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Journal ArticleDOI

Peptide receptor radionuclide therapy.

TL;DR: The combination of different radionuclides, such as 177Lu‐ and 90Y‐labeled somatostatin analogues, to reach a wider tumor region of high curability, has been described.
Abstract: On their plasma membranes, cells express receptor proteins with high affinity for regulatory peptides, such as somatostatin. Changes in the density of these receptors during disease, for example, overexpression in many tumors, provide the basis for new imaging methods. The first peptide analogues successfully applied for visualization of receptor-positive tumors were radiolabeled somatostatin analogues. The next step was to label these analogues with therapeutic radionuclides for peptide receptor radionuclide therapy (PRRT). Results from preclinical and clinical multicenter studies already have shown an effective therapeutic response when using radiolabeled somatostatin analogues to treat receptor-positive tumors. Infusion of positively charged amino acids reduces kidney uptake, enlarging the therapeutic window. For PRRT of CCK-B receptor-positive tumors, such as medullary thyroid carcinoma, radiolabeled minigastrin analogues currently are being successfully applied. The combination of different therapy modalities holds interest as a means of improving the clinical therapeutic effects of radiolabeled peptides. The combination of different radionuclides, such as (177)Lu- and (90)Y-labeled somatostatin analogues, to reach a wider tumor region of high curability, has been described. A variety of other peptide-based radioligands, such as bombesin and NPY(Y(1)) analogues, receptors for which are expressed on common cancers such as prostate and breast cancer, are currently under development and in different phases of (pre)clinical investigation. Multireceptor tumor targeting using the combination of bombesin and NPY(Y(1)) analogues is promising for scintigraphy and PRRT of breast carcinomas and their lymph node metastases.

Summary (3 min read)

RADIONUCLIDES AND SOMATOSTATIN ANALOGUES IN PEPTIDE RECEPTOR RADIONUCLIDE THERAPY

  • Several radiolabelled somatostatin analogues are currently used to treat patients with SSTR-positive metastasised GEP tumours.
  • Radionuclides emitting b-radiation have greater therapeutic potential since the emitted particle range exceeds the cell diameter.
  • SSTR2 remains the receptor subtype for which [111In-DTPA0]octreotide has the highest affinity.
  • Radiolabelled somatostatin analogues that had a higher affinity for SSTR2 than did 111In-octreotide, and were therefore potentially more effective for therapy, thus became available.

CLINICAL STUDIES

  • The outcome of several phase I and phase II PRRT studies, in which different radiolabelled somatostatin analogues were used, has been published.
  • Patients with stable disease and minor remission (17 out of 26; 65%) were considered to have shown a beneficial therapeutic effect as all patients had documented progressive disease at study entry.
  • And as a consequence a decrease in the number of therapeutic injections, could be more beneficial, it must be stressed that this was not a randomised controlled trial and the number of treated patients was low.
  • The reported results of therapy in terms of complete and partial remission percentages, ranging up to 37% (Table 4), indicated an improvement in therapeutic effectiveness compared with the studies with 111In-labelled octreotide.
  • The effect of 177Lu-DOTATATE therapy on tumour size, uptake on post-therapy scintigraphy, liver enzymes and the tumour marker chromogranin A in a patient who showed partial remission is shown in Figure 2.

Comparison of the different treatments

  • Treatment with 90Y- and 177Lu-labelled somatostatin analogues is very encouraging in terms of tumour shrinkage.
  • Direct comparison to evaluate the optimal treatment remains difficult.
  • Differences in treatment protocol, such as administered doses, dosing schemes and the tumour response criteria used, can be responsible for the observed differences in treatment outcome.
  • Therefore, randomised controlled trials are necessary to define the optimal PRRT and treatment scheme.

SIDE-EFFECTS AND RADIATION TOXICITY

  • Adverse reactions observed after PRRT can be divided into direct side-effects and the more delayed effects of radiotoxicity.
  • Direct effects commonly mentioned during and after therapy are nausea, vomiting and abdominal pain.
  • In general, these sideeffects occur in a minority of patients and are easily treated with anti-emetics or pain medication.
  • Mild hair loss was observed in patients treated with 177Lu-DOTATATE, but hair growth had normalised at follow-up 3–6 months after the last administration.
  • 17 Beside these mild side-effects, more serious toxicity may occur, especially to the bone marrow, kidneys and liver.

