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Tumor Vasculature (tumor + vasculature)
Selected AbstractsExpression of Integrin ,v,3 in Gliomas Correlates with Tumor Grade and Is not Restricted to Tumor VasculatureBRAIN PATHOLOGY, Issue 3 2008Oliver Schnell MD Abstract In malignant gliomas, the integrin adhesion receptors seem to play a key role for invasive growth and angiogenesis. However, there is still a controversy about the expression and the distribution of ,v,3 integrin caused by malignancy. The aim of our study was to assess the extent and pattern of ,v,3 integrin expression within primary glioblastomas (GBMs) compared with low-grade gliomas (LGGs). Tumor samples were immunostained for the detection of ,v,3 integrin and quantified by an imaging software. The expression of ,v,3 was found to be significantly higher in GBMs than in LGGs, whereby focal strong reactivity was restricted to GBMs only. Subsequent analysis revealed that not only endothelial cells but also, to a large extent, glial tumor cells contribute to the overall amount of ,v,3 integrin in the tumors. To further analyze the integrin subunits, Western blots from histologic sections were performed, which demonstrated a significant difference in the expression of the ,3 integrin subunit between GBMs and LGGs. The presented data lead to new insights in the pattern of ,v,3 integrin in gliomas and are of relevance for the inhibition of ,v,3 integrin with specific RGD peptides and interfering drugs to reduce angiogenesis and tumor growth. [source] Hemostatic complications of angiogenesis inhibitors in cancer patients,AMERICAN JOURNAL OF HEMATOLOGY, Issue 11 2008Francesca Elice Tumor vasculature and tumor-associated neo-angiogenesis have recently become major targets for rational drug design of antineoplastic agents. Five such agents with angiogenesis inhibiting activity (thalidomide, lenalidomide, bevacizumab, sunitinib, sorafenib) have already obtained US Food and Drug Administration approval for clinical use and many others have entered clinical trials. Vascular complications, including venous or arterial thromboembolism and hemorrhage, have emerged as relevant toxicities in several clinical trials with angiogenesis inhibitors. Given the well-known interplay between the blood clotting system, angiogenesis, and tumor growth, a better understanding of the impact of these new drugs on overall hemostatic balance is required. In this brief overview, we discuss the incidence of hemostatic complications, the likely pathogenetic mechanisms involved, and the critical need to establish in randomized clinical trials the usefulness of thrombosis prophylaxis to prevent these complications. Careful documentation of hemostatic complications during treatment with each of the new antiangiogenic drugs is warranted. Further studies are urgently required to better define the causal association of these new agents with hemostatic complications and to establish the best prophylactic strategy. Am. J. Hematol., 2008. © 2008 Wiley-Liss, Inc. [source] Therapy-induced antitumor vaccination by targeting tumor necrosis factor-, to tumor vessels in combination with melphalanEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 12 2007Lorenzo Mortara Abstract Treatment of tumor-bearing mice with mouse (m)TNF-,, targeted to tumor vasculature by the anti-ED-B fibronectin domain antibody L19(scFv) and combined with melphalan, induces a therapeutic immune response. Upon treatment, a highly efficient priming of CD4+ T cells and consequent activation and maturation of CD8+ CTL effectors is generated, as demonstrated by in vivo depletion and adoptive cell transfer experiments. Immunohistochemical analysis of the tumor tissue demonstrated massive infiltration of CD4+ and CD8+ T cells 6,days after treatment and much earlier in the anamnestic response to tumor challenge in cured mice. In fact, the curative treatment with L19mTNF-, and melphalan resulted in long-lasting antitumor immune memory, accompanied by a mixed Th1/Th2-type response and significant in vitro tumor-specific cytolytic activity. Finally, the combined treatment reduced the percentage and absolute number of CD4+CD25+ regulatory T cells in the tumor-draining lymph nodes of mice responding to therapy, and this was associated with the establishment of protective immunity. These findings pave the way for alternative therapeutic