PMID- 33231381 OWN - NLM STAT- MEDLINE DCOM- 20210720 LR - 20210720 IS - 2045-7634 (Electronic) IS - 2045-7634 (Linking) VI - 10 IP - 1 DP - 2021 Jan TI - Investigation of drugs affecting hypertension in bevacizumab-treated patients and examination of the impact on the therapeutic effect. PG - 164-172 LID - 10.1002/cam4.3587 [doi] AB - BACKGROUND: In patients treated with bevacizumab, hypertension may be a biomarker of therapeutic efficacy. However, it is not clear whether drugs that control blood pressure influence bevacizumab's efficacy. In this study, we investigated drugs that may affect hypertension in bevacizumab-treated patients and examined the impact on the therapeutic effect. PATIENTS AND METHODS: We analyzed 3,724,555 reports from the third quarter of 2010 to the second quarter of 2015. All data were obtained from the Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) analysis. In this retrospective cohort study, we investigated a total of 58 patients diagnosed with colorectal cancer and treated for the first time with bevacizumab containing XELOX or mFOLFOX6 at The University of Tokushima Hospital between January 2010 and December 2015. The effect of the treatment was evaluated according to Response Evaluation Criteria in Solid Tumors version 1.0. Thereafter, the effect was confirmed using Gene Expression Omnibus (GEO) and cultured cells. RESULTS: There are few reports in FAERS of hypertension in patients treated with omeprazole on bevacizumab. Based on the chart review, patients who used proton pump inhibitors (PPI) had a lower response to treatment than those who did not (response rate: 25% vs 50%). Furthermore, experiments on GEO and cell lines suggested that induction of vascular endothelial growth factor (VEGF) gene expression by PPIs is the cause of the reduced therapeutic effect. CONCLUSION: PPIs prevent hypertension in bevacizumab-treated patients but may reduce bevacizumab's anti-tumoral effects by inducing VEGF expression. CI - (c) 2020 The Authors. Cancer Medicine published by John Wiley & Sons Ltd. FAU - Yagi, Kenta AU - Yagi K AUID- ORCID: 0000-0003-0869-5786 AD - Clinical Research Center for Developmental Therapeutics, Tokushima University Hospital, Tokushima, Japan. FAU - Mitstui, Marin AU - Mitstui M AD - Department of Clinical Pharmacology and Therapeutics, University of Tokushima Graduate School of Biomedical Sciences, Tokushima, Japan. FAU - Zamami, Yoshito AU - Zamami Y AD - Department of Clinical Pharmacology and Therapeutics, University of Tokushima Graduate School of Biomedical Sciences, Tokushima, Japan. AD - Department of Pharmacy, Tokushima University Hospital, Tokushima, Japan. FAU - Niimura, Takahiro AU - Niimura T AD - Department of Clinical Pharmacology and Therapeutics, University of Tokushima Graduate School of Biomedical Sciences, Tokushima, Japan. FAU - Izawa-Ishizawa, Yuki AU - Izawa-Ishizawa Y AD - Department of Pharmacology, University of Tokushima Graduate School of Biomedical Sciences, Tokushima, Japan. FAU - Goda, Mitsuhiro AU - Goda M AD - Department of Pharmacy, Tokushima University Hospital, Tokushima, Japan. FAU - Chuma, Masayuki AU - Chuma M AD - Clinical Research Center for Developmental Therapeutics, Tokushima University Hospital, Tokushima, Japan. FAU - Fukunaga, Kimiko AU - Fukunaga K AD - Department of Clinical Pharmacology and Therapeutics, University of Tokushima Graduate