title: Interaction and cross-resistance of cisplatin and pemetrexed in malignant             pleural mesothelioma cell lines.
abstract: Although cisplatin and pemetrexed are key drugs in the treatment of malignant             pleural mesothelioma, their drug-drug interactions, cross-resistance and resistance             mechanisms in malignant pleural mesothelioma are not well understood. In the present             study, the interaction of these 2 agents was determined by clonogenic assays followed             by isobologram analysis of 4 human malignant pleural mesothelioma cell lines.             The cell lines were exposed to the agents using a stepwise dose-escalation method             to establish drug-resistant sublines. Thymidylate synthase mRNA expression was             evaluated in the drug-resistant sublines. As a consequence, cisplatin and pemetrexed             had synergistic effects in 3 cell lines and an additive effect in the fourth cell             line. The former 3 cell lines showed similar pemetrexed sensitivity in the parental             cells and their cisplatin-resistant sublines, whereas the fourth cell line exhibited             cross-resistance. In contrast, cisplatin had diverse effects on pemetrexed-resistant             sublines. High thymidylate synthase expression did not correlate with natural             pemetrexed resistance. Elevated thymidylate synthase expression correlated with             acquired pemetrexed resistance in 2 sublines. In conclusion, cisplatin and pemetrexed             showed synergistic activity and no cross-resistance in 3 of the 4 malignant pleural             mesothelioma cell lines, suggesting the clinical relevance of their combination             in chemotherapy. Thymidylate synthase expression did not necessarily correlate             with pemetrexed resistance. The information together with the experimental model             presented here would be useful for further investigating therapeutic targets of             malignant mesothelioma.
authors.affiliation: Department of Respirology, Graduate School of Medicine, Chiba                     University, Chiba, Japan.
authors.forename: Miyako
authors.initials: M
authors.lastname: Kitazono-Saitoh
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Takiguchi
authors.forename: Satoru
authors.initials: S
authors.lastname: Kitazono
authors.forename: Hironori
authors.initials: H
authors.lastname: Ashinuma
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kitamura
authors.forename: Yuji
authors.initials: Y
authors.lastname: Tada
authors.forename: Katsushi
authors.initials: K
authors.lastname: Kurosu
authors.forename: Emiko
authors.initials: E
authors.lastname: Sakaida
authors.forename: Ikuo
authors.initials: I
authors.lastname: Sekine
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Tanabe
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Tagawa
authors.forename: Koichiro
authors.initials: K
authors.lastname: Tatsumi
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology*; D004347:Drug Interactions; D019008:Drug Resistance, Neoplasm; D005971:Glutamates / Q000494:pharmacology*; D006147:Guanine / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D020128:Inhibitory Concentration 50; D008654:Mesothelioma; D000068437:Pemetrexed; D051026:Phosphoribosylglycinamide Formyltransferase / Q000378:metabolism; D010997:Pleural Neoplasms; D013762:Tetrahydrofolate Dehydrogenase / Q000378:metabolism; D013940:Thymidylate Synthase / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D005971:Glutamates; D000068437:Pemetrexed; D006147:Guanine; D013762:Tetrahydrofolate Dehydrogenase; D013940:Thymidylate Synthase; D051026:Phosphoribosylglycinamide Formyltransferase; D002945:Cisplatin