Preferential radioprotection to DNA of normal tissues by ferulic acid under ex vivo and in vivo conditions in tumor bearing mice

2006 ◽  
Vol 285 (1-2) ◽  
pp. 181-190 ◽  
Author(s):  
Dharmendra Kumar Maurya ◽  
Cherupally Krishnan Krishnan Nair
Keyword(s):  
Ferulic Acid ◽  
Ex Vivo ◽  
Normal Tissues ◽  
Tumor Bearing

Clinical Evaluation of Radio-Labelled Bleomycin for Tumor Detection

1978 ◽  
Vol 17 (06) ◽  
pp. 238-248
Author(s):  
H. Beekhuis ◽  
M.A.P.C. van de Poll ◽  
A. Versluis ◽  
H. Jurjens ◽  
M.G. Woldring ◽  
...  
Keyword(s):  
Clinical Evaluation ◽  
Acidic Solution ◽  
Tumor Detection ◽  
Neutral Solution ◽  
Normal Tissues ◽  
Patients With Cancer ◽  
Tumor Bearing

Investigations with bleomycin labelled with radionuclides other than 57Co in patients with cancer and in tumor-bearing animals are described. In patients 57Co-bleo appears to be a better tumor-seeking radiopharmaceutical than 111In-bleo, 99mTc-bleo or 197Hg-bleo. This can be explained by a higher stability in vivo and a better tumor-seeking property of 57Co-bleo and less disturbing activity in the cardiac pool and in bone and other normal tissues when assessing the scintigram.Results with 111In-bleo labelled in acidic solution are not essentially different from those with 111In-bleo labelled in neutral solution.Results of 197Hg-bleo are almost identical with those of 197HgCl2 regarding the tumor-seeking effect as well as the distribution in normal tissues and organs. Probably the complex of 197Hg to bleomycin is not stable in vivo. The superiority of 57Co-bleo over 99mTc-bleo, 197Hg-bleo and also over 67Cu-bleo is confirmed by experiments on tumor bearing animals.We may conclude that the indication for use of bleomycin as a tumor-seeking pharmaceutical labelled with 111In, 99mTc, 197Hg or 67Cu seems to be very limited.

IMMU-29. B-CELL-BASED VACCINE PRODUCES GLIOBLASTOMA-REACTIVE ANTIBODIES THAT CONTRIBUTE TO TUMOR CLEARANCE

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi98-vi98
Author(s):  
Brandyn Castro ◽  
Mark Dapash ◽  
David Hou ◽  
Aida Rashidi ◽  
Deepak Kanojia ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Humoral Immunity ◽  
Ex Vivo ◽  
Murine Models ◽  
Effector Functions ◽  
Tumor Bearing ◽  
Tumor Clearance ◽  
Cellular And Humoral Immunity

Abstract Glioblastomas (GBM) are characterized by a strong immunosuppressive environment, contributing to their poor prognosis and limited therapeutic response to immunotherapies. B-cells represent a unique opportunity to promote immunotherapy due to their potential to kill tumors by both cellular and humoral immunity. To generate our B-cell-based vaccine (BVax) platform, we activated 41BBL+ B cells from tumor bearing mice or GBM patient blood with BAFF, CD40, and IFNg. We have previously demonstrated that BVax potentiates radiation therapy, temozolomide and checkpoint blockade in murine models of GBM via enhancement of CD8+ T-cell based immunity. The aim of this current study is to evaluate the humoral effector functions of BVax. We examined the antibody (Ab) repertoire in vivo from serum of tumor-bearing B-cell knockout mice treated with BVax or by ex vivo stimulation of patient-derived BVax. Upon systemic administration, BVax infiltrates the tumor where it differentiates into plasmablasts. Murine BVax- and BNaive-derived serum immunoglobulin generated in vivo showed that the majority of murine BVax-derived Ab were IgG isotype, while BNaive mainly produced IgM isotype. Transfer of IgG from BVax treated mice directly into tumors of recipient animals significantly prolonged their survival, demonstrating anti-tumor cytotoxicity directly through humoral immunity. Patient-derived BVax activated ex vivo showed a plasmablast phenotype and the Ab repertoire supports the previous findings seen in our murine model. Our work suggests BVax-derived IgGs role in antibody-dependent cellular cytotoxicity and improved survival in murine models. This function, in addition to its role in cellular immunity against GBM, renders BVax a potentially effective alternative immunotherapeutic option for GBM patients.