School of Biomedical Sciences, Tokushima, Japan. FAU - Shibata, Takahiro AU - Shibata T AD - Department of Pharmacy, Tokushima University Hospital, Tokushima, Japan. FAU - Ishida, Shunsuke AU - Ishida S AD - Department of Pharmacy, Tokushima University Hospital, Tokushima, Japan. FAU - Sakurada, Takumi AU - Sakurada T AD - Department of Pharmacy, Tokushima University Hospital, Tokushima, Japan. FAU - Okada, Naoto AU - Okada N AUID- ORCID: 0000-0003-2476-9191 AD - Department of Pharmacy, Tokushima University Hospital, Tokushima, Japan. FAU - Hamano, Hirofumi AU - Hamano H AD - Department of Pharmacy, Tokushima University Hospital, Tokushima, Japan. FAU - Horinouchi, Yuya AU - Horinouchi Y AD - Department of Pharmacology, University of Tokushima Graduate School of Biomedical Sciences, Tokushima, Japan. FAU - Ikeda, Yasumasa AU - Ikeda Y AD - Department of Pharmacology, University of Tokushima Graduate School of Biomedical Sciences, Tokushima, Japan. FAU - Yanagawa, Hiroaki AU - Yanagawa H AD - Clinical Research Center for Developmental Therapeutics, Tokushima University Hospital, Tokushima, Japan. FAU - Ishizawa, Keisuke AU - Ishizawa K AD - Department of Clinical Pharmacology and Therapeutics, University of Tokushima Graduate School of Biomedical Sciences, Tokushima, Japan. AD - Department of Pharmacy, Tokushima University Hospital, Tokushima, Japan. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20201124 PL - United States TA - Cancer Med JT - Cancer medicine JID - 101595310 RN - 0 (Angiogenesis Inhibitors) RN - 0 (Antihypertensive Agents) RN - 0 (Antineoplastic Agents, Immunological) RN - 0 (Proton Pump Inhibitors) RN - 0 (VEGFA protein, human) RN - 0 (Vascular Endothelial Growth Factor A) RN - 2S9ZZM9Q9V (Bevacizumab) SB - IM MH - Adult MH - Adverse Drug Reaction Reporting Systems MH - Aged MH - Aged, 80 and over MH - Angiogenesis Inhibitors/*adverse effects MH - Antihypertensive Agents/adverse effects/*therapeutic use MH - Antineoplastic Agents, Immunological/*adverse effects MH - Bevacizumab/*adverse effects MH - Blood Pressure/*drug effects MH - Cell Line, Tumor MH - Colorectal Neoplasms/*drug therapy/metabolism MH - Databases, Factual MH - Drug Interactions MH - Female MH - Human Umbilical Vein Endothelial Cells/drug effects/metabolism MH - Humans MH - Hypertension/chemically induced/diagnosis/physiopathology/*prevention & control MH - Japan MH - Male MH - Middle Aged MH - Proton Pump Inhibitors/adverse effects/*therapeutic use MH - Retrospective Studies MH - Treatment Outcome MH - United States MH - United States Food and Drug Administration MH - Up-Regulation MH - Vascular Endothelial Growth Factor A/metabolism PMC - PMC7826469 OTO - NOTNLM OT - FAERS OT - bevacizumab OT - colorectal cancer OT - gene expression omnibus OT - hypertension OT - proton pump inhibitor COIS- The authors have no conflicts of interest directly relevant to the content of this article. EDAT- 2020/11/25 06:00 MHDA- 2021/07/21 06:00 PMCR- 2020/11/24 CRDT- 2020/11/24 08:40 PHST- 2020/09/09 00:00 [received] PHST- 2020/10/13 00:00 [revised] PHST- 2020/10/15 00:00 [accepted] PHST- 2020/11/25 06:00 [pubmed] PHST- 2021/07/21 06:00 [medline] PHST- 2020/11/24 08:40 [entrez] PHST- 2020/11/24 00:00 [pmc-release] AID - CAM43587 [pii] AID - 10.1002/cam4.3587 [doi] PST - ppublish SO - Cancer Med. 2021 Jan;10(1):164-172. doi: 10.1002/cam4.3587. Epub 2020 Nov 24.