|Expression changes in arrestin β 1 and genetic variation in catechol-O-methyltransferase are biomarkers for the response to morphine treatment in cancer patients|
Authors: Hiromichi Matsuoka, Tokuzo Arao, Chihiro Makimura, Masayuki Takeda, Hidemi Kiyota, Junji Tsurutani, Yoshihiko Fujita, Kazuko Matsumoto, Hideharu Kimura, Masatomo Otsuka, Atsuko Koyama, Chiyo K. Imamura, Yusuke Tanigawara, Takeharu Yamanaka, Kyoko Tanaka, Kazuto Nishio, Kazuhiko Nakagawa
Affiliations: Department of Medical Oncology, Kinki University Faculty of Medicine, Osaka 589-8511, Japan, Department of Genome Biology, Kinki University Faculty of Medicine, Osaka 589-8511, Japan, Department of Palliative Care, Sakai Hospital, Kinki University Faculty of Medicine, Osaka 590-0132, Japan, Department of Psychosomatic Medicine, Sakai Hospital, Kinki University Faculty of Medicine, Osaka 590-0132, Japan, Department of Clinical Pharmacokinetics and Pharmacodynamics, School of Medicine, Keio University, Tokyo 160-8582, Japan, Institute for Clinical Research, National Kyushu Cancer Center, Fukuoka 811-1395, Japan, Department of Oncology Nursing, School of Nursing, Osaka Prefecture University, Habikino Campus, Osaka 583-8555, Japan
Published online on: Thursday, January 26, 2012
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.