T-cell redirected killing and cure of pancreatic and gastric cancer xenografts by targeting Trop-2.

2015 ◽  
Vol 33 (3_suppl) ◽  
pp. 262-262
Author(s):  
David M. Goldenberg ◽  
Edmund A. Rossi ◽  
Diane L Rossi ◽  
Thomas M. Cardillo ◽  
Chien-Hsing Chang
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Ex Vivo ◽  
Control Group ◽  
Calcium Signal ◽  
Target Cells ◽  
Normal Tissues

262 Background: Trop-2 [also called tumor-associated calcium signal transducer 2 (TACSTD2), EGP-1 (epithelial glycoprotein-1), GA733-1, or M1S1]is a 35 kDa transmembrane glycoprotein that is overexpressed relative to normal tissues in a variety of human cancers, including pancreatic and gastric carcinomas, where increased expression correlates with poor prognosis. Trop-2 appears to be more tumor-specific than the related molecule, EpCAM (Trop-1). MT110, the EpCAM antibody x CD3 bispecific T-cell engager (BiTE), is currently undergoing a Phase I study in various solid tumors, including lung, gastric, colorectal, breast, prostate, and ovarian cancers. We produced a similar T-cell redirecting bispecific tandem scFv, E1-3, using the variable domains of hRS7 (humanized anti-Trop-2 mAb) and Okt-3 (anti-CD3 mAb). Methods: T-cell activation, cytokine induction and cytotoxicity were evaluated ex vivo using PBMCs or purified T cells with human pancreatic (Capan-1 and BxPC3) and gastric (NCI-N87) cancer cell lines as target cells. In vivo activity was assayed with NCI-N87 xenografts that were inoculated s.c. in a mixture with twice the number of human PBMCs and matrigel. Results: In the presence of target cells and PBMCs, E1-3 potently induced T-cell activation, proliferation, and dose-dependent cytokine production of IL-2 (>2 ng/mL), IL-6 (>1 ng/mL), IL-10 (>7 ng/mL), TNF-α (>1 ng/mL) and IFN-γ (>50 ng/mL). In vitro, E1-3 mediated a highly potent T-cell lysis of BxPC3 [IC50=0.09(±0.04) pM], Capan-1 [IC50=1.2(±1.1) pM] and NCI-N87 [IC50=1.2(±1.2) pM] target cells. In vivo, two 50-µg doses of E1-3 given three days apart cured all of the mice (N=8) bearing NCI-N87 xenografts (P=0.0005; Log-Rank). Tumors in the control group (PBMCs only) reached the endpoint (TV>1 cm3) with a median of 39.5 days. All mice remained tumor-free in the E1-3 group at 78 days. Conclusions: Trop-2 is an attractive target for T-cell-mediated killing of pancreatic, gastric and other epithelial cancers.

scholarly journals Knockdown of microRNA-135b in Mammary Carcinoma by Targeted Nanodiamonds: Potentials and Pitfalls of In Vivo Applications

Nanomaterials ◽  
2019 ◽  
Vol 9 (6) ◽  
pp. 866 ◽  
Author(s):  
Romana Křivohlavá ◽  
Eva Neuhӧferová ◽  
Katrine Q. Jakobsen ◽  
Veronika Benson
Keyword(s):  
Antisense Rna ◽  
Tumor Tissue ◽  
Immune Cell ◽  
Ex Vivo ◽  
Tumor Bearing ◽  
Intravenous Application ◽  
Effective Inhibition ◽  
Tumor Accumulation ◽  
Safe Approach

