Somatostatin receptor gene therapy combined with targeted therapy with radiolabeled octreotide: a new treatment for liver metastases.
OBJECTIVE
To evaluate the effect of peptide receptor radionuclide therapy (PRRT) on somatostatin receptor (SSR)-transfected colon carcinoma cells in a rat liver metastases model.


BACKGROUND
Previously the authors have shown highly effective therapy with PRRT of SSR-positive tumors. This treatment is SSR-mediated; successful treatment is seen only in SSR-positive tumors, with no effect in SSR-negative tumors. As many tumors lack this receptor, the idea arose to transfect SSR-negative tumor cells with an SSR gene to apply PRRT on these SSR-transfected tumor cells.


METHODS
CC531 colon carcinoma cells (SSR-negative) were transfected in vitro with an SSR (subtype 2) gene (CC2B). Liver metastases were produced after intraportal injection of these tumor cells in rats. On day 7, animals were treated with 185 or 370 MBq [177 Lu-DOTA0, Tyr3 ]octreotate. After 21 days rats were killed and liver metastases were counted.


RESULTS
Treatment with 370 MBq [177 Lu-DOTA0, Tyr3 ]octreotate showed a significant antitumor response in rats with CC2B liver metastases (SSR-positive) in comparison with controls. No significant antitumor effect was seen in PRRT-treated rats with CC531 liver metastases (SSR-negative). Also, a dose-dependent tumor response was seen in rats with CC2B liver metastases treated with 185 MBq [ 177Lu-DOTA0, Tyr3 ]octreotate compared with controls. In addition, rats with mixed liver metastases treated with 185 MBq [177 Lu-DOTA0, Tyr3 ]octreotate had significantly fewer metastases compared with controls.


CONCLUSIONS
The authors showed an impressive antitumor effect of SSR (subtype 2)-transfected colon carcinoma cells with PRRT in a rat liver metastasis model. Moreover, rats with mixed liver metastases had significantly fewer liver metastases compared with control rats, which may be due to a radiologic bystander effect of [177 Lu-DOTA0, Tyr3 ]octreotate. This phenomenon is beneficial in the concept of in vivo gene therapy.
Mearadji
Amir
A
Department of Surgery, Erasmus Medical Center Rotterdam, Rotherdam, The Netherlands.
Breeman
Wout
W
Hofland
Leo
L
van Koetsveld
Peter
P
Marquet
Richard
R
Jeekel
Johannes
J
Krenning
Eric
E
van Eijck
Casper
C
D000230:Adenocarcinoma / Q000556:secondary / Q000628:therapy; D000704:Analysis of Variance; D000818:Animals; D003110:Colonic Neoplasms / Q000473:pathology / Q000628:therapy; D003131:Combined Modality Therapy; D004195:Disease Models, Animal; D015316:Genetic Therapy / Q000379:methods*; D007205:Indium Radioisotopes / Q000494:pharmacology*; D008099:Liver / Q000473:pathology*; D008113:Liver Neoplasms / Q000556:secondary* / Q000628:therapy*; D008297:Male; D009368:Neoplasm Transplantation; D015282:Octreotide / Q000494:pharmacology*; D011336:Probability; D051381:Rats; D011919:Rats, Inbred Strains; D017481:Receptors, Somatostatin / Q000008:administration & dosage* / Q000235:genetics; D012016:Reference Values; D012680:Sensitivity and Specificity; D014407:Tumor Cells, Cultured
D007205:Indium Radioisotopes; D017481:Receptors, Somatostatin; D015282:Octreotide