Haematological toxicity

  • In general, the decrease in blood cell count was transient, and transfusion was only occasionally needed.
  • More serious side-effecs were reported from a clinical trial in which 50 patients were treated with 111In-octreotide.
  • The other two patients, who had had no previous cytotoxic therapy, developed myelodysplastic syndrome after more than 3 years.
  • In the report by Kwekkeboom et al,45 who studied the patients treated with 177Lu-DOTATATE as PRRT, one patient in the whole group of patients who had been treated or were being treated up to that time (201 patients, 637 administrations) developed myelodysplastic syndrome.

Renal toxicity

  • Chelated somatostatin analogues are cleared predominantly by the kidneys.
  • 49 Because of the rapid clearance, [111In-DTPA0]octreotide can be safely applied for diagnostic use without any damage to the kidneys.
  • Some years later, a case report of a patient who developed late-onset renal insufficiency with a total cumulative dose of less than 7.4 GBq/m2 indicated that even less radiation can cause renal damage at a later time point.
  • Two recent studies in which patients were treated with 90Y-DOTATOC provided more insight into individual kidney dosimetry and its importance in PRRT.
  • Preclinical studies have shown that the infusion of positively charged amino acids, mainly L-lysine and L-arginine, are able to reduce the tubular reabsorption of radiolabelled somatostatin analogues in rats.

Liver toxicity

  • Most patients treated with PRRT in the clinical trials studied had liver metastases.
  • It is therefore not unlikely that PRRT can induce hepatocellular radiation injury.
  • In the group of patients treated with 177Lu-DOTATATE, significantly increased liver function parameters (grade 4 liver toxicity) was evident in two patients after the first cycle of treatment (D.J. Kwekkeboom, personal communication, 2004).
  • One patient, who suffered from a rapidly growing neuroendocrine tumour with extensive liver involvement, clinically progressed to liver failure within 3 weeks and died shortly thereafter.
  • Gradually, the liver function parameters and hyperbilirubinaemia returned to pre-therapy levels.

CLINICAL PRACTICE

  • In patients with metastasised GEP tumours, for whom surgery is no longer an option, PRRT can be an effective alternative therapeutic modality with limited side-effects.
  • PRRT has not been widely recognised as alternative systemic therapy.
  • Indications for peptide receptor radionuclide therapy Candidates for PRRT are those patients with inoperable GEP tumours who have progressive disease or symptomatology that is difficult to manage with medication.
  • 10 High uptake during 111In-octreotide scintigraphy has been shown to be correlated with tumour regression after PRRT.17 Additionally, because of the radiation to the bone marrow and the risk of temporary bone marrow suppression, patients need to fulfil certain minimal haematological criteria.
  • Kidney function has to be determined before therapy to exclude patients with signs of impending renal failure (glomerular filtration rate !40 ml/minute).

Timing of therapy

  • There is currently no consensus about when to start PRRT in patients with GEP tumours.
  • In a recent report in which the relationship between delay of diagnosis, extent of disease and survival in 115 patients with carcinoid was studied, a mean delay in the diagnosis of 66 months was found.
  • Strikingly, the delay of the diagnosis did not correlate with the extent of the disease.
  • In the multicentre trial with 111In-octreotide,6 it was reported that PRRT for end-stage patients with a higher tumour burden was less likely to have a favourable outcome than for patients with lower tumour burden or in a better general condition.
  • The combined results suggest that patients may experience a clinical benefit from PRRT.

FUTURE DEVELOPMENTS

  • It might therefore be a promising analogue to be used for treatment of patients with tumours that not bear only SSTR2, but also express SSTR3 and/or SSTR5.
  • In vitro and in vivo studies show that the irradiation of neuroendocrine AR42J (rat pancreatic tumour) cells can upregulate the expression of SSTR2 and gastrin receptors.
  • Most research in PRRT is focused on the different SSTR subtypes.

SUMMARY

  • Using radiolabelled peptides, which bind with high affinity to specific receptors on cancer cells, it is possible to target the cancer efficiently.
  • In GEP tumours, radiolabelled somatostatin analogue therapy has been proven to be effective.
  • Dose-limiting organs are the bone marrow and the kidneys.
  • With the currently used maximum allowed dose, PRRT is relatively safe, and serious side-effects are rare.

