title: Combination of arsenic trioxide and chemotherapy in small cell lung cancer.
abstract: BACKGROUND
  Small cell lung cancer (SCLC) carries high mortality despite standard chemotherapy. Arsenic trioxide (ATO) has demonstrated clinical efficacy in leukemia and in vitro activity in various solid tumors. This study was conducted to determine the in vitro and in vivo combination effects of ATO and chemotherapy in SCLC.
  
  
  METHODS
  The in vitro model consisted of 5 SCLC cell lines (H187, H526, H69, H841 and DMS79) and the anti-proliferative effects of ATO, cisplatin, etoposide or combinations thereof were measured. Synergism was determined by calculation of the combination index (CI) according to Chou and Talalay. Assays for apoptosis, intracellular glutathione (GSH) content, and mitochondrial membrane depolarization (MMD) were performed. Arsenic content was measured by inductively coupled plasma-mass spectrometry. Expression level of MRP1, MRP2 and pH2AX was detected by Western blot while cellular pH2AX level was monitored by immunofluorescent staining. An in vivo xenograft model in nude mice was established with a H841 cell line to test the effects of drug combinations.
  
  
  RESULTS
  All 5 SCLC cell lines were sensitive to ATO, with IC(50) values (48 h) 1.6-8 μM. Synergistic or additive effects were obtained by combining cisplatin with ATO in all 5 cell lines. Combination of etoposide with ATO resulted in antagonistic or barely additive effects. Apoptotic assays and pH2AX immunofluorescent staining corroborated the synergistic combination of ATO and cisplatin. In addition, the ATO/cisplatin combination enhanced MMD, depleted GSH, downregulated MRP2 and elevated intracellular ATO content compared with either ATO or cisplatin alone. In vivo combination of ATO and cisplatin also demonstrated synergism in the H841 xenograft model.
  
  
  CONCLUSIONS
  There was clinically relevant in vitro activity of ATO in a panel of 5 SCLC cell lines. Significant synergism was demonstrated with the ATO/cisplatin combination, while antagonism was noted with the ATO/etoposide combination in both in vitro and in vivo models.
authors.affiliation: Division of Respiratory Medicine, Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong Special Administrative Region.
authors.forename: Chun-yan
authors.initials: CY
authors.lastname: Zheng
authors.forename: Sze-kwan
authors.initials: SK
authors.lastname: Lam
authors.forename: Yuan-yuan
authors.initials: YY
authors.lastname: Li
authors.forename: Bonnie Mei-wah
authors.initials: BM
authors.lastname: Fong
authors.forename: Judith Choi-wo
authors.initials: JC
authors.lastname: Mak
authors.forename: James Chung-man
authors.initials: JC
authors.lastname: Ho
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000008:administration & dosage / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology / Q000633:toxicity; D004249:DNA Damage; D004195:Disease Models, Animal; D004357:Drug Synergism; D005047:Etoposide / Q000494:pharmacology / Q000633:toxicity; D005260:Female; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism; D010087:Oxides / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity; D017382:Reactive Oxygen Species / Q000378:metabolism; D055752:Small Cell Lung Carcinoma / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D000077237:Arsenic Trioxide; D001152:Arsenicals; D002945:Cisplatin; D005047:Etoposide; D005978:Glutathione; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D010087:Oxides; D017382:Reactive Oxygen Species; C000715087:ABCC2 protein, human; C421109:multidrug resistance-associated protein 1
keywords: Arsenic trioxide; Cisplatin; Etoposide; Mechanism; Small cell lung cancer; Synergism