title: Radiopharmaceutical therapy of patients with metastasized melanoma with the melanin-binding benzamide 131I-BA52.
abstract: The performance of cytotoxic drugs is defined by their selectivity of uptake and action in tumor tissue. Recent clinical responses achieved by treating metastatic malignant melanoma with therapeutic modalities based on gene expression profiling showed that malignant melanoma is amenable to systemic treatment. However, these responses are not persistent, and complementary targeted treatment strategies are required for malignant melanoma.
  
  
  METHODS
  Here we provide our experience with different labeling procedures for the radioiodination of benzamides and report on initial dosimetry data and the first therapeutic application of (131)I-BA52, a novel melanin-binding benzamide in patients with metastatic malignant melanoma. Twenty-six adults with histologically documented metastasized malignant melanoma received a single dose of 235 ± 62 MBq of (123)I-BA52 for planar and SPECT/CT imaging. Nine patients were selected for radionuclide therapy and received a median of 4 GBq (minimum, 0.51 GBq; maximum, 6.60 GBq) of the β-emitting radiopharmaceutical (131)I-BA52.
  
  
  RESULTS
  A trimethyltin precursor-based synthesis demonstrated high radiochemical yields in the large-scale production of radioiodinated benzamides required for clinical application. (123)I-BA52 showed specific uptake and long-term retention in tumor tissue with low transient uptake in the excretory organs. In tumor tissue, a maximum dose of 12.2 Gy per GBq of (131)I-BA52 was calculated. The highest estimated dose to a normal organ was found for the lung (mean, 3.1 Gy/GBq). No relevant acute or mid-term toxicity was observed with the doses administered until now. Even though dosimetric calculations reveal that the doses applied in this early phase of clinical application can be significantly increased, we observed antitumor effects with follow-up imaging, and single patients of the benzamide-positive cohort of patients (3/5 of the patients receiving a dose > 4.3 GBq) demonstrated a surprisingly long survival of more than 2 y.
  
  
  CONCLUSIONS
  These data indicate that systemic radionuclide therapy using (131)I-BA52 as a novel approach for the therapy of malignant melanoma is of considerable potential. Future trials should be done to enhance the precision of dosimetry, validate the maximum tolerable dose, and evaluate the effectiveness of the treatment in a prospective manner.
authors.affiliation: Department of Nuclear Medicine, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Walter
authors.initials: W
authors.lastname: Mier
authors.forename: Clemens
authors.initials: C
authors.lastname: Kratochwil
authors.forename: Jessica C
authors.initials: JC
authors.lastname: Hassel
authors.forename: Frederik L
authors.initials: FL
authors.lastname: Giesel
authors.forename: Barbro
authors.initials: B
authors.lastname: Beijer
authors.forename: John W
authors.initials: JW
authors.lastname: Babich
authors.forename: Matthias
authors.initials: M
authors.lastname: Friebe
authors.forename: Michael
authors.initials: M
authors.lastname: Eisenhut
authors.forename: Alexander
authors.initials: A
authors.lastname: Enk
authors.forename: Uwe
authors.initials: U
authors.lastname: Haberkorn
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001549:Benzamides / Q000737:chemistry* / Q000627:therapeutic use*; D052117:Benzodioxoles / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D007457:Iodine Radioisotopes / Q000627:therapeutic use*; D008297:Male; D008543:Melanins / Q000737:chemistry*; D008545:Melanoma / Q000532:radiotherapy*; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D009154:Mutation; D009362:Neoplasm Metastasis; D010641:Phenotype; D011874:Radiometry; D019275:Radiopharmaceuticals / Q000627:therapeutic use*; D011878:Radiotherapy / Q000639:trends; D015899:Tomography, Emission-Computed, Single-Photon; D014057:Tomography, X-Ray Computed
chemical_list: D001549:Benzamides; D052117:Benzodioxoles; D007457:Iodine Radioisotopes; D008543:Melanins; D019275:Radiopharmaceuticals; C586676:benzo(1,3)dioxolo-5-carboxylic acid (4-(2-diethylaminoethylcarbamoyl)-2-iodo-5-methoxyphenyl)amide; C037689:benzamide
keywords: malignant melanoma; melanin; personalized medicine; radionuclide therapy; tumor targeting