strategies based on the targeted delivery of biological and pharmacological cytotoxic compounds that not only kill most of the tumor cells but, more importantly, trigger an effective and long-lasting antitumor adaptive immune response. [source] The angiogenic makeup of human hepatocellular carcinoma does not favor vascular endothelial growth factor/angiopoietin-driven sprouting neovascularization,,HEPATOLOGY, Issue 5 2008Wenjiao Zeng Quantitative data on the expression of multiple factors that control angiogenesis in hepatocellular carcinoma (HCC) are limited. A better understanding of the mechanisms underlying angiogenesis in HCC will improve the rational choice of anti-angiogenic treatment. We quantified gene and protein expression of members of the vascular endothelial growth factor (VEGF) and angiopoietin systems and studied localization of VEGF, its receptors VEGFR-1 and VEGFR-2, Angiopoietin (Ang)-1 and Ang-2, and their receptor, in HCC in noncirrhotic and cirrhotic livers. We employed real-time reverse transcription polymerase chain reaction (RT-PCR), western blot, and immunohistology, and compared the outcome with highly angiogenic human renal cell carcinoma (RCC). HCC in noncirrhotic and cirrhotic livers expressed VEGF and its receptors to a similar extent as normal liver, although in cirrhotic background, VEGFR-2 levels in both tumor and adjacent tissue were decreased. Ang-1 expression was slightly increased compared with normal liver, whereas Tie-2 was strongly down-regulated in the tumor vasculature. Ang-2 messenger RNA (mRNA) levels were also low in HCCs of both noncirrhotic and cirrhotic livers, implying that VEGF-driven angiogenic sprouting accompanied by angiopoietin-driven vascular destabilization is not pronounced. In RCC, VEGF-A levels were one order of magnitude higher. At the same time, endothelially expressed Ang-2 was over 30-fold increased compared with expression in normal kidney, whereas Ang-1 expression was decreased. Conclusion: In hepatocellular carcinoma, tumor vascularization is not per se VEGF/angiopoietin driven. However, increased CD31 expression and morphological changes representative of sinusoidal capillarization in tumor vasculature indicate that vascular remodeling is taking place. This portends that therapeutic intervention of HCC at the level of the vasculature is optional, and that further studies into the molecular control thereof are warranted. (HEPATOLOGY 2008.) [source] DNA vaccines suppress tumor growth and metastases by the induction of anti-angiogenesisIMMUNOLOGICAL REVIEWS, Issue 1 2004Ralph A. Reisfeld Summary:, Four novel oral DNA vaccines provide long-lived protection against melanoma, colon, breast, and non-small cell lung carcinoma in mouse model systems. The vaccines are delivered by attenuated Salmonella typhimurium to secondary lymphoid organs and are directed against targets such as carcinoembryonic antigen, tyrosine-related protein, vascular endothelial growth factor receptor-2 [also called fetal liver kinase-1 (FLK-1)], and transcription factor Fos-related antigen-1 (Fra-1). The FLK-1 and Fra-1 vaccines are effective in suppressing angiogenesis in the tumor vasculature. All four vaccines are capable of inducing potent cell-mediated protective immunity, breaking peripheral T-cell tolerance against these self-antigens resulting in effective suppression of tumor growth and metastasis. It is anticipated that such research efforts will contribute toward the rational design of future DNA vaccines that will be effective for prevention and treatment of human cancer. [source] Glioblastoma cells incorporate into tumor vasculature and contribute to vascular radioresistanceINTERNATIONAL JOURNAL OF CANCER, Issue 9 2010Candice A. Shaifer Abstract Glioblastoma multiforme (GBM) remains the most devastating neoplasm of the central nervous system and has a dismal prognosis. Ionizing radiation represents an effective therapy for GBM, but radiotherapy remains only palliative because of radioresistance. In this study, we demonstrate that glioma cells participate in tumor vascularization and contribute to vascular radioresistance. Using a 3-dimensional coculture system, we observed an intimate interaction of glioma cells with endothelial cells whereby endothelial cells form vascular structures, followed by the recruitment and vascular patterning of glioma cells. In addition, tumor