title: In vitro evaluation of targeted antisense 177Lu radiotherapy.
abstract: BACKGROUND
  The BCL2 proto-oncogene in non-Hodgkin's lymphoma is a dominant inhibitor of apoptosis. The goal of this work was to develop a (177)Lu-labeled anti-BCL2-peptide nucleic acid (PNA) conjugate designed for dual modality NHL therapy, i.e., simultaneous down-regulation of BCL2-mediated resistance to apoptosis and delivery of cytotoxic internally emitted radiation.
  
  
  METHODS
  The effect of 1,4,7,10-tetraazacyclododecane-N,N',N",N"'-tetra-acetic acid (DOTA)-anti-BCL2-Tyr(3)-octreotate was evaluated by uptake, efflux, proliferation, and viability assays, using Mec-1 lymphoma cells. In vitro dosimetry was modeled with a Monte Carlo projection.
  
  
  RESULTS
  Cellular efflux indicated moderate retention of radioactivity in the Mec-1 cells. Viability studies using the (177)Lu-labeled PNA conjugate indicated a mass-dose dependence and strongly additive statistical effect in reducing cellular viability.
  
  
  CONCLUSIONS
  These studies demonstrate the ability of a BCL2 antisense PNA conjugate to specifically target, be retained in, and reduce cellular viability in Mec-1 NHL cells. The results also hold promise for the development of a therapeutic radiopharmaceutical with potential dual modality function.
authors.affiliation: Area of Pathobiology, University of Missouri-Columbia, MO, U.S.A.
authors.forename: Ethan R
authors.initials: ER
authors.lastname: Balkin
authors.forename: Fang
authors.initials: F
authors.lastname: Jia
authors.forename: William H
authors.initials: WH
authors.lastname: Miller
authors.forename: Michael R
authors.initials: MR
authors.lastname: Lewis
mesh_terms: D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D056148:Chromatography, Reverse-Phase; D006801:Humans; D008187:Lutetium / Q000627:therapeutic use*; D058990:Molecular Targeted Therapy / Q000379:methods*; D015282:Octreotide / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D009942:Organometallic Compounds / Q000737:chemistry / Q000494:pharmacology; D020135:Peptide Nucleic Acids / Q000494:pharmacology*; D000090063:Proto-Oncogene Mas; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D011868:Radioisotopes / Q000627:therapeutic use*; D011874:Radiometry; D011878:Radiotherapy / Q000379:methods*
chemical_list: C000715470:MAS1 protein, human; D009942:Organometallic Compounds; D020135:Peptide Nucleic Acids; D000090063:Proto-Oncogene Mas; D019253:Proto-Oncogene Proteins c-bcl-2; D011868:Radioisotopes; D008187:Lutetium; C447941:lutetium Lu 177 dotatate; D015282:Octreotide