title: Changes in the in vitro activity of platinum drugs when administered in two aliquots.
abstract: The management of ovarian cancer remains a challenge. Because of the lack of early symptoms, it is often diagnosed at a late stage when it is likely to have metastasized beyond ovaries. Currently, platinum based chemotherapy is the primary treatment for the disease. However acquired drug resistance remains an on-going problem. As cisplatin brings about apoptosis by intrinsic and extrinsic pathways, this study aimed to determine changes in activity of platinum drugs when administered in two aliquots as against a bolus and sought to determine association with changes in GSH, speciation of platinum drugs and changes in protein expression.
  
  
  
  The efficacy of administering cisplatin, carboplatin and oxaliplatin in two aliquots with a time gap was investigated in ovarian A2780, A2780(cisR), A2780(ZD0473R) and SKOV-3 cell lines. The cellular accumulation of platinum, level of platinum - DNA binding and cellular glutathione level were determined, and proteomic studies were carried out to identify key proteins associated with platinum resistance in ovarian A2780(cisR) cancer cell line.
  
  
  
  Much greater cell kill was observed with solutions left standing at room temperature than with freshly prepared solutions, indicating that the increase in activity on ageing was related to speciation of the drug in solution. Proteomic studies identified 72 proteins that were differentially expressed in A2780 and A2780(cisR) cell lines; 22 of them were restored back to normal levels as a result of synergistic treatments, indicating their relevance in enhanced drug action.
  
  
  
  The proteins identified are relevant to several different cellular functions including invasion and metastasis, cell cycle regulation and proliferation, metabolic and biosynthesis processes, stress-related proteins and molecular chaperones, mRNA processing, cellular organization/cytoskeleton, cellular communication and signal transduction. This highlights the multifactorial nature of platinum resistance in which many different proteins with diverse functions play key roles. This means multiple strategies can be harnessed to overcome platinum resistance in ovarian cancer. The results of the studies can be significant both from fundamental and clinical view points.
authors: Discipline of Biomedical Science, Sydney Medical School, University of Sydney, Sydney, NSW, 2141, Australia.|Department of Medical Laboratory Sciences, Faculty of Allied Health Science, Hashemite University, Zarqa, Hashemite Kingdom of Jordan.
authors: Zaynab
authors: Z
authors: Al-Eisawi
authors: Sydney Cancer Centre, Concord Hospital, Sydney, NSW, 2139, Australia.
authors: Philip
authors: P
authors: Beale
authors: Department of Pathology, Concord Hospital, Sydney, NSW, 2139, Australia.
authors: Charles
authors: C
authors: Chan
authors: Discipline of Biomedical Science, Sydney Medical School, University of Sydney, Sydney, NSW, 2141, Australia.
authors: Jun Qing
authors: JQ
authors: Yu
authors: Mass Spectrometry Unit, School of Chemistry, University of Sydney, Sydney, NSW, 2006, Australia.
authors: Nicholas
authors: N
authors: Proschogo
authors: Australian Proteome Analysis Facility, Macquarie University, Sydney, NSW, 2109, Australia.
authors: Mark
authors: M
authors: Molloy
authors: Discipline of Biomedical Science, Sydney Medical School, University of Sydney, Sydney, NSW, 2141, Australia. Fazlul.Huq@sydney.edu.au.|Discipline of Biomedical Science, School of Medical Sciences, Sydney Medical School, The University of Sydney, Cumberland Campus C42, 75 East Street, Lidcombe, NSW, 1825, Australia. Fazlul.Huq@sydney.edu.au.
authors: Fazlul
authors: F
authors: Huq
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage*; D017209:Apoptosis / Q000187:drug effects; D016190:Carboplatin / Q000008:administration & dosage*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects*; D002945:Cisplatin / Q000008:administration & dosage*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D009944:Organoplatinum Compounds / Q000008:administration & dosage*; D010051:Ovarian Neoplasms; D000077150:Oxaliplatin; D040901:Proteomics; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
chemical_list: D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D016190:Carboplatin; D002945:Cisplatin
keywords: Aging effect; Carboplatin (CB); Cisplatin (CS); Drug combination; Drug resistance; Drug uptake; Oxaliplatin (OX); Synergism