cells stabilize the vascular structures and render them radioresistant. Blocking initial endothelial vascular formation with endothelial-specific inhibitors prevented tumor cells from forming any structures. However, these inhibitors exhibited minimum effects on vascular structures formed by tumor cells, due to the absence of the targeted receptors on tumor cells. Consistent with the in vitro findings, we show that glioma cells form perfused blood vessels in xenograft tumor models. Together, these data suggest that glioma cells mimic endothelial cells and incorporate into tumor vasculature, which may contribute to radioresistance observed in GBM. Therefore, interventions aimed at the glioma vasculature should take into consideration the chimeric nature of the tumor vasculature. [source] Detection of different tumor growth kinetics in single transgenic mice with oncogene-induced mammary carcinomas by flat-panel volume computed tomographyINTERNATIONAL JOURNAL OF CANCER, Issue 1 2009Katharina Jannasch Abstract Transgenic mouse models offer an excellent opportunity for studying the molecular basis of cancer development and progression. Here we applied flat-panel volume computed tomography (fpVCT) to monitor tumor progression as well as the development of tumor vasculature in vivo in a transgenic mouse model for oncogene-induced mammary carcinogenesis (WAP-T mice). WAP-T mice develop multiple mammary carcinomas on oncogene induction within 3 to 5 months. Following induction, 3-dimensional fpVCT data sets were obtained by serial single scans of entire mice in combination with iodine containing contrast agents and served as basis for precise measurements of tumor volumes. Thereby, we were able to depict tumors within the mammary glands at a very early stage of the development. Tumors of small sizes (0.001 cm3) were detected by fpVCT before being palpable or visible by inspection. The capability to determine early tumor onset combined with longitudinal noninvasive imaging identified diverse time points of tumor onset for each mammary carcinoma and different tumor growth kinetics for multiple breast carcinomas that developed in single mice. Furthermore, blood supply to the breast tumors, as well as blood vessels around and within the tumors, were clearly visible over time by fpVCT. Three-dimensional visualization of tumor vessels in high resolution was enhanced by the use of a novel blood pool contrast agent. Here, we demonstrate by longitudinal fpVCT imaging that mammary carcinomas develop at different time points in each WAP-T mouse, and thereafter show divergent growth rates and distinct vascularization patterns. © 2009 UICC [source] Disparity between prostate tumor interior versus peripheral vasculature in response to verteporfin-mediated vascular-targeting therapyINTERNATIONAL JOURNAL OF CANCER, Issue 3 2008Bin Chen Abstract Photodynamic therapy (PDT) is a light-based cancer treatment modality. Here we employed both in vivo and ex vivo fluorescence imaging to visualize vascular response and tumor cell survival after verteporfin-mediated PDT designed to target tumor vasculature. EGFP-MatLyLu prostate tumor cells, transduced with EGFP using lentivirus vectors, were implanted in athymic nude mice. Immediately after PDT with different doses of verteporfin, tumor-bearing animals were injected with a fluorochrome-labeled albumin. The extravasation of fluorescent albumin along with tumor EGFP fluorescence was monitored noninvasively with a whole-body fluorescence imaging system. Ex vivo fluorescence microscopy was performed on frozen sections of tumor tissues taken at different times after treatment. Both in vivo and ex vivo imaging demonstrated that vascular-targeting PDT with verteporfin significantly increased the extravasation of fluorochrome-labeled albumin in the tumor tissue, especially in the tumor periphery. Although PDT induced substantial vascular shutdown in interior blood vessels, some peripheral tumor vessels were able to maintain perfusion function up to 24 hr after treatment. As a result, viable tumor cells were typically detected in the tumor periphery in spite of extensive tumor cell death. Our results demonstrate that vascular-targeting PDT with verteporfin causes a dose- and time-dependent increase in vascular permeability and decrease in blood perfusion. However, compared to the interior blood vessels, peripheral