Pharmacology and pharmacodynamics of bevacizumab as monotherapy or in combination with cytotoxic therapy in preclinical studies.
By H. Gerber, N. Ferrara. Cancer Research, 2005
645 citations recorded by the source corpus.
Preclinical models have examined the pharmacologic and pharmacodynamic activities of an anti-vascular endothelial growth factor (VEGF) humanized, monoclonal antibody, bevacizumab, and/or its murine equivalent A4.6.1. These studies found that single-agent therapy with bevacizumab/A4.6.1 resulted in tumor growth inhibition of 20 different human tumor cell lines (13 tumor types) implanted into nude mice irrespective of the route of administration or tumor location. Several of these studies also observed significant inhibition of tumor metastases. Various studies have examined the feasibility of combining anti-VEGF therapy with cytotoxic or biological agents. Combining bevacizumab/A4.6.1 with doxorubicin, topotecan, paclitaxel, docetaxel, or radiotherapy resulted in additive or synergistic tumor growth inhibition. Changes in vascular functions were frequently reported, including decreased vessel diameter, density, and permeability in response to treatment. A reduction in interstitial fluid pressure was also observed. In some studies, these improvements resulted in an increase in intratumoral uptake of chemotherapy, implying that the most effective use of anti-VEGF therapy is in combination with chemotherapy. Alternatively, combination treatment with radiation increased tumor oxygenation and tumor growth inhibition. Interestingly, anti-VEGF therapy has also been reported to reduce the development of ascites in ovarian mouse models. Finally, safety pharmacology studies with bevacizumab in cynomolgus monkeys showed that this agent is generally well tolerated with no unexpected adverse events.
Subfields: Cancer Research, Molecular Biology, Oncology
View Paper: https://www.semanticscholar.org/paper/b60b526474f5019971ac0e218dcaabc652c46d53
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Citations in the corpus
- VEGF in Signaling and Disease: Beyond Discovery and Development (2019, background): “Several studies have shown that it stems, at least in part, from direct anti-vascular effects of the cytotoxic agents that amplify the pro-apoptotic effects of anti-VEGF agents on the vascular endothelium (Gerber and Ferrara, 2005; Klement et al., 2000; Sweeney et al., 2001).”
- Ten years of anti-vascular endothelial growth factor therapy (2016, background): “…was to simultaneously target the endothelial cells and the tumour cells, and, indeed, preclinical studies confirmed a synergistic effect between bevacizumab and cytotoxic therapies, in part because VEGFA blockade seems to sensitize the endothelium to the effects of the cytotoxic agents 73–75 .”
- Antiangiogenic agents can increase lymphocyte infiltration into tumor and enhance the effectiveness of adoptive immunotherapy of cancer (2010, positive): “1, was shown to suppress the growth of human rhabdomyosarcoma, glioblastoma, leiomyosarcoma, and various other tumors implanted in immunodeficient mice (16, 17).”
- Angiogenesis as a therapeutic target (2005, background): “Subsequent studies have shown that many additional tumour cell lines, regardless of the tumour's origin, are inhibited in vivo by the same anti-VEGF monoclonal antibody (reviewed in ref”
- Tumor refractoriness to anti-VEGF treatment is mediated by CD11b+Gr1+ myeloid cells (2007, background): “VEGF-A blockade using the humanized anti-VEGF-A monoclonal antibody (mAb) bevacizumab (Avastin) or its murine precursor significantly inhibited angiogenesis and growth of human tumor xenograft”