title: In vitro evaluation of dichloro-bis(pyrazole)palladium(II) and dichloro-bis(pyrazole)platinum(II) complexes as anticancer agents.
abstract: BACKGROUND
  Cisplatin (cis-diamminedichloroplatinum) was first identified for its anti-bacterial activity, and was later also shown to be an efficient anticancer agent. However, the therapeutic use of this anticancer drug is somewhat limited by its toxic side effects, which include nephrotoxicity, nausea, and vomiting. Furthermore the development of drug-resistant tumours is commonly observed following therapy with cisplatin. Hence there is a need for improved platinum derived drugs to overcome these limitations.
  
  
  OBJECTIVE
  Apoptosis contributes significantly to the cytotoxic effects of anticancer agents such as cisplatin; therefore in this study the potential anticancer properties of a series of pyrazole palladium(II) and platinum(II) complexes, [(3,5-R(2)pz)(2)PdCl(2)] [R = H (1), R = Me (2)] and [(3,5-R(2)pz)(2)PtCl(2)] [R = H (3), R = Me (4)], were evaluated by assessment of their pro-apoptotic activity.
  
  
  METHODS
  The induction of apoptosis was measured in CHO cells by the detection of phosphatidylserine (PS) exposure using the annexin V and APOPercentage assays; DNA fragmentation using the Terminal deoxynucleotide transferase dUTP Nick End Labelling (TUNEL) assay; and the detection of activated caspase-3.
  
  
  RESULTS
  The platinum complexes were shown to be considerably more active than the palladium complexes, with complex 3 demonstrating the highest level of cytotoxic and pro-apoptotic activity. The LD(50) values for complex 3 and cisplatin were 20 and 70 microM, respectively, demonstrating that the cytotoxic activity for complex 3 was three times higher than for cisplatin. Various human cancer cell lines, including CaSki, HeLa, as well as the p53 mutant Jurkat T cell line were also shown to be susceptible to complex 3.
  
  
  CONCLUSIONS
  Collectively, this in vitro study provides insights into action of palladium and platinum complexes and demonstrates the potential use of these compounds, and in particular complex 3, in the development of new anticancer agents.
authors: Department of Chemistry, University of Johannesburg, P.O. Box 524, Auckland Park, 2006, South Africa.
authors: Frankline K
authors: FK
authors: Keter
authors: Stonard
authors: S
authors: Kanyanda
authors: Sylvester S L
authors: SS
authors: Lyantagaye
authors: James
authors: J
authors: Darkwa
authors: D Jasper G
authors: DJ
authors: Rees
authors: Mervin
authors: M
authors: Meyer
mesh_terms: D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D016466:CHO Cells / Q000187:drug effects; D045744:Cell Line, Tumor / Q000187:drug effects; D006224:Cricetinae; D003412:Cricetulus; D004353:Drug Evaluation, Preclinical; D006367:HeLa Cells / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D019169:Jurkat Cells / Q000187:drug effects; D015394:Molecular Structure; D009942:Organometallic Compounds / Q000737:chemistry / Q000494:pharmacology*; D009944:Organoplatinum Compounds / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D018906:Antineoplastic Agents, Alkylating; D009942:Organometallic Compounds; D009944:Organoplatinum Compounds; C533696:dichlorobis(3,5-dimethylpyrazole)palladium(II); C533695:dichlorobis(3,5-dimethylpyrazole)platinum(II); C533694:dichlorobis(pyrazole)palladium(II); C533697:dichlorobis(pyrazole)platinum(II)