title: Cytotoxic activities of nucleoside and nucleobase analog drugs in malignant mesothelioma: characterization of a novel nucleobase transport activity.
abstract: This study was designed to evaluate the cytotoxic activity of several nucleoside and nucleobase analog drugs as possible new agents for treatment of malignant mesothelioma and to identify factors responsible for the clinical variation of nucleoside analog drug response in chemotherapy of mesothelioma. Three human mesothelioma cell lines (MSTO-211H, H2452 and H2052) were tested for gemcitabine sensitivity and nucleoside transport activity. MSTO-211H, H2452 and H2052 exhibited differences in sensitivity to gemcitabine, nucleoside transport rates and hENT1 site densities. In H2052 cells, gemcitabine, 5-fluoro-2'-deoxyuridine, clofarabine and cladribine were most active with IC(50) values of 46, 43, 240 and 490 nM, respectively, whereas 5-fluorouracil was the least cytotoxic drug tested. In H2052 cells, the combination of gemcitabine and fludarabine or cladribine resulted in synergistic cytotoxic response. In nucleobase transport studies, hypoxanthine and 6-mercaptopurine but not 5-fluorouracil was transported into H2052 cells by a novel purine-specific, sodium-independent nucleobase transport activity. In summary differences in nucleoside analog drug transport activities are likely to contribute to the observed clinical variation in nucleoside analog response in patients and for the first time a correlation between nucleobase drug sensitivities and transport activities was shown. A novel combination of gemcitabine and fludarabine or cladribine had synergistic cytotoxic activity against the least sensitive mesothelioma cell line. These drug combinations merit further evaluation as effective therapeutic regimens in patients with aggressive mesothelioma.
authors: Department of Oncology, University of Alberta, Alberta, Canada.
authors: Deepti
authors: D
authors: Damaraju
authors: Vijaya L
authors: VL
authors: Damaraju
authors: Miranda
authors: M
authors: Brun
authors: Delores
authors: D
authors: Mowles
authors: Michelle
authors: M
authors: Kuzma
authors: Richard C
authors: RC
authors: Berendt
authors: Michael B
authors: MB
authors: Sawyer
authors: Carol E
authors: CE
authors: Cass
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D001692:Biological Transport / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004176:Dipyridamole / Q000494:pharmacology; D004357:Drug Synergism; D033721:Equilibrative Nucleoside Transporter 1 / Q000378:metabolism; D006801:Humans; D008654:Mesothelioma / Q000188:drug therapy / Q000378:metabolism*; D009705:Nucleosides / Q000494:pharmacology*; D010208:Papaverine / Q000494:pharmacology; D011687:Purines / Q000378:metabolism / Q000494:pharmacology*; D011743:Pyrimidines / Q000378:metabolism / Q000494:pharmacology*; D013868:Thioinosine / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D033721:Equilibrative Nucleoside Transporter 1; D009705:Nucleosides; D011687:Purines; D011743:Pyrimidines; C438649:SLC29A1 protein, human; D013868:Thioinosine; D004176:Dipyridamole; D010208:Papaverine; C001789:4-nitrobenzylthioinosine