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Figures (8)

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8
Peptide receptor radionuclide therapy
Jaap J.M. Teunissen
*
MD
Dik J. Kwekkeboom
MD, PhD
Marion de Jong
PhD
Jan-Paul Esser
MD
Roelf Valkema
MD, PhD
Eric P. Krenning
MD, PhD
Professor and Head of the Department of Nuclear Medicine
Department of Nuclear Medicine, Erasmus MC,
Dr Molewaterplein 40, 3015 Rotterdam GD, The Netherlands
Peptide receptor radionuclide therapy is a new treatment modality for patients with inoperable or
metastasised neuroendocrine gastroenteropancreatic tumours. After the successful implementation
of somatostatin receptor scintigraphy in daily clinical practice, the next logical step was to increase
the radiation dose of the administered radiolabelled somatostatin analogue in an attempt to induce
tumour shrinkage. Since then, an increasing numberof patients has been successfully treated with this
approach, resulting in a substantial numbers of patient with objective tumour shrinkage. Serious side-
effects have been rare. This article reviews the effectiveness of the different radiolabelled
somatostatin analogues used, the currently known side-effects and the survival data available.
Furthermore, clinical issues, including indication and timing of therapy, are discussed. Finally,
important directions for future research are briefly mentioned to illustrate that, although the
currently available results already suggest a favourable outcome compared with other systemic
therapies, new strategies are being developed to increase efficacy.
Key words: neuroendocrine tumours; carcinoid tumour; somatostatin receptors; radiotherapy;
radionuclides.
Best Practice & Research Clinical Gastroenterology
Vol. 19, No. 4, pp. 595–616, 2005
doi:10.1016/j.bpg.2005.04.001
available online at http://www.sciencedirect.com
1521-6918/$ - see front matter Q 2005 Elsevier Ltd. All rights reserved.
*
Corresponding author. Address: Department of Nuclear Medicine, Erasmus MC, Dr Molewaterplein 40,
3015 GD Rotterdam, The Netherlands. Tel.: C31 10 463 4889; Fax: C31 10 463 5997.
E-mail addresses: j.teunissen@erasmusmc.nl (J.J.M. Teunissen), d.j.kwekkeboom@erasmusmc.nl (D.
J. Kwekkeboom), m.hendriks-dejong@erasmusmc.nl (M. de Jong), j.esser@erasmusmc.nl (J.-P. Esser),
r.valkema@erasmusmc.nl (R. Valkema), e.p.krenning@erasmusmc.nl (E.P. Krenning).

Somatostatin receptor (SSTR) scintigraphy, which was developed in the late 1980s, has
become an important image modality in patients with SSTR-positive tumours.
1,2
This is
not only because of its high sensitivity for visualising somatostatin-positive tumours and
thereby its ability to localise otherwise undetectable disease, but also because of the
selection of known metastatic disease for peptide receptor radionuclide therapy
(PRRT) with radiolabelled somatostatin analogues. This new modality of targeted
therapy is very promising, especially in patients with inoperable or metastatic
gastroenteropancreatic (GEP) tumours (i.e. gastrointestinal carcinoids and functioning
and non-functioning pancreatic endocrine tumours).
RADIONUCLIDES AND SOMATOSTATIN ANALOGUES IN PEPTIDE
RECEPTOR RADIONUCLIDE THERAPY
Several radiolabelled somatostatin analogues are currently used to treat patients with
SSTR-positive metastasised GEP tumours. These conjugates all consist of a
somatostatin analogue, such as octreotide or octreotate, a complexing moiety (or
chelator) and a radionuclide. The chelator, which is attached to the somatostatin
analogue, allows a stable connection between the analogue and the radionuclide. The
basic principle of tumour-targeting after systemic administration of the conjugate
involves binding to SSTRs, which are expressed on the cell surface of the tumour cell,
followed by effective internalisation of the radionuclide-peptide complex.
3–5
The
emitted radiation can damage the DNA, which may subsequently lead to the induction
of cell death. In clinical practice, different combinations of radionuclides and
somatostatin analogues are used to target the SSTR-positive tumour. These analogues
differ from each other in their affinity for the various SSTR subtypes. This variable
affinity is important because it can have great influence on the clinical effectiveness of
the radiolabelled somatostatin analogue. The available radionuclides and somatostatin
analogues used will be discussed.
Radionuclides in peptide receptor radionuclide therapy
Indium (
111
In), yttrium (
90
Y) and lutetium (
177
Lu) have been the most frequently used
radionuclides for targeted radiotherapy in the various clinical trials over the past
decade. Differences in the physical properties of these radionuclides, which are
important for the effectiveness of the therapy, relate to, for example, emitted particles,
particle energy and tissue penetration range (Ta b l e 1 ).
111
In, coupled via the chelator
DTPA to D-Phe
1
-octreotide ([
111
In-DTPA
0
]octreotide;
111
In-octreotide), was used in
the first clinical trials in which patients with metastasised GEP tumours were
treated with radiolabelled somatostatin analogues.
6–8
Besides g-radiation, which makes
111
In a suitable radionuclide for imaging, it emits both Auger and conversion electrons
with a medium-to-short tissue penetration range (0.02–10 and 200–500 mm,
respectively). In vitro PRRT studies with [
111
In-DTPA
0
]octreotide showed that the
therapeutic effect was dependent on internalisation, which enables the Auger electrons
to reach the nucleus.
9
These results suggest that the Auger electrons and not the
conversion electrons can be held responsible for the reported tumour responses with
111
In-labelled somatostatin analogues.
In an attempt to increase the efficacy of PRRT, clinical trials that followed used
b-emitting radionuclides, such as
90
Yor
177
Lu. Radionuclides emitting b-radiation have
596 J. J. M. Teunissen et al

