title: Effectiveness of two novel anionic and cationic platinum complexes in the treatment of osteosarcoma.
abstract: OBJECTIVE
  This study aimed to characterize the cellular basis of the platinum cytotoxicity of two novel platinum complexes, 3Pt and 1Pt, in comparison with that of cisplatin. 3Pt comprises anionic phosphate moieties, while 1Pt comprises neutral aromatic ligands.
  
  
  METHODS
  We compared the cytotoxic potency of 3Pt and 1Pt with that of cisplatin in osteosarcoma cell lines and an orthotopic mouse model.
  
  
  RESULTS
  The cytotoxic potency of 3Pt was markedly higher than that of cisplatin in all cell lines. Both novel platinum complexes showed a complete lack of cross resistance in cisplatin-resistant cells. Caffeine enhanced the cytotoxic potency of these novel platinum complexes, as observed for cisplatin. Apoptosis after drug administration was observed by DNA ladder formation and an annexin V/PI assay. DNA double-strand breaks were confirmed by phosphorylation of histone H2AX. In vivo, the antitumor activity of 3Pt and 1Pt was superior and similar, respectively, to that of cisplatin. Both novel platinum complexes exerted strong antitumor effects on osteosarcoma in vitro and in vivo.
  
  
  CONCLUSIONS
  3Pt may be an effective drug for the treatment of bone cancer because the PO3 moiety has a high affinity to bone, as exhibited by bisphosphonates, and is expected to decrease the incidence of side effects at extraskeletal sites and overcome drug resistance. Cationic 1Pt may also be an effective antitumor drug because of its unique chemical structure and properties. Further investigations to detail the antitumor effects of these ionic Pt complexes on osteosarcoma are warranted.
authors.forename: Kentaro
authors.initials: K
authors.lastname: Igarashi
authors.forename: Norio
authors.initials: N
authors.lastname: Yamamoto
authors.forename: Katsuhiro
authors.initials: K
authors.lastname: Hayashi
authors.forename: Akihiko
authors.initials: A
authors.lastname: Takeuchi
authors.forename: Shinji
authors.initials: S
authors.lastname: Miwa
authors.forename: Akira
authors.initials: A
authors.lastname: Odani
authors.affiliation: Department of Orthopedic Surgery, Kanazawa University, 13-1 Takaramachi, Kanazawa 920-8641, Japan. tsuchi@med.kanazawa-u.ac.jp.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Tsuchiya
mesh_terms: D000818:Animals; D000838:Anions / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D002412:Cations / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D005260:Female; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D015394:Molecular Structure; D009944:Organoplatinum Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D012516:Osteosarcoma / Q000188:drug therapy* / Q000473:pathology; D013329:Structure-Activity Relationship
chemical_list: D000838:Anions; D000970:Antineoplastic Agents; D002412:Cations; D009944:Organoplatinum Compounds