Chemoprotection by VEGF: Rationale for combination nab-paclitaxel and bevacizumab

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 1064-1064 ◽  
Author(s):  
V. Trieu ◽  
S. Ran ◽  
C. Bivens ◽  
N. Desai
Keyword(s):  
Protective Effect ◽  
Tumor Cells ◽  
Breast Tumor ◽  
T Test ◽  
Receptor Expression ◽  
Vegf Receptor ◽  
Vegf Expression ◽  
Clonogenic Assays

1064 Background: Nanoparticle albumin-bound (nab-) paclitaxel (ABX) has shown greater efficacy and less toxicity than solvent-based paclitaxel (TAX) in xenograft models and clinical trials. The goal of this study was to determine the effects of VEGF modulation in human MDA-MB-231 breast tumor cell line and the effects of ABX and VEGF-neutralizing antibody bevacizumab (AVA) combination on the growth and metastasis of orthotopically implanted MDA-MB-231 tumors. Methods: VEGF expression was evaluated by ELISA in MDA-MB-231 tumor extract one week after treatment (qdx5) with saline, doxorubicin (10 mg/kg), TAX (10 mg/kg), or ABX (15 mg/kg). VEGF-receptor expression in MDA-MB-231 was quantitated by RT-PCR. MDA-MB-231 cytotoxicity with ABX, VEGF, AVA alone or in combination was measured by cytotoxicity and clonogenic assays. Implanted MDA-MB-231 tumors expressing luciferase were treated with saline, 2 cycles of ABX (10 mg/kg, two qdx5 cycles separated by 1 week, N=5) alone or in combination with AVA (2, 4 and 8 mg/kg, 2/wkx6). Tumor lymph node and pulmonary metastasis was determined by measuring luciferase activity. Results: Compared with saline, MDA-MB-231 tumors following chemotherapies exhibited significant tumor shrinkage (p≤0.006, t-test) and VEGF induction (p<0.0001, t-test). MDA-MB-231 was shown to express VEGFR2. Exogenous VEGF had a protective effect on MDA-MB-231 tumor cells by reducing cytotoxicity of ABX in both cytotoxicity and clonogenic assays. Sequestration of VEGF with AVA increased cytotoxicity of ABX in vitro. Treatment of MDA-MB-231 breast tumors with ABX and AVA combination resulted in greater than additive antitumor response and significantly reduced metastasis to the lungs (p=0.025 vs control) and LN (p=0.022) at the highest AVA dose. Conclusions: Chemotherapies induced VEGF expression in MDA-MD-231 breast tumor in vivo. In vitro, VEGF exerted a protective effect against ABX chemotherapy in VEGFR2-expressing MDA-MD-231 cells, which was abrogated by addition of AVA. In vivo, ABX and AVA combination significantly inhibited the metastatic potential of MDA-MB-231 tumor cells. These data provide a rational basis for the combination of nab- paclitaxel and bevacizumab in VEGF-receptor expressing tumors. [Table: see text]

scholarly journals Promising potential of [177Lu]Lu-DOTA-folate to enhance tumor response to immunotherapy—a preclinical study using a syngeneic breast cancer model

2020 ◽  
Author(s):  
Patrycja Guzik ◽  
Klaudia Siwowska ◽  
Hsin-Yu Fang ◽  
Susan Cohrs ◽  
Peter Bernhardt ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Survival Time ◽  
Tumor Cells ◽  
Median Survival ◽  
Breast Tumor ◽  
Median Survival Time ◽  
Therapy Outcome ◽  
Minor Effect

Abstract Purpose It was previously demonstrated that radiation effects can enhance the therapy outcome of immune checkpoint inhibitors. In this study, a syngeneic breast tumor mouse model was used to investigate the effect of [177Lu]Lu-DOTA-folate as an immune stimulus to enhance anti-CTLA-4 immunotherapy. Methods In vitro and in vivo studies were performed to characterize NF9006 breast tumor cells with regard to folate receptor (FR) expression and the possibility of tumor targeting using [177Lu]Lu-DOTA-folate. A preclinical therapy study was performed over 70 days with NF9006 tumor-bearing mice that received vehicle only (group A); [177Lu]Lu-DOTA-folate (5 MBq; 3.5 Gy absorbed tumor dose; group B); anti-CTLA-4 antibody (3 × 200 μg; group C), or both agents (group D). The mice were monitored regarding tumor growth over time and signs indicating adverse events of the treatment. Results [177Lu]Lu-DOTA-folate bound specifically to NF9006 tumor cells and tissue in vitro and accumulated in NF9006 tumors in vivo. The treatment with [177Lu]Lu-DOTA-folate or an anti-CTLA-4 antibody had only a minor effect on NF9006 tumor growth and did not substantially increase the median survival time of mice (23 day and 19 days, respectively) as compared with untreated controls (12 days). [177Lu]Lu-DOTA-folate sensitized, however, the tumors to anti-CTLA-4 immunotherapy, which became obvious by reduced tumor growth and, hence, a significantly improved median survival time of mice (> 70 days). No obvious signs of adverse effects were observed in treated mice as compared with untreated controls. Conclusion Application of [177Lu]Lu-DOTA-folate had a positive effect on the therapy outcome of anti-CTLA-4 immunotherapy. The results of this study may open new perspectives for future clinical translation of folate radioconjugates.

