Up-regulation of somatostatin receptor density on rat CA20948 tumors escaped from low dose [177Lu-DOTA0,Tyr3]octreotate therapy.
OBJECTIVE
Peptide receptor radionuclide therapy using the somatostatin analogue [(177)Lu-DOTA(0),Tyr(3)]octreotate is a convincing treatment modality for metastasized neuroendocrine tumors. Therapeutic doses are administered in 4 cycles with 6-10 week intervals. A high somatostatin receptor density on tumor cells is a prerequisite at every administration to enable effective therapy. In this study, the density of the somatostatin receptor subtype 2 (sst2) was investigated in the rat CA20948 pancreatic tumor model after low dose [(177)Lu-DOTA(0), Tyr(3)]octreotate administration resulting in approximately 20 Gy tumor radiation absorbed dose, whereas 60 Gy is needed to induce complete tumor regression in these and the majority of tumors.


METHODS
Sixteen days after inoculation of the CA20948 tumor, male Lewis rats were injected with 185 MBq [(177)Lu-DOTA(0),Tyr(3)]octreotate to initiate a decline in tumor size. Approximately 40 days after injection, tumors re-grew progressively after initial response. Quantification of sst2 expression was performed using in vitro autoradiography on frozen sections of three groups: control (not-treated) tumors, tumors in regression and tumors in re-growth. Histology and proliferation were determined using HE- and anti-Ki-67-staining.


RESULTS
The sst2 expression on CA20948 tumor cells decreased significantly after therapy to 5% of control level. However, tumors escaping from therapy showed an up-regulated sst2 level of 2-5 times higher sst2 density compared to control tumors.


CONCLUSIONS
After a suboptimal therapeutic dose of [(177)Lu-DOTA(0),Tyr(3)]octreotate, escape of tumors is likely to occur. Since these cells show an up-regulated sst2 receptor density, a next therapeutic administration of radiolabelled sst2 analogue can be expected to be highly effective.
Melis
M
M
Department of Nuclear Medicine, Erasmus MC Rotterdam Rotterdam, The Netherlands. m.melis@erasmusmc.nl
Forrer
F
F
Capello
A
A
Bijster
M
M
Bernard
B F
BF
Reubi
J C
JC
Krenning
E P
EP
De Jong
M
M
D000818:Animals; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic / Q000528:radiation effects; D008297:Male; D015282:Octreotide / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D009942:Organometallic Compounds / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D010190:Pancreatic Neoplasms / Q000378:metabolism* / Q000532:radiotherapy*; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D011879:Radiotherapy Dosage; D051381:Rats; D011917:Rats, Inbred Lew; D017481:Receptors, Somatostatin / Q000378:metabolism*; D016896:Treatment Outcome; D015854:Up-Regulation
D009942:Organometallic Compounds; D019275:Radiopharmaceuticals; D017481:Receptors, Somatostatin; C115977:Sstr2 protein, rat; C447941:lutetium Lu 177 dotatate; D015282:Octreotide