tumor blood vessels were found less sensitive to PDT-induced vascular shutdown, which was associated with subsequent tumor recurrence in the tumor periphery. © 2008 Wiley-Liss, Inc. [source] Inhibition of telomerase in the endothelial cells disrupts tumor angiogenesis in glioblastoma xenograftsINTERNATIONAL JOURNAL OF CANCER, Issue 6 2008Maria Laura Falchetti Abstract Tumor angiogenesis is a complex process that involves a series of interactions between tumor cells and endothelial cells (ECs). In vitro, glioblastoma multiforme (GBM) cells are known to induce an increase in proliferation, migration and tube formation by the ECs. We have previously shown that in human GBM specimens the proliferating ECs of the tumor vasculature express the catalytic component of telomerase, hTERT, and that telomerase can be upregulated in human ECs by exposing these cells to GBM in vitro. Here, we developed a controlled in vivo assay of tumor angiogenesis in which primary human umbilical vascular endothelial cells (HUVECs) were subcutaneously grafted with or without human GBM cells in immunocompromised mice as Matrigel implants. We found that primary HUVECs did not survive in Matrigel implants, and that telomerase upregulation had little effect on HUVEC survival. In the presence of GBM cells, however, the grafted HUVECs not only survived in Matrigel implants but developed tubule structures that integrated with murine microvessels. Telomerase upregulation in HUVECs enhanced such effect. More importantly, inhibition of telomerase in HUVECs completely abolished tubule formation and greatly reduced survival of these cells in the tumor xenografts. Our data demonstrate that telomerase upregulation by the ECs is a key requisite for GBM tumor angiogenesis. © 2007 Wiley-Liss, Inc. [source] CNTO 859, a humanized anti-tissue factor monoclonal antibody, is a potent inhibitor of breast cancer metastasis and tumor growth in xenograft modelsINTERNATIONAL JOURNAL OF CANCER, Issue 6 2007Cam V. Ngo Abstract Thromboembolic complications are frequently associated with advanced cancer. Interestingly, one of the major initiators of blood coagulation, tissue factor (TF), is reported to be overexpressed in several tumor types and can be found on both tumor cells and tumor vasculature. Although the exact mechanisms have yet to be elucidated, TF expressed on tumor cells can trigger intracellular signaling events through various pathways that can lead to tumor angiogenesis, proliferation, and metastasis. There exists preclinical evidence that disruption of TF dependent signaling can effectively inhibit tumor cell migration, metastasis, and angiogenesis. Here, we report for the first time that an antibody to tissue factor can also prevent tumor growth in vivo. Prophylactic administration of CNTO 859, a humanized anti-human TF antibody, was shown to inhibit experimental lung metastasis of MDA-MB-231 human breast carcinoma cells by over 99% compared to a control antibody. Furthermore, therapeutic doses of CNTO 859 were shown to reduce tumor incidence and growth of orthotopically implanted MDA-MB-231 cells. © 2006 Wiley-Liss, Inc. [source] Epigallocatechin-3-Gallate Inhibits Photocarcinogenesis Through Inhibition of Angiogenic Factors and Activation of CD8+ T Cells in TumorsPHOTOCHEMISTRY & PHOTOBIOLOGY, Issue 5 2005Sudheer K. Mantena ABSTRACT There has been considerable interest in the use of botanical supplements to protect skin from the adverse effects of solar UV radiation, including photocarcinogenesis. We and others have shown that topical application of (,)-epigallocatechin-3-gallate (EGCG) from green tea prevents photocarcinogenesis in mice; however, the chemopreventive mechanism of EGCG in an in vivo tumor model is not clearly understood. In this study, UV-B-induced skin tumors with and without treatment of EGCG (,1 mg/cm2) and age-matched skin biopsies from SKH-1 hairless mice were used to identify potential molecular targets of skin cancer prevention by EGCG. These biopsies were analyzed for various biomarkers of angiogenesis and antitumor immune response using immunostaining, Western blotting and gelatinolytic zymography. We report that compared to non-EGCG-treated tumors, topical application of EGCG in UV-induced tumors resulted in inhibition of protein expression and activity of matrix metalloproteinase (MMP)-2 and MMP-9, which play crucial roles