Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0035412 (rhabdomyosarcoma)
 6,156 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The delivery of cell-specific protein toxins to the interstitium of solid tumors was examined in athymic mice bearing s.c. human rhabdomyosarcoma (TE671) tumors. The toxins are diphtheria toxin (DT), Mr = 60,000, and an immunotoxin, Mr = 210,000. The immunotoxin is a chemical conjugate of a mutant DT defective in binding and a monoclonal antibody specific for the human transferrin receptor. The plasma, tumor, and muscle concentrations of DT, immunotoxin, and closely related nonbinding controls were measured 2, 6, and 24 h after i.v. injection into tumor-bearing mice. Both DT and immunotoxin are specific for the human xenograft in the mouse because DT is very toxic to human cells but not to murine cells and immunotoxin is directed against a human cell receptor. A compartmental pharmacokinetic model was developed for the analysis of the in vivo data to provide plasma-to-tissue transport constants (capillary permeability-area products), binding parameters (products of the association constant and the initial binding site concentration), and the interstitial fluid flow rate. The model also provides a simple mathematical framework for understanding the effect of these variables on the localization of macromolecules in tumors. The plasma-to-tissue transport constant of immunotoxin in TE671 tumor was 0.13 microliters/min/g, compared to 0.29 microliters/min/g for DT. However, despite the lower capillary permeability of the larger molecular weight toxin, the cumulative tumor exposure to immunotoxin was 80% higher than that to DT after 24 h. A longer plasma half-life and higher apparent in vivo binding parameter of immunotoxin compared to DT contributed to the higher tumor exposure. Plasma-to-tissue transport constants for tumor were 60 to 100% higher than those for muscle. This finding is consistent with observations by others that tumor vasculature is more permeable than are normal muscle capillaries. Also, the interstitial fluid flow of the tumor, 0.80 microliters/min/g, was higher than that of muscle, 0.58 microliters/min/g. The product of the binding affinity and binding site concentration for immunotoxin in vivo was 530 times lower than that predicted based on in vitro measurements. Lower expression of antigen binding sites, inaccessibility of binding sites in vivo, and degradation of the toxin are several possible factors that may account for the in vitro-in vivo differences in binding. This study illustrates the interrelationship of plasma kinetics, capillary permeability, and binding and their effects on toxin concentrations that are achieved in the tissue interstitium.
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PMID:Pharmacokinetic analysis of immunotoxin uptake in solid tumors: role of plasma kinetics, capillary permeability, and binding. 222 66

Cell loss patterns of five tumors and their histological findings were investigated in WHT/Ht strain mice. The tumors investigated were squamous cell carcinoma H, squamous cell carcinoma NOS, squamous cell carcinoma TAK, rhabdomyosarcoma KAS, and fibrosarcoma YAS. The present study revealed that histological findings of tumor tissues are not necessarily corded structure presented by Thomlinson and Gray. The five were divided into two groups according to their histological findings, i.e. a corded structure (squamous carcinoma H and NOS) and a non-corded structure (squamous cell carcinoma TAK, rhabdomyosarcoma KAS and fibrosarcoma YAS). The cell loss patterns (125I-iododeoxyuridine retention curves) were also divided into two groups which corresponded to the histological structures. Two tumors with the corded structure (squamous cell carcinoma H and NOS) have a cell loss pattern with a constant shoulder portion (a migration time of tumor cells through a tumor cord from capillary to necrotic region). In these tumors, the cell loss occurred in the necrotic regions. In the other tumors with the non-corded structure, cell loss curves have no constant shoulder portion and cell loss might occur throughout the tumor. The origin of hypoxic cells in these two types of histology are presumably different. The diffusion-limited hypoxia, i.e. chronically hypoxic cells, may be the main cause for the tumors with corded structure. On the other hand, hypoxia as a result of temporary cessation of blood flow within the tumor vasculature, i.e. acutely hypoxic cells, may mainly occur in the tumor with non-corded structure.
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PMID:Two different types of cell loss patterns of murine tumors and their corresponding histological findings and possible mechanisms of production of hypoxic cells. 850 92

