title: The effect of drug dose and drug exposure time on the binding, internalization, and cytotoxicity of radiolabeled somatostatin analogs.
abstract: BACKGROUND
  Creation of protease-resistant somatostatin analogs has allowed development of these peptides as clinically useful drugs. Widespread diagnostic use of radiolabeled somatostatin analogs has enhanced interest in the binding and intracellular distribution of these peptides. The degree of drug internalization and length of drug retention may be critical for drug-induced cytotoxicity. We hypothesized that the ability of a radiolabeled peptide to bind to a cell, be internalized, and induce cytotoxicity is proportional to both the radioligand concentration and the exposure time.
  
  
  METHODS
  To test this hypothesis, somatostatin receptor-expressing cells (IMR-32) were incubated with (111)In-pentetreotide, a sst 2 preferring somatostatin analogue. Radioligand exposure time and/or concentration were varied.
  
  
  RESULTS
  Prolonged exposure to a fixed concentration of radioligand resulted in progressive increases in whole cell binding and internalization over time. Cells exposed to a relatively fixed number of microCi-Hr yielded constant whole cell binding and internalization. Increasing the microCi-Hr resulted in a proportionate increase in binding. Cytotoxicity was also proportional to the dose of radiation regardless of whether the exposure was internalized radiation (microCi-Hr from (111)In-pentetreotide) or from external beam radiation (cGy).
  
  
  CONCLUSIONS
  Both drug exposure time and drug concentration contribute to cell binding and cytotoxicity in this model and their relative contributions are inversely related.
authors.affiliation: Department of Surgery, Louisiana State University Health Sciences Center, New Orleans 70112, USA.
authors.forename: Catherine T
authors.initials: CT
authors.lastname: Anthony
authors.forename: Susan
authors.initials: S
authors.lastname: Hughey
authors.forename: John
authors.initials: J
authors.lastname: Lyons
authors.forename: Sean
authors.initials: S
authors.lastname: Weiss
authors.forename: Conrad A
authors.initials: CA
authors.lastname: Hornick
authors.forename: George J
authors.initials: GJ
authors.lastname: Drouant
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Fuselier
authors.forename: David H
authors.initials: DH
authors.lastname: Coy
authors.forename: William A
authors.initials: WA
authors.lastname: Murphy
authors.forename: Eugene A
authors.initials: EA
authors.lastname: Woltering
mesh_terms: D001692:Biological Transport; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007205:Indium Radioisotopes; D009994:Osmolar Concentration; D011869:Radioligand Assay; D013004:Somatostatin / Q000008:administration & dosage* / Q000031:analogs & derivatives* / Q000378:metabolism* / Q000493:pharmacokinetics; D013997:Time Factors
chemical_list: D007205:Indium Radioisotopes; D013004:Somatostatin; C081788:pentetreotide