in tumor growth and metastasis. In contrast, tissue inhibitor of MMP-1 (TIMP-1), which inhibits MMP activity, was increased in tumors. With respect to the tumor vasculature, EGCG decreased the expression of CD31, a cell surface marker of vascular endothelial cells, and inhibited the expression of vascular endothelial growth factor in tumors, which are essential for angiogenesis. EGCG inhibited proliferating cell nuclear antigen in UV-B-induced tumors as well. Additionally, higher numbers of cytotoxic T lymphocytes (CD8+ T cells) were detected in EGCG-treated tumors compared with non-EGCG-treated tumors. Together, these in vivo tumor data suggested that inhibition of photocarcinogenesis in mice by EGCG is associated with inhibition of angiogenic factors and induction of antitumor immune reactivity. [source] Antivascular Tumor Eradication by Hypericin-mediated Photodynamic Therapy,PHOTOCHEMISTRY & PHOTOBIOLOGY, Issue 5 2002Bin Chen ABSTRACT Photodynamic therapy (PDT) with hypericin has been shown to inhibit tumor growth in different tumor models, and tumor vascular damage was suggested to be mainly responsible for the antitumoral effect. Here, we demonstrate tumor vascular damage and its consequence on local tumor control after hypericin-mediated PDT by using both short and long drug,light intervals. Radiation-induced fibrosarcoma-1 tumors were exposed to laser light at either 0.5 or 6 h after a 5 mg/kg dose of hypericin. Tumor perfusion was monitored by fluorescein dye,exclusion assay and by Hoechst 33342 staining of functional blood vessels. Significant reduction in tumor perfusion was found immediately after both PDT treatments. A complete arrest of vascular perfusion was detected by 15 h after the 0.5 h-interval PDT, whereas well-perfused areas could still be found at this time in tumors after the 6 h-interval PDT. A histological study confirmed that primary vascular damage was involved in both PDT treatments. Tumor cells appeared intact shortly after light treatment, degenerated at later hours and became extensively pycnotic at 24 h after the 0.5 h-interval PDT. PDT under this condition led to complete tumor cure. In contrast, significant numbers of viable tumor cells, especially at the tumor periphery, were found histologically at 24 h after the 6 h-interval PDT. No tumor cure was obtained when PDT was performed at this time. Our results strongly suggest that targeting the tumor vasculature by applying short drug,light interval PDT with hypericin might be a promising way to eradicate solid tumors. [source] Development and characterization of a synthetic promoter for selective expression in proliferating endothelial cellsTHE JOURNAL OF GENE MEDICINE, Issue 4 2006P. Szymanski Abstract Background Systemic administration of non-viral gene therapy provides better access to tumors than local administration. Development of a promoter that restricts expression of cytotoxic proteins to the tumor vasculature will increase the safety of the system by minimizing expression in the non-dividing endothelial cells of the vasculature of non-target tissues. Methods Cell cycle promoters were tested for selective expression in dividing cells vs. non-dividing cells in vitro and promoter strength was compared to the cytomegalovirus (CMV) promoter. Successful promoter candidates were tested in vivo using two proliferating endothelium mouse models. Ovarectomized mice were injected with estradiol prior to lipoplex administration and expression levels were measured in the lungs and uterus 4 days after administration. The second model was a subcutaneous tumor model and expression levels were measured in the lungs and tumors. For both animal models, expression levels from the proliferating endothelium promoter were compared to that obtained from a CMV promoter. Results The results showed that the Cdc6 promoter yielded higher expression in proliferating vs. non-proliferating cells. Secondly, promoter strength could be selectively increased in endothelial cells by the addition of a multimerized endothelin enhancer (ET) to the Cdc6 promoter. Thirdly, comparison of expression levels in the lungs vs. uterus in the ovarectomized mouse model and lungs vs. tumor in the mouse tumor model showed expression was much higher in the uterus and the tumor than in the lungs for the ET/Cdc6 promoter, and expression levels were comparable to that of the CMV