Nanodiamonds (ND) serve as RNA carriers with potential for in vivo application. ND coatings and their administration strategy significantly change their fate, toxicity, and effectivity within a multicellular system. Our goal was to develop multiple ND coating for effective RNA delivery in vivo. Our final complex (NDA135b) consisted of ND, polymer, antisense RNA, and transferrin. We aimed (i) to assess if a tumor-specific coating promotes NDA135b tumor accumulation and effective inhibition of oncogenic microRNA-135b and (ii) to outline off-targets and immune cell interactions. First, we tested NDA135b toxicity and effectivity in tumorospheres co-cultured with immune cells ex vivo. We found NDA135b to target tumor cells, but it binds also to granulocytes. Then, we followed with NDA135b intravenous and intratumoral applications in tumor-bearing animals in vivo. Application of NDA135b in vivo led to the effective knockdown of microRNA-135b in tumor tissue regardless administration. Only intravenous application resulted in NDA135b circulation in peripheral blood and urine and the decreased granularity of splenocytes. Our data show that localized intratumoral application of NDA135b represents a suitable and safe approach for in vivo application of nanodiamond-based constructs. Systemic intravenous application led to an interaction of NDA135b with bio-interface, and needs further examination regarding its safety.

The Cole Relaxation Frequency as a Parameter to Identify Cancer in Lung Tissue: Preliminary Animal and ex vivo Patient Studies (Preprint)

2021 ◽  
Author(s):  
Les Bogdanowicz ◽  
Onur Fidaner ◽  
Donato Ceres ◽  
Alex Grycuk ◽  
David Demos
Keyword(s):  
Lung Cancer ◽  
Ex Vivo ◽  
Human Subjects ◽  
Small Animal ◽  
Relaxation Frequency ◽  
Normal Tissues ◽  
Electrical Bioimpedance ◽  
Benign Nodules ◽  
Porcine Lungs

UNSTRUCTURED Lung cancer is the world’s leading cause of cancer deaths, and diagnosis remains challenging. Lung cancer starts as small nodules; early and accurate diagnosis allows timely surgical resection of malignant nodules while avoiding unnecessary surgery in patients with benign nodules. The Cole Relaxation Frequency (CRF) is a derived electrical bioimpedance signature, which may be utilized to distinguish cancerous tissues from normal tissues. Here we show that CRF allows for diagnosis of cancer in human subjects, based on evaluation of 60 specimens obtained from 30 patients. We observed clear discrimination of CRF values in tumor and distant normal tissues, resulting in a high degree of sensitivity (97%) and specificity (87%) in cancer diagnosis. Furthermore, we tested 20 xenograft small animal model specimens, observing a similar separation of CRF values as in the human in-vivo measurements. We also obtained CRF measurements in pressurized and unpressurized lungs by implanting tumors into ex-vivo porcine lungs. CRF measurements align with previous tests in human and small animal models.

529 Cancer cells educate natural killer cells to a metastasis promoting cell state

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A565-A565
Author(s):  
Isaac Chan ◽  
Hildur Knútsdóttir ◽  
Gayathri Ramakrishnan ◽  
Veena Padmanaban ◽  
Manisha Warrier ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Nk Cells ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Nk Cell ◽  
Ex Vivo ◽  
Tumor Bearing ◽  
Growth Promoting ◽  
Tumor Organoids

