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Jang, Soomin; Wientjes, M. Guillaume; Lü, Dan; Au, Jessie L.-S.

doi:10.1023/a:1025785505977

Cited by 423 publications

(166 citation statements)

References 98 publications

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“…Another factor is a collagen-rich and stiff extracellular matrix (5). Some of these barriers also can affect the entry of standard low-molecular-weight chemotherapeutic agents (6). One way to improve the uptake of antibodies by tumors is to administer large amounts, achieving high blood levels.…”

mentioning

confidence: 99%

Immunotoxin and Taxol synergy results from a decrease in shed mesothelin levels in the extracellular space of tumors

Zhang

Xiang²,

Hassan³

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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Recombinant immunotoxins are chimeric proteins composed of the Fv portion of a tumor-specific antibody fused to a toxin. SS1P (CAT-5001) is an immunotoxin composed of an antimesothelin Fv fused to a 38-kDa portion of Pseudomonas exotoxin A. Immunotoxins have been shown to be active in lymphomas and leukemias, but are much less active against solid tumors. We recently reported that Taxol and other chemotherapeutic agents show striking synergistic antitumor activity in mice when immunotoxin SS1P, which targets the mesothelin antigen on solid tumors, is given with Taxol. Using a pair of Taxol-sensitive and Taxol-resistant KB tumors equally sensitive to immunotoxin SS1P, we examined the mechanism of synergy. We show that synergy is only observed with Taxol-sensitive tumors, ruling out an effect of Taxol on endothelial cells. We also show that the KB tumors have high levels of shed mesothelin in their extracellular space; these levels increase with tumor size and, after Taxol treatment, dramatically fall in the drug-sensitive but not the drug-resistant tumors. Because the mesothelin levels in the tumor exceed the levels of SS1P in the tumor, and because shed mesothelin is being continuously released into the circulation at a high rate, we propose that synergy is due to the Taxol-induced fall in shed antigen levels.chemotherapy ͉ drug resistance ͉ immunotherapy ͉ mesothelioma ͉ ovarian cancer A ntibody-based therapies now play an important role in cancer treatment. These therapies include humanized or fully human unmodified antibodies, as well as antibodies used to deliver toxic payloads such as radioisotopes, toxins, and lowmolecular-weight cytotoxic drugs (1, 2). One well recognized impediment to effective antibody-based therapy is tumor penetration. Several factors contribute to this poor penetration, including a defective vasculature characterized by abnormal blood vessels, a lack of functional lymphatics so that proteins can only enter slowly by diffusion, and elevated interstitial fluid pressure generating an outward flow of fluid. There also is a site barrier limiting the entry of antibodies and other antibody-based therapeutics caused by the binding of antibodies to the first layer of cells they encounter as they leave capillaries within the tumors (3, 4). Another factor is a collagen-rich and stiff extracellular matrix (5). Some of these barriers also can affect the entry of standard low-molecular-weight chemotherapeutic agents (6). One way to improve the uptake of antibodies by tumors is to administer large amounts, achieving high blood levels. However, this strategy cannot be used with immunoconjugates and immunotoxins because the cytotoxic payload produces side effects not observed with naked antibodies (7,8). To improve the efficacy of antibody-based therapies, they have been combined with chemotherapy, and striking increases in antitumor activity have been observed (9-12).Recombinant immunotoxins are genetically engineered proteins composed of the Fv portion of an antibody fused to a bacterial or plant t...

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mentioning

confidence: 99%

Immunotoxin and Taxol synergy results from a decrease in shed mesothelin levels in the extracellular space of tumors

Zhang

Xiang²,

Hassan³

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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“…Culturing of 3D cell cultures known as Multicell Spheroids (MCS), have become a preferred means to study and simulate an in-vivo environment [1]. 3D cell cultures with resembling structural and functional properties to real tissues has helped in understanding growth of tumorous, effects and penetration of toxins within a tissue and developing targeted drugdelivery systems [2][3][4].…”

Section: Introductionmentioning

confidence: 99%

Nanomechanical Analysis of Extracellular Matrix and Cells in Multicellular Spheroids