greater therapeutic potential since the emitted particle range exceeds the cell
diameter.
10–12
Furthermore, the ability to irradiate neighbouring cells is an advantage
with tumours, such as breast carcinomas, that are characterised by a heterogeneous
SSTR tissue distribution, with regions of high density next to regions that lack receptor
expression.
13
As expected, the clinical and preclinical studies in which
90
Y- o r
177
Lu-
coupled somatostatin analogues were used demonstrated more effectiveness in
terms of tumour shrinkage than was reported with somatostatin analogues coupled to
111
In.
14–17
O’Donoghue et al,
12
who used a mathematical model to examine tumour
curability and its relationship to tumour size for 22 b-emitting radionuclides, calculated
an optimal tumour diameter for cure of 34 and 2 mm for
90
Y and
177
Lu, respectively.
With respect to these calculations, the preclinical studies by de Jong et al,
14,18
in
which Lewis rats bearing SSTR-positive pancreatic CA20948 tumours of different
sizes (0.1–15 cm
2
) were treated with [
177
Lu-DOTA
0
,Tyr
3
]octreotate (
177
Lu-DOTA-
TATE) and [
90
Y-DOTA
0
,Tyr
3
]octreotide (
90
Y-DOTATOC) are of special interest.
After treatment with
177
Lu-DOTATATE (total cumulative dose 555 MBq, maximum
estimated tumour dose 60 Gy), a higher cure rate was observed in the group of rats
bearing small tumours (%1cm
2
) than in the rats bearing larger tumours (R1cm
2
,
mean approximately 5 cm
2
). In contrast, treatment with a single dose of 370 MBq
90
Y-DOTATOC, leading up to a maximum of 60 Gy in the medium-sized (3–9 cm
2
)
tumours, showed less cure within the group of rats bearing small (%1cm
2
) tumours
compared with the rats bearing medium-sized tumours (Figure 1).
19
These results
suggested that treatment with a combination of
90
Y- and
177
Lu-labelled somatostatin
analogues can be more effective in the treatment of multiple tumours that differ in size
than can one of the analogues separately. Recently, de Jong et al
20
reported the
results of such a combination versus single analogue therapy. In rats bearing both a small
(!0.5 cm
2
) and a large tumour (7–9 cm
2
), significantly better survival was observed
after PRRTwith the combination of 185 MBq (half-dose)
90
Y-DOTATOC and 278 MBq
(half-dose)
177
Lu-DOTATATE than after a single full dose of 370 MBq
90
Y-DOTATOC or
555 MBq
177
Lu-DOTATATE.
To translate these results to the clinical setting with patients with GEP tumours,
90
Y-labelled somatostatin analogues may be more effective in larger tumours, whereas
177
Lu-labelled somatostatin analogues may be more effective in smaller tumours, with
the combination of both radionuclides as the most suitable therapy for the clinical
Table 1. Physical characteristics of the radionuclides used in peptide receptor radionuclide therapy.
Radionuclides
Emitted
particle
Particle energy
(mean keV)
Maximum tissue penetration
range (approximate number
of cells
a
) Half-life (days)
Indium (
111
In) Auger
electrons
3 and 19 keV 10 mm(!1) 2.8
g-radiation 171 and
245 keV
Yttrium (
90
Y) b-radiation 935 keV 12 mm (approximately 600) 2.7
Lutetium (
177
Lu) b-radiation 130 keV 2 mm (approximately 100) 6.7
g-radiation 113 and
208 keV
a
Number of cells based on an average tumour cell size of 20 mm.
Peptide receptor radionuclide therapy 597