We have previously demonstrated that vascular endothelial growth factor-165 (VEGF), a tumor-secreted angiogenic factor, can acutely and chronically induce fenestrations in microvascular endothelium (Cancer Res 1997, 57:765-772). Because the morphology and function of microvascular endothelium differs from tissue to tissue, we undertook studies to examine whether the neovasculature in tumors also differed depending upon tumor location. Four tumor types implanted in the brain or subcutis in nude mice were studied: a murine rhabdomyosarcoma (M1S), a murine mammary carcinoma (EMT), and two human glioblastomas (U87 and U251). In addition, we studied Chinese hamster ovary cells stably transfected with human VEGF165. As previously reported, tumors grown in the subcutaneous space had a microvasculature that was fenestrated and had open endothelial gaps. The identical tumors when grown in the brain also had fenestrated endothelium and vessels with open endothelial gaps, but they were drastically reduced in occurrence. Open endothelial gaps were not seen in all tumors implanted in the brain (EMT and M1S), although fenestrated endothelium was always seen. VEGF and VEGF receptors were measured in tumors from both locations by immunoblotting and competitive polymerase chain reaction, respectively. VEGF amount was not significantly different between the tumor locations. Interestingly, total tumor vascular mRNA expression of both Flk-1 and Flt-1 was greater in tumor vessels derived from the brain compared with tumor vessels derived from subcutaneous tissues. These results demonstrate that the host microvascular environment determines the morphology and function of the tumor vasculature and that endothelia from different tissues vary in their ability to express the VEGF receptors given identical stimuli.
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PMID:Host microvasculature influence on tumor vascular morphology and endothelial gene expression. 977 55

In 1999, Maniotis described a novel process by which tumors develop a highly patterned microcirculation that was independent of angiogenesis: in aggressive primary and metastatic melanomas, tumor cells generate non-endothelial cell-lined microcirculatory channels composed of extracellular matrix and lined externally by tumor cells. They named the process "vasculogenic mimicry" (VM). Folberg used PAS staining to show VM network, and identified 7 morphologic patterns of PAS-positive channels uveal melanomas which were confirmed as tubular type and patterned matrix type. Maniotis suggested PAS-positive patterns of VM in uveal melanoma are indeed a form of tumor microcirculation which is different from angiogenesis, and it is not a stromal host response at the interface between the tumor and the surrounding host stroma. VM has also been observed in carcinomas of the breast, prostate, ovary and lung, glioblastoma, synoviosarcoma, rhabdomyosarcoma, and phaeochromocytoma, and in the process of placenta formation from cytotrophoblasts. The molecular "signature" of aggressive melanoma cells is illustrative of an undifferentiated cell with a gene expression profile that is similar to that of embryonic-like cells. VE-cadherin, EphA2, laminin5 gamma2, matrix metalloproteinases (MMPs), vascular endothelial growth factor-C (VEGF-C), LYVE1, TF and NOTCH are important components of molecular switch of vasculogenic mimicry. The heterogeneity of tumor vasculature and the molecular regulation mechanisms present an opportunity for tumor therapy.
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PMID:[Vasculogenic mimicry--potential target for tumor therapy]. 1683 Dec 90

Ionizing radiation is an important component of multimodal therapy for alveolar rhabdomyosarcoma (ARMS). We sought to evaluate the ability of IFN-beta to enhance the activity of ionizing radiation. Rh-30 and Rh-41 ARMS cells were treated with IFN-beta and ionizing radiation to assess synergistic effects in vitro and as orthotopic xenografts in CB17 severe combined immunodeficient mice. In addition to effects on tumor cell proliferation and xenograft growth, changes in the tumor microenvironment including interstitial fluid pressure, perfusion, oxygenation, and cellular histology were assessed. A nonlinear regression model and isobologram analysis indicated that IFN-beta and ionizing radiation affected antitumor synergy in vitro in the Rh-30 cell line; the activity was additive in the Rh-41 cell line. In vivo continuous delivery of IFN-beta affected normalization of the dysfunctional tumor vasculature of both Rh-30 and Rh-41 ARMS xenografts, decreasing tumor interstitial fluid pressure, increasing tumor perfusion (as assessed by contrast-enhanced ultrasonography), and increasing oxygenation. Tumors treated with both IFN-beta and radiation were smaller than control tumors and those treated with radiation or IFN-beta alone. Additionally, treatment with high-dose IFN-beta followed by radiation significantly reduced tumor size compared with radiation treatment followed by IFN-beta. The combination of IFN-beta and ionizing radiation showed synergy against ARMS by sensitizing tumor cells to the cytotoxic effects of ionizing radiation and by altering tumor vasculature, thereby improving oxygenation. Therefore, IFN-beta and ionizing radiation may be an effective combination for treatment of ARMS.
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PMID:IFN-beta restricts tumor growth and sensitizes alveolar rhabdomyosarcoma to ionizing radiation. 2019 2