title: Expression changes in arrestin β 1 and genetic variation in catechol-O-methyltransferase             are biomarkers for the response to morphine treatment in cancer patients.
abstract: Genetic differences in individuals with regard to opioid-receptor signaling             create clinical difficulties for opioid treatment; consequently, useful pharmacodynamic             and predictive biomarkers are needed. In this prospective study, we studied gene             expression changes in peripheral blood leukocytes using a microarray and real-time             RT-PCR analysis to identify pharmacodynamic biomarkers for monitoring the effect             of morphine in a cohort of opioid-treatment-naïve cancer patients. We also examined             genetic variations in opioid receptor mu 1 (OPRM1, 118A→G) and catechol-O-methyltransferase             (COMT, 472G→A) to evaluate predictive biomarkers of the treatment outcome of morphine.             The plasma concentration of morphine was measured using a liquid chromatography-tandem             mass spectrometry method. Microarray analysis revealed that the mRNA expression             levels of arrestin β 1 (ARRB1) were significantly down-regulated by morphine treatment.             Real-time RT-PCR analysis against independent samples confirmed the results (P=0.003)             and changes during treatment were negatively correlated with the plasma morphine             concentration (R=-0.42). No correlation was observed between the genotype of OPRM1             and morphine treatment; however, the plasma concentration of morphine and the             required dose of morphine were significantly lower for the A/A genotype of COMT             (vs. A/G+G/G, P=0.008 and 0.03). We found that changes in the expression of ARRB1             may be a novel pharmacodynamic biomarker and the COMT 472G→A genotype may be a             predictive biomarker of the response to morphine treatment.
authors.affiliation: Department of Medical Oncology, Kinki University Faculty of Medicine, and Department of Palliative Care, Sakai Hospital, Osaka 589-8511, Japan.
authors.forename: Hiromichi
authors.initials: H
authors.lastname: Matsuoka
authors.forename: Tokuzo
authors.initials: T
authors.lastname: Arao
authors.forename: Chihiro
authors.initials: C
authors.lastname: Makimura
authors.forename: Masayuki
authors.initials: M
authors.lastname: Takeda
authors.forename: Hidemi
authors.initials: H
authors.lastname: Kiyota
authors.forename: Junji
authors.initials: J
authors.lastname: Tsurutani
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Fujita
authors.forename: Kazuko
authors.initials: K
authors.lastname: Matsumoto
authors.forename: Hideharu
authors.initials: H
authors.lastname: Kimura
authors.forename: Masatomo
authors.initials: M
authors.lastname: Otsuka
authors.forename: Atsuko
authors.initials: A
authors.lastname: Koyama
authors.forename: Chiyo K
authors.initials: CK
authors.lastname: Imamura
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Tanigawara
authors.forename: Takeharu
authors.initials: T
authors.lastname: Yamanaka
authors.forename: Kyoko
authors.initials: K
authors.lastname: Tanaka
authors.forename: Kazuto
authors.initials: K
authors.lastname: Nishio
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Nakagawa
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000097:blood / Q000627:therapeutic use*; D019390:Arrestins / Q000235:genetics*; D015415:Biomarkers / Q000378:metabolism; D002394:Catechol O-Methyltransferase / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005819:Genetic Markers; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D009020:Morphine / Q000008:administration & dosage / Q000097:blood / Q000627:therapeutic use*; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics*; D012333:RNA, Messenger / Q000378:metabolism; D016896:Treatment Outcome; D000071559:beta-Arrestin 1; D000071557:beta-Arrestins
chemical_list: C000605253:ARRB1 protein, human; D000701:Analgesics, Opioid; D019390:Arrestins; D015415:Biomarkers; D005819:Genetic Markers; D012333:RNA, Messenger; D000071559:beta-Arrestin 1; D000071557:beta-Arrestins; D009020:Morphine; D002394:Catechol O-Methyltransferase