BackgroundMetastatic disease drives breast cancer mortality. We recently discovered that leading cells at the invasive edge of mammary tumor organoids retain a conserved basal epithelial program defined by their expression of keratin-14 (K14), establishing K14 as a good marker of invasive breast cancer cells. K14-positive invasive cells also exhibit characteristics that make them targets of immunosurveillance by natural killer (NK) cells. While NK cells are key immune mediators in the control of metastasis, our understanding of the specific mechanisms behind this regulation and its eventual evasion by metastatic cells remains incomplete.MethodsWe have developed a novel preclinical 3D co-culture assay to discover mechanisms behind interactions between K14+ invasive breast cancer cells and NK cells. Combined with in vivo assays of metastasis, we are able to determine how NK cells limit the early stages of metastasis and also how tumor cells can influence key NK cell properties.ResultsIn ex vivo co-culture assays of NK cells isolated from healthy mouse donors and mammary tumor organoids from MMTV-PyMT and C31T mouse models of breast cancer, we demonstrate that NK cells limit the early stages of metastasis. Antibodies to invasive K14+ cells were able to enhance the ability of NK cells to limit colony formation, suggesting antibody-dependent cell mediated cytotoxicity. Surprisingly, when isolated from tumor bearing mice, NK cells did not limit invasion and instead promoted colony formation. The in vivo adoptive transfer of NK cells from healthy donors prevents the progression of early lung metastatic seeds to macrometastases, while the adoptive transfer of cells isolated from tumor bearing donors promotes macrometastatic development. Transcriptomic analysis of reprogrammed NK cells demonstrate they have similar profiles to resting NK cells. This growth promoting phenotype can be reversed with antibodies targeting inhibitory cell surface receptors or the epigenome.ConclusionsOur ex vivo and in vivo data demonstrate that healthy donor NK cells can limit metastasis through the directed cytotoxicity against pioneering K14+ invasive cells. However, prolonged exposure to tumors reprogram NK cells from tumor killing to tumor promoting, specifically in promoting the outgrowth of macrometastases. Further, we can neutralize this effect using NK cell specific inhibitory antibodies and epigenetic modifiers. This is the first time inhibitory signaling on NK cells have been linked with a growth promoting phenotype. These data can provide insight into when the use of NK cell directed therapies can be used to treat or prevent clinically relevant metastatic disease.

scholarly journals Synthesis of a novel 89Zr labeled HER2 affibody and its application study in tumor PET imaging

2020 ◽  
Author(s):  
Yuping Xu ◽  
Lizhen Wang ◽  
Donghui Pan ◽  
Junjie Yan ◽  
Xinyu Wang ◽  
...  
Keyword(s):  
Pet Imaging ◽  
Radiochemical Purity ◽  
Ex Vivo ◽  
Radiochemical Yield ◽  
Immunohistochemical Analysis ◽  
In Vivo Studies ◽  
Potential Candidate ◽  
Synthesis Time ◽  
Normal Tissues

Abstract Background: Human epidermal growth factor receptor-2 (HER2) is an essential biomarker for tumor treatment. Affibody is an ideal vector for preparing HER2 specific probes because of high affinity and rapid clearance from normal tissues etc. Zirconium-89 is a PET imaging isotope with a long half-life and suitable for monitoring biological processes for more extended periods. In this study, a novel 89 Zr-labeled HER2 affibody, [ 89 Zr]Zr-DFO-MAL-Cys-MZHER2, was synthesized, and its imaging characters were also assessed. Results: The precursor, DFO-MAL-Cys-MZHER2, was obtained with a yield of nearly 50%. The radiochemical yield of [ 89 Zr]Zr -DFO-MAL-Cys-MZHER2 was 90.2±1.9% , and the radiochemical purity was higher than 95%. The total synthesis time was only 30 minutes. The probe was stable in PBS and serum. The tracer accumulated in HER2 overexpressing human ovarian cancer SKOV-3 cells. In vivo studies in mice bearing tumors showed that the probe highly retained in SKOV-3 xenografts even for 48 hours. The tumors were visualized with good contrast to normal tissues. ROI analysis revealed that the average uptake values in the tumor were greater than 5%IA/g during 48 hours postinjection. On the contrary, the counterparts of MCF-7 tumors kept low levels（~1%IA/g）. The outcome was consistent with the immunohistochemical analysis and ex vivo autoradiography. The probe quickly cleared from the normal organs except kidneys and mainly excreted through the urinary system. Conclusion: The novel HER2 affibody for PET imaging was easily prepared with satisfactory labeling yield and radiochemical purity. [ 89 Zr]Zr-DFO-MAL-Cys-MZHER2 is a potential candidate for detecting HER2 expression. It may play specific roles in clinical cancer theranostics.

