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Additive and Synergistic Interactions of Monoclonal Antibodies and Immunotoxins Reactive with Breast and Ovarian Cancer
Published in Ronald H. Goldfarb, Theresa L. Whiteside, Tumor Immunology and Cancer Therapy, 2020
Robert C. Bast, Fengji Xu, Yinhua Yu, Jennie Crews, Yair Argon, Yaron Lidor, Andrew Berchuck, Cinda M. Boyer
Several models might explain these observations. First, if the natural ligand stimulated tumor growth, the antibodies might inhibit growth by displacing the ligand from its binding site. On the other hand, Lupu and her collaborators have shown that binding of ligand to SKBr3 cells that overexpress p185 inhibits, rather than stimulates, tumor growth.(9) Thus, binding of antibody to the extracellular domain of p185 might mimic ligand and inhibit tumor growth by interacting with the ligand binding site. Alternatively, for those antibodies that do not recognize epitopes near the ligand binding site, allosteric changes might decrease affinity for ligand or alter the kinase activity of the intracellular domain. Finally, bivalent antibodies could enhance dimerization according to the model of Schlessinger for activation of the EGFR. In the case of multiple monoclonal antibodies, aggregation of p185 could be achieved on the cell surface. Possible internalization of p185 once antibody is bound must also be taken into consideration. Against the possibility that antibodies simply enhance dimerization is the observation that Fab fragments are approximately as active as the intact immunoglobulin in down-regulating anchorage independent tumor growth.
Spectral CT Imaging Using MARS Scanners
Published in Katsuyuki Taguchi, Ira Blevis, Krzysztof Iniewski, Spectral, Photon Counting Computed Tomography, 2020
Aamir Y. Raja, Steven P. Gieseg, Sikiru A. Adebileje, Steven D. Alexander, Maya R. Amma, Fatemeh Asghariomabad, Ali Atharifard, Benjamin Bamford, Stephen T. Bell, Srinidhi Bheesette, Anthony P. H. Butler, Philip H. Butler, Pierre Carbonez, Alexander I. Chernoglazov, Shishir Dahal, Jérôme Damet, Niels J. A. de Ruiter, Robert M. N. Doesburg, Brian P. Goulter, Joseph L. Healy, Praveen K. Kanithi, Stuart P. Lansley, Chiara Lowe, V. B. H. Mandalika, Emmanuel Marfo, Aysouda Matanaghi, Mahdieh Moghiseh, Raj K. Panta, Hannah M. Prebble, Nanette Schleich, Emily Searle, Jereena S. Sheeja, Rayhan Uddin, Lieza Vanden Broeke, V. S. Vivek, E. Peter Walker, Michael F. Walsh, Manoj Wijesooriya
Figure 7.11 shows a proof of concept using a similar methodology as stated above; AuNPs monoclonal antibodies and MARS imaging show in vitro proof of principle that spectral molecular CT can measure gold-labeled specific antibodies targeted to specific cancer cells. A crossover study was performed with Raji lymphoma cancer cells and HER2 positive SKBR3 breast cancer cells using a MARS scanner. Raji cells were incubated with gold-labeled monoclonal antibody Rituximab (specific antibody that binds to CD20 antigen on human B-cell lymphomas) and Herceptin (as a control). HER2 positive SKBR3 breast cancer cells were incubated with the gold-labeled monoclonal antibody Herceptin (specific antibody to HER2 positive cancer cells) and Rituximab (as a control). For more details on this, we direct the reader to our paper [3]. Figure 7.12 shows in vivo imaging of gold in mice with implanted tumor.
