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.