111In-labelled somatostatin analogues in a rat tumour model: somatostatin receptor status and effects of peptide receptor radionuclide therapy.
OBJECTIVE
Peptide receptor scintigraphy with the radioactive somatostatin analogue 111In-DTPA-octreotide is a sensitive and specific technique to show in vivo the presence of somatostatin receptors on various tumours. Since 111In emits not only gamma rays but also therapeutic Auger and internal conversion electrons with a medium to short tissue penetration (0.02-10 microm and 200-550 microm, respectively), 111In-DTPA-octreotide is also being used for peptide receptor radionuclide therapy (PRRT). In this study we investigated the therapeutic effects of 111In-DTPA-octreotide in tumours of various sizes. Regrowth of a tumour despite PRRT with 111In-DTPA-octreotide may be due to the lack of crossfire from 111In, whereby any possible receptor-negative tumour cell can multiply. We therefore also investigated the somatostatin receptor status of the tumour before and after PRRT.


METHODS
The radiotherapeutic effects of different doses of 111In-DTPA-octreotide in vivo were investigated in Lewis rats bearing small (< or = 1 cm2) or large (> or = 8 cm2) somatostatin receptor-positive rat pancreatic CA20948 tumours expressing the somatostatin receptor subtype 2 (sst2). In addition, the somatostatin receptor density on the tumour after injection of a therapeutic labelled somatostatin analogue was investigated when the tumour was either declining in size or regrowing after an initial reduction in size. To initiate a partial response of the tumour (so that regrowth would follow) and not a complete response, a relatively low dose was administered.


RESULTS
Impressive radiotherapeutic effects of 111In-labelled octreotide were observed in this rat tumour model. Complete responses (up to 50%) were found in the animals bearing small (< or 1 cm2) tumours after at least three injections of 111 MBq or a single injection of 370 MBq 111In-DTPA-octreotide, leading to a dose of 6.3-7.8 mGy/MBq (1-10 g tumour). In the rats bearing the larger (> or = 8 cm2) tumours, the effects were much less pronounced and only partial responses were achieved in these groups. Clear sst2 expression was found in the control as well as in the treated tumours. A significantly higher tumour receptor density (p<0.001) was found when the tumours regrew after an initial decline in size after low-dose PRRT in comparison with the untreated tumours.


CONCLUSIONS
Therapy with 111In-labelled somatostatin analogues is feasible but should preferably start as early as possible during tumour development. One might also consider the use of radiolabelled somatostatin analogues in an adjuvant setting after surgery of somatostatin receptor-positive tumours in order to eradicate occult metastases. We showed that PRRT led to an increase in the density of somatostatin receptors when the tumours regrew after an initial decline in size because of PRRT. Upregulation of the somatostatin receptor may lead to higher uptake of radiolabelled peptides in therapeutic applications, which would probably make repeated injections of radiolabelled peptides more effective.
Capello
Astrid
A
Nuclear Medicine, Erasmus MC, Dr Molewaterplein 40, 3015 Rotterdam, The Netherlands.
Krenning
Eric
E
Bernard
Bert
B
Reubi
Jean-Claude
JC
Breeman
Wout
W
de Jong
Marion
M
D000818:Animals; D014408:Biomarkers, Tumor / Q000378:metabolism; D001835:Body Weight / Q000528:radiation effects; D045744:Cell Line, Tumor; D004307:Dose-Response Relationship, Radiation; D008297:Male; D015282:Octreotide / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D010190:Pancreatic Neoplasms / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000532:radiotherapy*; D004369:Pentetic Acid / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics / Q000627:therapeutic use; D011879:Radiotherapy Dosage; D051381:Rats; D011917:Rats, Inbred Lew; D017481:Receptors, Somatostatin / Q000378:metabolism*; D015996:Survival Rate; D014018:Tissue Distribution; D016896:Treatment Outcome
C497824:111In-octreotide, DTPA(0)-; D014408:Biomarkers, Tumor; D019275:Radiopharmaceuticals; D017481:Receptors, Somatostatin; D004369:Pentetic Acid; D015282:Octreotide