promoter in the hypervascularized tissues. Conclusions These results demonstrate that the combination of the endothelin enhancer with the Cdc6 promoter yields selective expression in proliferating endothelium and can be used to express cytotoxic proteins to treat vascularized tumors. Copyright © 2006 John Wiley & Sons, Ltd. [source] Enhanced antitumor efficacy of folate-linked liposomal doxorubicin with TGF-, type I receptor inhibitorCANCER SCIENCE, Issue 10 2010Yukimi Taniguchi Tumor cell targeting of drug carriers is a promising strategy and uses the attachment of various ligands to enhance the therapeutic potential of chemotherapy agents. Folic acid is a high-affinity ligand for folate receptor, which is a functional tumor-specific receptor. The transforming growth factor (TGF)-, type I receptor (T,R-I) inhibitor A-83-01 was expected to enhance the accumulation of nanocarriers in tumors by changing the microvascular environment. To enhance the therapeutic effect of folate-linked liposomal doxorubicin (F-SL), we co-administrated F-SL with A-83-01. Intraperitoneally injected A-83-01-induced alterations in the cancer-associated neovasculature were examined by magnetic resonance imaging (MRI) and histological analysis. The targeting efficacy of single intravenous injections of F-SL combined with A-83-01 was evaluated by measurement of the biodistribution and the antitumor effect in mice bearing murine lung carcinoma M109. A-83-01 temporarily changed the tumor vasculature around 3 h post injection. A-83-01 induced 1.7-fold higher drug accumulation of F-SL in the tumor than liposome alone at 24 h post injection. Moreover F-SL co-administrated with A-83-01 showed significantly greater antitumor activity than F-SL alone. This study shows that co-administration of T,R-I inhibitor will open a new strategy for the use of FR-targeting nanocarriers for cancer treatment. (Cancer Sci 2010); 00: 000,000 [source] Antitumor effect of photodynamic therapy with chlorin-based photosensitizer DH-II-24 in colorectal carcinomaCANCER SCIENCE, Issue 12 2009Young-Cheol Lim While photodynamic therapy (PDT) has been recognized as a promising therapeutic modality for the treatment of various cancers and diseases, developments of effective photosensitizers are highly desired to improve the prospect for the use of PDT. In this study, we evaluated DH-II-24, a new photosensitizer, for antitumor PDT in vitro and in vivo. Loaded into human colorectal carcinoma cells (HCT116), DH-II-24 was primarily accumulated in mitochondria, lysosomes, and endoplasmic reticula. Administration of DH-II-24 followed by light exposure induced necrotic cell death in a dose-dependent manner, whereas DH-II-24 in the absence of light induced minimal cell death. In order to investigate the distribution and phamacokinetics of the photosensitizer in vivo, DH-II-24 was intravenously injected to female BALB/c nude mice. Fluorescence imaging in vivo showed that DH-II-24 was rapidly distributed across the entire body and then mostly eliminated at 24 h. Next, effectiveness of DH-II-24-mediated PDT was examined on colorectal carcinoma xenografts established subcutaneously in BALB/c nude mice. DH-II-24 (1 mg/kg, i.v. administration) followed by light exposure significantly suppressed growth of xenograft tumors, compared to light exposure or DH-II-24 alone. Histological examination revealed necrotic damage in PDT-treated tumors, concomitantly with severe damage of tumor vasculature. These results suggest that DH-II-24 is a potential photosensitizer of photodynamic therapy for cancer. (Cancer Sci 2009; 100: 2431,2436) [source] Antivascular effects of TZT-1027 (Soblidotin) on murine Colon26 adenocarcinomaCANCER SCIENCE, Issue 12 2006Junichi Watanabe We investigated the ability of TZT-1027 (Soblidotin), a novel antimicrotubule agent, to induce antivascular effects, because most vascular targeting agents that selectively disrupt tumor vasculature also inhibit tubulin polymerization. Treatment with 10,7 g/mL TZT-1027 rapidly disrupted the microtubule cytoskeleton in human umbilical vascular endothelial cells (HUVEC), and significantly enhanced vascular permeability in HUVEC monolayers. In addition, single intravenous administration of 2 mg/kg TZT-1027 to mice bearing Colon26 tumors significantly reduced tumor perfusion and caused extravascular leakage of erythrocytes 1 h after