Vyas

Solomon

D’Souza

et al. 2017

Preprint

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Nanomechanical investigation with Atomic Force Microscope has revealed new details regarding various nanomechanical heterogeneities for cells that are embedded in extracellular matrix in Multicellular spheroidal culture. This investigation sheds new insight into dynamic relationship of cells with their surrounding environment in tumors and 3D multicellular cultures.Nanotechnology has revolutionized the field of cancer biology and has opened new avenues towards understanding nanomechanical variations in rapidly growing tumors. Over the last decade Atomic Force Microscope (AFM) has played an important role in understanding nanomechanical properties of various cancer cell lines. This study is focused on Lewis Lung Carcinoma Cell (LLC) tumors as 3D multicellular spheroid (MS). Such multicellular structures have enabled investigation of various components of tumors in-vitro. To better comprehend mechanical properties of cells and its surrounding extracellular matrix (ECM), depth dependent indentation measurements were conducted with Atomic Force Microscope (AFM). Force-vs-indentation curves were used to create stiffness profiles as function of depth. Here studies were focused on outer most layer i.e. proliferation zone of the spheroid. AFM investigations of sample a MS revealed three nanomechanical topographies, Type A- high modulus due to collagen stress fibers, Type B- high stiffness at cell membrane & ECM interface and Type C - increased modulus due to cell lying deep inside matrix at the a depth of 1.35 microns. Various nanomechanical heterogeneities revealed in this investigation can shed new light in developing correct dosage regime for various tumor dissolving drugs and designing more controlled artificial extracellular matrix systems for replicating tissue growth in-vitro.Short Statistical SummaryThis article describes nanomechanical characteristics of the cells embedded in extracellular matrix in a multicellular spheroid. The paper contains 6350 words including title page and references. Graphical Content contains 46 words. This article contains 6 Figures and zero tables.

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“…Drug penetration into the tumor from the vasculature is limited by a relatively constant pressure throughout the tumor bulk, meaning that diffusion dominates convection in this context. Since large molecules do not readily diffuse, the distribution is localized, and particles are more likely to get trapped in the matrix 31,32 . However, it should be noted that tumor heterogeneity could yield a moderate amount of drug penetration depending on the distribution of vasculature and the shape of the tumor 33 .…”

Section: Physical Barriers To Therapeutic Efficacymentioning

confidence: 99%

“…Specifically, convection is dominant in these tissues when the molecular weight of the solute is significantly large, while diffusion dominates with very small particles 32 . This rationale was further used to explore the transport effects of large molecules within the tumor interstitium and corresponding implications for antibody-based drug delivery 30 .…”

Section: Drug Transport In the Tumor Microenvironmentmentioning

confidence: 99%

“…Systemic chemotherapeutic delivery has been limited, first and foremost, by transport restrictions to and within tumors 32 . Specifically, the tumor microenvironment (TME), defined as the tumor cells, tumor-associated cells, extracellular matrix, and biomechanical forces 1,2 , that interact in and around the tumor, provides two distinct barriers to drug delivery.…”

Section: Introductionmentioning

confidence: 99%

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Agent-Based Models of the Tumor Microenvironment: Predicting Flow-Mediated Invasion and Cancer Viability in Response to Interstitial Flow, Chemotherapy, and Stromal Cell Density

Logsdon¹

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Abstract: The effectiveness of cancer therapy depends in part on adequate delivery of the therapeutic agents to tumor cells. A better understanding of the processes and contribution of these factors governing drug delivery may lead to new cancer therapeutic strategies.

Cited by 423 publications

References 98 publications

Immunotoxin and Taxol synergy results from a decrease in shed mesothelin levels in the extracellular space of tumors

Immunotoxin and Taxol synergy results from a decrease in shed mesothelin levels in the extracellular space of tumors

Nanomechanical Analysis of Extracellular Matrix and Cells in Multicellular Spheroids

Agent-Based Models of the Tumor Microenvironment: Predicting Flow-Mediated Invasion and Cancer Viability in Response to Interstitial Flow, Chemotherapy, and Stromal Cell Density

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