Molecular imaging and treatment of malignant gliomas following adenoviral transfer of the herpes simplex virus-thymidine kinase gene and the somatostatin receptor subtype 2 gene.
Patients suffering from malignant glioma have a very poor prognosis. New therapy approaches for gliomas are necessary; these tumors are attractive targets for gene therapy. Our research concentrated on evaluation of the use of the Herpes Simplex Virus-thymidine kinase (tk) enzyme and the somatostatin receptor subtype 2 (sst2). DOTA-Tyr3-octreotate is an analog of somatostatin with high affinity for sst2. It shows rapid internalization in sst2-positive tumor cells in vitro and in vivo. For gene therapy, we used the adenoviral vector Ad5.tk.sstr, which carries the tk gene and the sst2 gene. The aim of our study was to compare uptake of the tk substrate 1-(2-fluoro-2-deoxy-beta-D-ribofuranosyl)-5-[*I]iodouracil (FIRU) labeled with 125I and the somatostatin analog 111In-DOTA-Tyr3-octreotate in several glioma cell lines after infection with Ad5.tk.sstr. Uptake of 125I-FIRU was measured in rat 9L-tk glioma cells without infection with Ad5.tk.sstr. Results showed that the uptake of 125I-FIRU was concentration and time dependent. We also used several rat and human glioma cell lines for infection with Ad5.tk.sstr. Forty-eight hours after infection, uptake studies were performed using 125I-FIRU and 111In-DOTA-Tyr3-octreotate. In all cell lines, the uptake of 125I-FIRU and 111In-DOTA-Tyr3-octreotate increased with increasing multiplicity of infection of virus and showed that the uptake of 111In-DOTA-Tyr3-octreotate was higher than that of 125I-FIRU in all cell lines. We conclude that the sst2 imaging and therapy modality is most promising for glioma gene therapy, either alone or in combination with HSV-tk suicide gene therapy. Therapy can be performed using combinations of DOTA-Tyr3-octreotate radiolabeled with 177Lu or 90Y, 131I-FIRU and/or the prodrug ganciclovir.
Verwijnen
Suzanne M
SM
Department of Nuclear Medicine, Erasmus MC, Rotterdam, The Netherlands. s.m.verwijnen@erasmusmc.nl
Sillevis Smith
Peter A E
PA
Hoeben
Rob C
RC
Rabelink
Martin J W E
MJ
Wiebe
Leonard
L
Curiel
David T
DT
Hemminki
Akseli
A
Krenning
Eric P
EP
de Jong
Marion
M
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D045744:Cell Line, Tumor; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000235:genetics; D005910:Glioma / Q000000981:diagnostic imaging* / Q000235:genetics / Q000378:metabolism / Q000628:therapy*; D018259:Herpesvirus 1, Human / Q000201:enzymology* / Q000235:genetics; D006801:Humans; D007205:Indium Radioisotopes / Q000493:pharmacokinetics; D007457:Iodine Radioisotopes / Q000493:pharmacokinetics; D009705:Nucleosides / Q000493:pharmacokinetics; D015282:Octreotide / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D011877:Radionuclide Imaging; D051381:Rats; D017481:Receptors, Somatostatin / Q000235:genetics / Q000627:therapeutic use*; D013937:Thymidine Kinase / Q000235:genetics / Q000627:therapeutic use*; D014162:Transfection
D007205:Indium Radioisotopes; D007457:Iodine Radioisotopes; D009705:Nucleosides; D017481:Receptors, Somatostatin; C093733:somatostatin receptor 2; D013937:Thymidine Kinase; D015282:Octreotide; C106246:Edotreotide