title: Preclinical combination therapy of the investigational drug NAMI-A(+) with doxorubicin for mammary cancer.
abstract: OBJECTIVE
  The tumor metastases targeting ruthenium complex NAMI-A synergistically improves the activity of gemcitabine in combination therapies. High-throughput screening was used to identify other potential drug combinations from a library of FDA approved drugs. Doxorubicin was identified as a hit compound and was therefore evaluated in combination with NAMI-A in vitro and in a preclinical in vivo model.
  
  
  RESULTS
  High-throughput screening identified eight structurally diverse compounds that synergize with NAMI-A including doxorubicin. The combination index on MCF-7 cells showed synergism as the concentration of NAMI-A increases independent of the doxorubicin concentration. In MCa mammary carcinoma of CBA mice, NAMI-A (35 mg/kg/day i.p. on days 7-12) followed by doxorubicin (10 mg/kg i.p. on day 16), significantly increased the effects of the individual drugs on metastases with 70 % animals resulting free of macroscopically detectable tumor nodules in the lungs at sacrifice. NAMI-A, unlike doxorubicin, cured 60 % of the treated mice but the combination therapy was toxic to the animals.
  
  
  CONCLUSIONS
  The combined therapy of NAMI-A with doxorubicin synergizes on lung metastasis in a preclinical mouse model. The combination therapy at the maximum tolerated doses of the two drugs is toxic. Hence, this combination is not suitable for clinical studies using maximum tolerated doses.
authors.affiliation: Callerio Foundation Onlus, via A. Fleming 22-31/b, 34127, Trieste, Italy.
authors.forename: Alberta
authors.initials: A
authors.lastname: Bergamo
authors.forename: Tina
authors.initials: T
authors.lastname: Riedel
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Dyson
authors.forename: Gianni
authors.initials: G
authors.lastname: Sava
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D002470:Cell Survival / Q000187:drug effects; D004121:Dimethyl Sulfoxide / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D004317:Doxorubicin / Q000008:administration & dosage; D006801:Humans; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008168:Lung / Q000378:metabolism; D008175:Lung Neoplasms / Q000188:drug therapy / Q000556:secondary; D061986:MCF-7 Cells; D015674:Mammary Neoplasms, Animal / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008808:Mice, Inbred CBA; D009942:Organometallic Compounds / Q000008:administration & dosage / Q000493:pharmacokinetics; D012428:Ruthenium / Q000378:metabolism; D017975:Ruthenium Compounds
chemical_list: D009942:Organometallic Compounds; D017975:Ruthenium Compounds; C113661:imidazolium-bis(imidazole)dimethylsulfoxideimidazotetrachlororuthenate(III); D012428:Ruthenium; D004317:Doxorubicin; D004121:Dimethyl Sulfoxide