administration. Subsequently, thrombus formation with deposition of fibrin and tumor necrosis was observed 3 and 24 h after administration, respectively. These results strongly suggest that TZT-1027 possesses antivascular effects. TZT-1027 induced apoptosis not only in HUVEC but also in C26 cancer cells (cell line of Colon26 solid tumor) in vitro, suggesting it exerts direct cytotoxicity against tumor cells in addition to its antivascular effects. A single intravenous administration of 1, 2 and 4 mg/kg TZT-1027 significantly prolonged the survival of mice with advanced-stage Colon26 tumors in a dose-dependent manner. Furthermore, TZT-1027 itself less markedly enhanced the permeability of normal vessels, but was additive with vascular endothelial growth factor, indicating the possibility that TZT-1027 selectively exerts its activity on tumor vessels. In summary, these results suggest that TZT-1027 exerts both an indirect antivascular effect and a direct cytotoxic effect, resulting in strong antitumor activity against advanced-stage tumors, and that TZT-1027 may be useful clinically for treating solid tumors. (Cancer Sci 2006; 97: 1410,1416) [source] Molecular mechanisms of angiogenesis in non-small cell lung cancer, and therapeutics targeting related moleculesCANCER SCIENCE, Issue 6 2003Seiji Yano Angiogenesis, neovascularization from pre-existing vasculature, is necessary to supply oxygen and nutrition for tumor growth in both primary and distant organs. It consists of sprouting and non-sprouting (the enlargement, splitting, and fusion of pre-existing vessels) processes, and both can occur concurrently. Growth of solid tumors, including non-small cell lung cancer (NSCLC), is usually dependent on angiogenesis, which is regulated by complex mechanisms involving various angiogenesis-related molecules. Vascular endothelial growth factor (VEGF), also known as vascular permeability factor (VPF), one of the most potent angiogenic molecules, regulates both angiogenesis and vascular permeability, and hence promotes tumor progression and development of malignant pleural effusions in NSCLC. Signals via epidermal growth factor receptor (EGFR) promote not only the tumor cell cycle, but also the process of angiogenesis. Therefore, these molecules are potential targets for anti-tumor vasculature therapy. Many agents targeting tumor vasculature have been developed, and several compounds have shown anti-tumor potential in pre-clinical studies. Their efficacy against NSCLC is currently being evaluated in clinical trials. [source] Pharmaceutical and Biomedical Differences between Micellar Doxorubicin (NK911) and Liposomal Doxorubicin (Doxil)CANCER SCIENCE, Issue 10 2002Yoshihisa Tsukioka The stability and biological behavior of an in vitro system of doxorubicin (DXR) entrapped in NK911, polymer micelles, was examined and compared with those of DXR entrapped in Doxil, polyethylene-glycol-conjugated liposomes. The fluorescence of DXR inside micelles or liposomes in an aqueous solution is known to be strongly quenched by the outer shells of the micellar or liposomal formation. Thus, by measuring the fluorescence intensity of DXR released from NK911 or Doxil, we could determine the stability of the micellar or liposomal DXR formation. Furthermore, NK911 was found to be less stable than Doxil in saline solution. In drug distribution experiments using an in vitro solid tumor model, when spheroids formed from two human colonic cancer lines, HT-29 and WiDr, and a human stomach cancer line, MKN28, were exposed to NK911, DXR was distributed throughout the spheroids, including their center. On the other hand, when the spheroids were exposed to Doxil, DXR was distributed only to the surface of the spheroids. It has been suggested that Doxil can deliver DXR to a solid tumor more efficiently than NK911 via the EPR (enhanced permeability and retention) effect, because Doxil may be more stable in plasma than NK911. On the other hand, DXR packed in NK911 may be distributed by diffusion to cancer cells distant from the tumor vessel, because NK911 can leak out of the tumor vessel and may be able to release free DXR more easily than Doxil. It has been suggested that drug carrier systems such as liposomes and micelles should be selected appropriately bearing in mind the characteristics of the tumor vasculature and the tumor interstitium. [source] | |||||||||||||||||||||||||