scholarly journals TGFBI expression reduces in vitro and in vivo metastatic potential of lung and breast tumor cells

2011 ◽  
Vol 308 (1) ◽  
pp. 23-32 ◽  
Author(s):  
Gengyun Wen ◽  
Michael A. Partridge ◽  
Bingyan Li ◽  
Mei Hong ◽  
Wupeng Liao ◽  
...  
Keyword(s):  
Tumor Cells ◽  
Breast Tumor ◽  
Metastatic Potential ◽  
Breast Tumor Cells

The Internal Ribosome Entry Site-Medaited Expression of VEGF Rescues HS Sultan Tumor Cells From Mammalian Target of Rapamycin (mTOR)-Inhibitors Induced Apoptosis in Vivo

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1659-1659
Author(s):  
Patrick Frost ◽  
Joseph Gera ◽  
Alan K. Lichtenstein
Keyword(s):  
Tumor Cells ◽  
Resistance Mechanism ◽  
Mtor Inhibitors ◽  
G1 Arrest ◽  
Vegf Expression ◽  
Tumor Cell Apoptosis ◽  
Safe Mechanism ◽  
Fail Safe

Abstract Abstract 1659 An important molecular target of mTOR inhibitors in cancer therapy is VEGF expression and neo-angiogenesis. In prior studies, we demonstrated that, although rapalog mTOR inhibitors only induce G1 arrest in B-cell tumor lines, their administration in vivo in xenograft models resulted in tumor cell apoptosis that correlated with inhibition of neo-angiogenesis and VEGF expression within the tumor bed. Other in vitro studies have shown that IRES-dependent translation of myc and D-cyclins can provide a fail-safe mechanism for expression when mTOR inhibitors prevent cap-dependent translation and may act as a resistance mechanism to induction of G1 arrest in vitro. We, thus, tested if VEGF IRES activity could likewise regulate induction of anti-tumor effects and apoptosis in vivo. To test if VEGF IRES activity can regulate anti-tumor responses in vivo, we utilized the HS-Sultan B cell lymphoma line that is PTEN null. Its heightened AKT activity disarms the VEGF IRES, preventing this fail-safe mechanism and sensitizing to mTOR inhibitors. We ectopically expressed a version of the VEGF ORF in these cells fused to the p27 IRES (p27-VEGF), an IRES which is insensitive to AKT and effective in PTEN-null tumors. p27-VEGF transfected tumor cells were used as subcutaneous challenges in immunodeficient mice and results of mTOR inhibitor treatment compared to control mice challenged with tumor cells transfected with the VEGF ORF but without an AKT-resistant IRES. The anti-tumor responses were enumerated by assessing tumor size and tumor apoptosis, neo-angiogenesis and VEGF expression assessed by immunohistochemistry, ELISA, and Western blot analysis of tumor lysate. Ectopic expression of VEGF fused to the p27 IRES specifically enhanced VEGF expression and neo-angiogenesis in tumors of mice treated with the rapalog temsirolimus or active site mTOR inhibitor pp242 and significantly reduced tumor cell apoptosis and anti-tumor responses. The results confirm the critical role of VEGF expression in tumors during treatment with mTOR inhibitors and, furthermore, underscore the importance of IRES activity as a resistance mechanism to such targeted therapy. Disclosures: No relevant conflicts of interest to declare.