scholarly journals Synthesize of a novel 89Zr labeled HER2 affibody and its application study in tumor PET imaging

2020 ◽  
Author(s):  
Yuping Xu ◽  
Lizhen Wang ◽  
Donghui Pan ◽  
Junjie Yan ◽  
Xinyu Wang ◽  
...  
Keyword(s):  
Pet Imaging ◽  
Radiochemical Purity ◽  
Ex Vivo ◽  
Growth Factor Receptor ◽  
Immunohistochemical Analysis ◽  
In Vivo Studies ◽  
Potential Candidate ◽  
Synthesis Time ◽  
Normal Tissues

Abstract Background: Human epidermal growth factor receptor-2 (HER2) is an essential biomarker for tumor treatment. Affibody is an ideal vector for preparing HER2 specific probes because of high affinity and rapid clearance from normal tissues etc. 89 Zr is a PET imaging isotope with a long half-life and suitable for monitoring biological processes for more extended periods. In this study, a novel 89 Zr labeled HER2 affibody, 89 Zr-DFO-MAL-Cys-MZHER2, was synthesized, and its imaging characters were also assessed. Results: The precursor, DFO-MAL-Cys-MZHER2, was obtained with a yield of nearly 50%. The yield of 89 Zr-DFO-MAL-Cys-MZHER2 was 90.2±1.9% , and the radiochemical purity was higher than 95%. The total synthesis time was only 30 minutes. The probe was stable in PBS and serum. The tracer accumulated in HER2 overexpressing human ovarian cancer SKOV-3 cells. In vivo studies in mice bearing tumors showed that the probe highly retained in SKOV-3 xenografts even for 48 hours. The tumors were visualized with good contrast to normal tissues. ROI analysis revealed that the average uptake values in the tumor were greater than 5 %IA/g during 48 hours postinjection. On the contrary, the counterparts of MCF-7 tumors kept low levels（~1%IA/g）. The outcome was consistent with the immunohistochemical analysis and ex vivo autoradiography. The probe quickly cleared from the normal organs except kidneys and mainly excreted through the urinary system. Conclusion: The novel HER2 affibody for PET imaging was easily prepared with satisfactory labeling yield and radiochemical purity. 89 Zr-DFO-MAL-Cys-MZHER2 is a potential candidate for detecting HER2 expression and may play specific roles in clinical cancer theranostics.

scholarly journals The Cole Relaxation Frequency as a Parameter to Identify Cancer in Lung Tissue: Preliminary Animal and ex vivo Patient Studies

2021 ◽  
Author(s):  
Les Bogdanowicz ◽  
Onur Fidaner ◽  
Donato Ceres ◽  
Alex Grycuk ◽  
Davis Demos
Keyword(s):  
Lung Cancer ◽  
Ex Vivo ◽  
Human Subjects ◽  
Small Animal ◽  
Relaxation Frequency ◽  
Normal Tissues ◽  
Electrical Bioimpedance ◽  
Benign Nodules ◽  
Porcine Lungs

Abstract Lung cancer is the world’s leading cause of cancer deaths, and diagnosis remains challenging. Lung cancer starts as small nodules; early and accurate diagnosis allows timely surgical resection of malignant nodules while avoiding unnecessary surgery in patients with benign nodules. The Cole Relaxation Frequency (CRF) is a derived electrical bioimpedance signature, which may be utilized to distinguish cancerous tissues from normal tissues. Here we show that CRF allows for diagnosis of cancer in human subjects, based on evaluation of 60 specimens obtained from 30 patients. We observed clear discrimination of CRF values in tumor and distant normal tissues, resulting in a high degree of sensitivity (97%) and specificity (87%) in cancer diagnosis. Furthermore, we tested 20 xenograft small animal model specimens, observing a similar separation of CRF values as in the human in-vivo measurements. We also obtained CRF measurements in pressurized and unpressurized lungs by implanting tumors into ex-vivo porcine lungs. CRF measurements align with previous tests in human and small animal models.

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