Tyrosine Kinase Inhibitors: Targets Other Than FLT3, BCR-ABL, and c-KIT
Published in Gertjan J. L. Kaspers, Bertrand Coiffier, Michael C. Heinrich, Elihu Estey, Innovative Leukemia and Lymphoma Therapy, 2019
Suzanne R. Hayman, Judith E. Karp
Novobiocin and structurally related compounds, chlorobiocin and coumermycin Al, are being evaluated as alternative Hsp90 inhibitors. Unlike the BA and radicicol, the mechanism of action of these coumarin antibiotics does not appear to relate to binding within the hydrophobic ATP/ADP site in the amino terminus of Hsp90 but rather to an interaction with a previously unrecognized domain in the carboxy-terminus of Hsp90 (33). Novobiocin blocks the ability of Hsp90 to complex with either p23 or p70 (32). Marcu et al. demonstrated reductions in the Hsp90-dependent signaling proteins, mutated p53, p185erbB2, and Raf-1 in a dose-dependent fashion using novobiocin in SKBR3 breast cancer cells, with maximum activity occurring at 500 to 800 µM (33). The p60v-src protein was also reduced in v-Src-transformed NIH 3T3 cells after exposure to 600 µM novobiocin for 16 hours (33). The depletion of these oncogenic proteins appears to be independent of the known topoisomerase II inhibition of the coumarins, since treatment with the topoisomerase II inhibitors, etoposide and doxorubicin, did not result in reduced levels of p185erbB2 (33).
Dipeptidyl peptidase 4 (DPP-4) inhibitors and the risk of lung cancer: current evidence and future directions
Published in Expert Review of Clinical Pharmacology, 2023
Harmanjit Singh, Jatin Sharma, Pallavi Sikarwar, Ashish Kumar Kakkar
Another in vitro study done by Garcia et al. in 2013 on breast cancer cell lines (MDA-MB-453, SK-BR-3, BT-474) concluded that SP is responsible for activation of HER2 receptor which leads to progression and therapeutic resistance in breast carcinoma cells. In vitro results of the study were confirmed by designing an in vivo study using SCID mice bearing MDA-MB-231 (HER2-) or MDA-MB-453-derived (HER2+) xenograft tumor tissue. The results of the study suggested that long term administration of SP in the tumor area could increase the expression of HER2 in cancer cells affecting response to anti-ERBB targeted treatments. The work highlighted oncogenic cooperation between NK1R and HER2 that might contribute to the relationship between inflammation, cancer progression and pharmacoresistance [30].
Natural source, bioactivity and synthesis of 3-Arylcoumarin derivatives
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2022
Qiang Zhang, Yu-hang Miao, Teng Liu, Yin-ling Yun, Xiao-ya Sun, Tao Yang, Jie Sun
In recent years, the 3-phenylcoumarin skeleton has been studied in more detail in its antitumor activity26–30. It has been reported to inhibit cell growth and proliferation in various human cancer cell lines. Zhao et al. designed and synthesised a library of 3-arylcoumarin derivatives containing the structural features of KU-398 and silybin and identified them as novel inhibitors of Hsp90 protein. The compound showed the strongest anti-proliferative activity against SKBr3 cells and MCF-7 cells31. These indicate that some compounds have drug-like properties. In addition, the potential of 3-arylcoumarin derivatives was first known as potent, non-substrate, uncompetitive inhibitors of Theileria annulata enolase (TaENO)32. These compounds are the priority for the treatment of special disease.
A bivalent, bispecific Dab-Fc antibody molecule for dual targeting of HER2 and HER3
Published in mAbs, 2021
Alexander Rau, Katharina Kocher, Mirjam Rommel, Lennart Kühl, Maximilian Albrecht, Hannes Gotthard, Nadine Aschmoneit, Bettina Noll, Monilola A. Olayioye, Roland E. Kontermann, Oliver Seifert
Since HRG also induces cell migration, we next analyzed the inhibitory effects of Dab-Fc 2 × 3 on cell motility in scratch wounding assays. In NCI-N87 cells, basal as well as HRG-induced cell motility was strongly and significantly suppressed by Dab-Fc 2 × 3 when compared to the untreated control cells and as measured by wound closure after 5 hours, and this inhibition was maintained during the 24-h observation period (Figure 5). While Dab-Fc 2 × 3 blocked migration by 85% at this time point, inhibition by the combination of both parental antibodies reached only 37% (-HRG) and 44% (+HRG), respectively. This is most likely due to the potent suppression of the PI3K-Akt pathway, a driver of cell motility, by Dab-Fc 2 × 3 (see Figure 3).28 Inhibition of cell migration was also observed for SKBR3 cells, although the effects were less pronounced but also strongest for Dab-Fc 2 × 3 (Fig. S7). Taken together, the biological activity of the bispecific Dab-Fc 2 × 3 was similar and in many settings even superior to the activity of the parental antibodies.