Breast tumor cells isolated from in vitro resistance to trastuzumab remain sensitive to trastuzumab anti-tumor effects in vivo and to ADCC killing

2009 ◽  
Vol 58 (11) ◽  
pp. 1887-1896 ◽  
Author(s):  
Timothy E. Kute ◽  
Lori Savage ◽  
John R. Stehle ◽  
Jung W. Kim-Shapiro ◽  
Michael J. Blanks ◽  
...  
Keyword(s):  
Tumor Cells ◽  
Breast Tumor ◽  
Breast Tumor Cells

NK cells that are activated by CXCL10 can kill dormant tumor cells that resist CTL-mediated lysis and can express B7-H1 that stimulates T cells

Blood ◽  
2005 ◽  
Vol 105 (6) ◽  
pp. 2428-2435 ◽  
Author(s):  
Aurore Saudemont ◽  
Nathalie Jouy ◽  
Dominique Hetuin ◽  
Bruno Quesnel
Keyword(s):  
T Cells ◽  
Protective Effect ◽  
Nk Cells ◽  
Tumor Cells ◽  
Cytotoxic T Lymphocyte ◽  
Interferon Γ ◽  
Leukemic Cells ◽  
Cytotoxic Lymphocytes

AbstractTumor dormancy is a phenomenon where small numbers of tumor cells persist in the host for months or years. We previously showed in the DA1-3b/C3H mouse model of acute myeloid leukemia that dormant tumor cells resist cytotoxic T-lymphocyte (CTL)–mediated killing because they overexpress B7-H1. Here, we vaccinated mice with DA1-3b cells transduced with CXCL10. Vaccinated mice developed a strong systemic immunity that led to the cure of established leukemia without persistence of dormant tumor cells. In vivo depletion of natural killer (NK) cells from the mice abrogated the protective effect of the vaccine. Long-term persistent leukemic cells resist CTL-mediated lysis but were killed by NK cells from mice vaccinated with DA1-3b/CXCL10. These NK cells expressed B7-H1. Recombinant CXCL10, CXCL9, CXCL11, and CXCL12 chemokines induced expression of B7-H1 on mouse and human NK cells in vitro. Mouse and human B7-H1+ NK cells induced proliferation of T cells and production of interferon γ and tumor necrosis factor α in vitro, and in vivo blocking of B7-H1 inhibited the protective effect of vaccination. Thus, CXCL10 induces antileukemic immunity, at least partially by stimulating NK cells to express B7-H1+. This antitumor effect is in contrast to the effect of B7-H1 when expressed on tumor cells because it stops cytotoxic lymphocytes from killing those tumor cells.

scholarly journals Mammalian Target of Rapamycin Inhibitors Induce Tumor Cell ApoptosisIn VivoPrimarily by Inhibiting VEGF Expression and Angiogenesis

2013 ◽  
Vol 2013 ◽  
pp. 1-12 ◽  
Author(s):  
Patrick Frost ◽  
Eileen Berlanger ◽  
Veena Mysore ◽  
Bao Hoang ◽  
YiJiang Shi ◽  
...  
Keyword(s):  
Tumor Cells ◽  
Critical Role ◽  
Xenograft Model ◽  
Mtor Inhibitors ◽  
B Cell Lymphoma ◽  
G1 Arrest ◽  
Vegf Expression ◽  
Entry Site

We found that rapalog mTOR inhibitors induce G1 arrest in the PTEN-null HS Sultan B-cell lymphoma linein vitro, but that administration of rapalogs in a HS Sultan xenograft model resulted in significant apoptosis, and that this correlated with induction of hypoxia and inhibition of neoangiogenesis and VEGF expression. Mechanistically, rapalogs prevent cap-dependent translation, but studies have shown that cap-independent, internal ribosome entry site (IRES)-mediated translation of genes, such as c-myc and cyclin D, can provide a fail-safe mechanism that regulates tumor survival. Therefore, we tested if IRES-dependent expression of VEGF could likewise regulate sensitivity of tumor cellsin vivo. To achieve this, we developed isogenic HS Sultan cell lines that ectopically express the VEGF ORF fused to the p27 IRES, an IRES sequence that is insensitive to AKT-mediated inhibition of IRES activity and effective in PTEN-null tumors. Mice challenged with p27-VEGF transfected tumor cells were more resistant to the antiangiogenic and apoptotic effects of the rapalog, temsirolimus, and active site mTOR inhibitor, pp242. Our results confirm the critical role of VEGF expression in tumors during treatment with mTOR inhibitors and underscore the importance of IRES activity as a resistance mechanism to such targeted therapy.

