N Ichihashi1, Y Kitajima. 1. Department of Dermatology, Gifu University School of Medicine, 40 Tukasa-machi, Gifu City 500-8705, Japan. ichihasi@cc.gifu-u.ac.jp
Abstract
BACKGROUND: Human malignant melanoma is notoriously resistant to chemotherapeutic agents. Melanoma-derived cell lines are often markedly chemoresistant, suggesting that cellular mechanisms mediate generation of the multidrug resistance (MDR) phenotype. This phenotype is often due to P-glycoprotein (Pgp) and the MDR-associated protein (MRP), which are drug transporter proteins associated with resistance to a broad spectrum of lipophilic drugs. OBJECTIVES: To determine the relationships between the expression of the MDR gene MDR-1 (the product of which is Pgp) or the MRP gene, and clinical chemoresistance of malignant melanoma. METHODS: We examined changes in the expression of MDR-1 and MRP genes at the mRNA level before and after chemotherapy by reverse transcription-polymerase chain reaction (RT-PCR) analysis using formalin-fixed, paraffin-embedded sections of 18 specimens taken from eight melanoma patients. mRNA expression of the MDR-1 and MRP gene-specific PCR products was quantitatively determined by densitometry and compared with that of an internal standard (beta-actin). RESULTS: Five of seven primary melanomas were found to express the MRP gene to a certain extent even before chemotherapy. After first and second courses of chemotherapy, six patients had an increased ratio of MRP mRNA to beta-actin mRNA compared with the prechemotherapy levels in the same patients. None of the cases of melanoma expressed MDR-1. CONCLUSIONS: These results suggest that a significant mRNA level of MRP gene was intrinsically present in malignant melanoma even before exposure to chemotherapeutic drugs and increased in its expression after chemotherapy, suggesting that MRP plays a part in increasing the chemoresistance of malignant melanoma during chemotherapy.
BACKGROUND:Humanmalignant melanoma is notoriously resistant to chemotherapeutic agents. Melanoma-derived cell lines are often markedly chemoresistant, suggesting that cellular mechanisms mediate generation of the multidrug resistance (MDR) phenotype. This phenotype is often due to P-glycoprotein (Pgp) and the MDR-associated protein (MRP), which are drug transporter proteins associated with resistance to a broad spectrum of lipophilic drugs. OBJECTIVES: To determine the relationships between the expression of the MDR gene MDR-1 (the product of which is Pgp) or the MRP gene, and clinical chemoresistance of malignant melanoma. METHODS: We examined changes in the expression of MDR-1 and MRP genes at the mRNA level before and after chemotherapy by reverse transcription-polymerase chain reaction (RT-PCR) analysis using formalin-fixed, paraffin-embedded sections of 18 specimens taken from eight melanomapatients. mRNA expression of the MDR-1 and MRP gene-specific PCR products was quantitatively determined by densitometry and compared with that of an internal standard (beta-actin). RESULTS: Five of seven primary melanomas were found to express the MRP gene to a certain extent even before chemotherapy. After first and second courses of chemotherapy, six patients had an increased ratio of MRP mRNA to beta-actin mRNA compared with the prechemotherapy levels in the same patients. None of the cases of melanoma expressed MDR-1. CONCLUSIONS: These results suggest that a significant mRNA level of MRP gene was intrinsically present in malignant melanoma even before exposure to chemotherapeutic drugs and increased in its expression after chemotherapy, suggesting that MRP plays a part in increasing the chemoresistance of malignant melanoma during chemotherapy.
Authors: N Walsh; S Kennedy; A M Larkin; D Tryfonopoulos; A J Eustace; T Mahgoub; C Conway; I Oglesby; D Collins; J Ballot; W S Ooi; G Gullo; M Clynes; J Crown; L O'Driscoll Journal: Br J Cancer Date: 2010-03-16 Impact factor: 7.640
Authors: Marine Chartrain; Joëlle Riond; Aline Stennevin; Isabelle Vandenberghe; Bruno Gomes; Laurence Lamant; Nicolas Meyer; Jean Edouard Gairin; Nicolas Guilbaud; Jean Philippe Annereau Journal: PLoS One Date: 2012-05-24 Impact factor: 3.240
Authors: Lourdes Hontecillas-Prieto; Daniel J Garcia-Dominguez; Diego Pascual Vaca; Rosa Garcia-Mejias; David Marcilla; Gema L Ramirez-Villar; Carmen Saez; Enrique de Álava Journal: Oncotarget Date: 2017-02-14