, and the extent of vascularization in tumors is accordingly reduced. （ii） the overall blood perfusion inside of tumor is declined, the plateau of tumor interstitial fluid pressure （IFP） is relieved, the interstitial fluid oozing out from the tumor periphery into the surrounding normal tissue is reduced, the reduction of overall extravasation across vasculature to tumor interstium is much less than the decreased overall blood perfusion, due to the decline of IFP, the intravasations is remarkablely effected by the change, in some cases there are no intravasation flow appear.