Human Immunoglobulin A Receptor (FcRI, CD89) Function in Transgenic Mice Requires Both FcR γ Chain and CR3 (CD11b/CD18)

Blood ◽  
1999 ◽  
Vol 93 (12) ◽  
pp. 4387-4394 ◽  
Author(s):  
Marjolein van Egmond ◽  
A.J. Hanneke van Vuuren ◽  
H. Craig Morton ◽  
Annemiek B. van Spriel ◽  
Li Shen ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Tumor Cells ◽  
Immunoglobulin A ◽  
Surface Expression ◽  
Receptor Expression ◽  
Regulatory Sequences ◽  
Functional Studies ◽  
Human Situation

Abstract Even though more immunoglobulin A (IgA) is produced in humans than all other isotypes combined, relatively little is known about receptors that bind the Fc part of IgA. The myeloid IgA receptor, FcRI (CD89), triggers various effector functions in vitro, but its in vivo role remains unclear. Here, a transgenic mouse model is described in which FcRI is expressed under its own regulatory sequences. Receptor expression and regulation by cytokines was comparable to the human situation and hFcRI can trigger phagocytosis and lysis of tumor cells. To analyze the contribution of the FcR γ chain or the β2 integrin CR3 (CD11b/CD18) in FcRI biological function, FcRI transgenic mice were crossed with either FcR γ chain −/− or CR3 −/− mice. In contrast to in vitro data, FcR γ chain was essential for surface expression of hFcRI in vivo. Functional studies in hFcRI/ γ−/−mice were, therefore, limited. In vitro studies showed FcR γ chain to be necessary for phagocytosis. Neither hFcRI expression nor phagocytosis, triggered via hFcRI, were influenced by CR3. Remarkably, the capacity to lyse tumor targets was ablated in hFcRI transgenic/ CR3−/− mice, although binding of neutrophils to tumor cells was intact. This shows a previously unrecognized importance of CR3 for hFcRI-mediated antibody-dependent cellular cytotoxicity (ADCC).

Androgens Stimulate EPC-Mediated Neovascularization and Are Associated with Increased Coronary Collateralization

Endocrinology ◽  
2020 ◽  
Vol 161 (5) ◽  
Author(s):  
Yuen Ting Lam ◽  
Chi-Jen Hsu ◽  
Philippa J L Simpson ◽  
Louise L Dunn ◽  
Renee W Chow ◽  
...  
Keyword(s):  
Blood Flow ◽  
Serum Testosterone ◽  
Receptor Expression ◽  
Flow Index ◽  
Vegf Receptor ◽  
Collateral Flow ◽  
Dependent Manner ◽  
Artery Disease

Abstract Endothelial progenitor cells (EPCs) play a key role in neovascularization and have been linked to improved cardiovascular outcomes. Although there is a well-established inverse relationship between androgen levels and cardiovascular mortality in men, the role of androgens in EPC function is not fully understood. In this study, we investigated the effects of androgens on 2 subpopulations of EPCs, early EPCs (EEPCs) and late outgrowth EPCs (OECs), and their relationships with coronary collateralization. Early EPCs and OECs were isolated from the peripheral blood of young healthy men and treated with dihydrotestosterone (DHT) with or without androgen receptor (AR) antagonist, hydroxyflutamide, in vitro. Dihydrotestosterone treatment enhanced AR-mediated proliferation, migration, and tubulogenesis of EEPCs and OECs in a dose-dependent manner. Furthermore, DHT augmented EPC sensitivity to extracellular stimulation by vascular endothelial growth factor (VEGF) via increased surface VEGF receptor expression and AKT activation. In vivo, xenotransplantation of DHT pretreated human EPCs augmented blood flow recovery and angiogenesis in BALB/c nude male mice, compared to mice receiving untreated EPCs, following hindlimb ischemia. In particular, DHT pretreated human OECs exhibited higher reparative potential than EEPCs in augmenting postischemic blood flow recovery in mice. Furthermore, whole blood was collected from the coronary sinus of men with single vessel coronary artery disease (CAD) who underwent elective percutaneous intervention (n = 23). Coronary collateralization was assessed using the collateral flow index. Serum testosterone and EPC levels were measured. In men with CAD, circulating testosterone was positively associated with the extent of coronary collateralization and the levels of OECs. In conclusion, androgens enhance EPC function and promote neovascularization after ischemia in mice and are associated with coronary collateralization in men.

Trehalose liposomes induce apoptosis of breast tumor cells in vitro and in vivo

2020 ◽  
Vol 532 (4) ◽  
pp. 505-512
Author(s):  
Hideaki Ichihara ◽  
Keiji Kuwabara ◽  
Yoko Matsumoto
Keyword(s):  
Tumor Cells ◽  
Breast Tumor ◽  
Breast Tumor Cells
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