title: Preclinical animal research on therapy dosimetry with dual isotopes.
abstract: Preclinical research into radionuclide therapies based on radiation dosimetry will enable the use of any LET-equivalent radionuclide. Radiation dose and dose rate have significant influence on dose effects in the tumour depending on its radiation sensitivity, possibilities for repair of sublethal damage, and repopulation during or after the therapy. Models for radiation response of preclinical tumour models after peptide receptor radionuclide therapy based on the linear quadratic model are presented. The accuracy of the radiation dose is very important for observation of dose-effects. Uncertainties in the radiation dose estimation arise from incomplete assay of the kinetics, low accuracy in volume measurements and absorbed dose S-values for stylized models instead of the actual animal geometry. Normal dose uncertainties in the order of 20% might easily make the difference between seeing a dose-effect or missing it altogether. This is true for the theoretical case of a homogeneous tumour type behaving in vivo in the same way as its cells do in vitro. Heterogeneity of tumours induces variations in clonogenic cell density, radiation sensitivity, repopulation capacity and repair kinetics. The influence of these aspects are analysed within the linear quadratic model for tumour response to radionuclide therapy. Preclinical tumour models tend to be less heterogenic than the clinical conditions they should represent. The results of various preclinical radionuclide therapy experiments for peptide receptor radionuclide therapy are compared to the outcome of theoretical models and the influence of increased heterogeneity is analysed when the results of preclinical research is transferred to the clinic. When the radiation dose and radiobiology of the tumour response is known well enough it may be possible to leave the current phenomenological approach in preclinical radionuclide therapy and start basing these experiments on radiation dose. Then the use of a gamma ray-emitting radionuclides for a chemically comparable beta-particle-emitting paired isotope for therapy evaluation would be feasible.
authors.affiliation: Nuclear Medicine Department, Erasmus MC, Rotterdam, The Netherlands. m.konijnenberg@erasmusmc.nl
authors.forename: Mark W
authors.initials: MW
authors.lastname: Konijnenberg
authors.forename: Marion
authors.initials: M
authors.lastname: de Jong
mesh_terms: D000818:Animals; D004307:Dose-Response Relationship, Radiation; D004353:Drug Evaluation, Preclinical / Q000379:methods; D007205:Indium Radioisotopes / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use; D008187:Lutetium / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use; D009369:Neoplasms / Q000532:radiotherapy*; D011829:Radiation Dosage; D011868:Radioisotopes / Q000008:administration & dosage* / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D011874:Radiometry / Q000379:methods*; D019275:Radiopharmaceuticals / Q000627:therapeutic use; D011879:Radiotherapy Dosage; D051381:Rats; D015021:Yttrium Radioisotopes / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use
chemical_list: D007205:Indium Radioisotopes; D011868:Radioisotopes; D019275:Radiopharmaceuticals; D015021:Yttrium Radioisotopes; D008187:Lutetium