Pharmacology and pharmacodynamics of bevacizumab as monotherapy or in combination with cytotoxic therapy in preclinical studies.
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.
Gerber
Hans-Peter
HP
Departments of Molecular Oncology, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA. gerberhp@gene.com
Ferrara
Napoleone
N
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D000068258:Bevacizumab; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D042461:Vascular Endothelial Growth Factor A; D000068258:Bevacizumab