situation in which most patients have tumour metastases varying in size. Unfortunately,
randomised controlled clinical studies comparing the therapeutic efficacy of
90
Y and
177
Lu somatostatin analogues or combination-based regimens are still lacking.
Somatostatin analogues in peptide receptor radionuclide therapy
The various
111
In-,
90
Y- o r
177
Lu-labelled somatostatin analogues differ in their affinity
for the expressed SSTRs. Five human SSTR subtypes (SSTR1–SSTR5) that bind native
human somatostatin (SS14) and its high-affinity 28 amino acid precursor (SS28) have
been cloned.
21–23
However, their affinities for synthetic somatostatin analogues differ
considerably. The ‘cold’ analogue octreotide, which is frequently used to control
symptoms related to hormone overproduction by GEP tumours, binds with high affinity
to SSTR2 and with low affinity to SSTR3 and SSTR5, whereas it does not bind to SSTR1
and SSTR4.
24,25
Furthermore, autoradiography studies by Reubi et al
26
demonstrated
that, after labelling octreotide, via DTPA, with
111
In, the affinities to SSTR2 and SSTR5
were diminished (Ta bl e 2). However, despite the change in affinities, SSTR2
[
90
Y-DOTA
0
, Tyr
3
]octreotide
< 1 cm
2
3-9 cm
2
0
25
50
75
100
CR
PR
percentage (%)
[
177
Lu-DOTA
0
, Tyr
3
]octreotate
< 1 cm
2
> 1 cm
2
0
25
50
75
100
C
R
PR
percentage (%)
Figure 1. Cure rate (expressed as percentage of cured rats) found in groups of rats bearing CA20948
tumours of different indicated sizes after treatment with 370 MBq[
90
Y- D OTA
0
,Tyr
3
]octreotide or
555 MBq[
177
Lu-DOTA
0
,Tyr
3
]octreotate (maximum estimated tumour dose of 60 Gy for both treatments).
CR, complete response; PR, partial response. (Modified from de Jong et al.
14
).
598 J. J. M. Teunissen et al

remains the receptor subtype for which [
111
In-DTPA
0
]octreotide has the
highest affinity. Hofland et al
27
demonstrated that the uptake of [
111
In-DTPA
0
]octreo-
tide in the SSTR-positive organs of mice was predominantly determined by SSTR2.
Moreover, John et al
28
demonstrated that a positive [
111
In-DTPA
0
]octreotide
scintigram in patients with neuroendocrine tumours is mainly the result of
SSTR2 expression, whereas SSTR1, SSTR3, SSTR4 and probably SSTR5 are less
important.
Radiolabelled somatostatin analogues that had a higher affinity for SSTR2 than did
111
In-octreotide, and were therefore potentially more effective for therapy, thus
became available. Small structural changes in the radioligand molecule, for example a
different radionuclide, chelator or peptide, revealed distinct differences in the
binding properties of the analogue for the various SSTR subtypes (Table 2).
26
In
animal experiments, several
111
In-labelled somatostatin analogues showed a higher
specific uptake than
111
In-labelled [DTPA
0
]octreotide in SSTR-positive organs.
5
Furthermore, the analogue [DOTA
0
,Tyr
3
]octreotate has a ninefold higher affinity for
SSTR2 compared with [DOTA
0
,Tyr
3
]octreotide, whereas the affinities for SSTR3
and SSTR5 were found to be lower.
26
In line with the higher affinity for SSTR2,
biodistribution studies on
111
In-octreotide and
177
Lu-DOTATATE scintigraphy
showed a three- to fourfold higher tumour uptake in four out of five patients
with somatostatin-positive tumours, of whom three had GEP tumours.
29
As most
GEP tumours are known to predominantly express SSTR2, all clinical studies
selected a radiolabelled somatostatin analogue for PRRT with at least a high affinity
for SSTR2.
Table 2. Affinity profiles (IC
50
)
a
for human somatostatin receptors SSTR1–SSTR5 (hSSTR1–hSSTR5) of a
series of somatostatin analogues.
Peptides hSSTR1 hSSTR2 hSSTR3 hSSTR4 hSSTR5
Somatostatin-28 5.2G0.3 (19) 2.7G0.3 (19) 7.7G0.9 (19) 5.6G0.4 (19) 4.0G0.3 (19)
Octreotide O10,000 (5) 2.0G0.7 (5) 187G55 (3) O1,000 (5) 22G6 (5)
DTPA-octreotide O10,000 (6) 12G2 (5) 376G84 (5) O1,000 (5) 299G50 (6)
111
In-octreotide O10,000 (5) 22G3.6 (5) 182G13 (5) O1,000 (5) 237G52 (5)
DOTATOC O10,000 (7) 14G2.6 (6) 880G324 (4) O1,000 (6) 393G84 (6)
90
Y- DOTATOC O10,000 (4) 11G1.7 (6) 389G135 (5) O10,000 (5) 114G29 (5)
DOTALAN O10,000 (7) 26G3.4 (6) 771G229 (6) O10,000 (4) 73G12 (6)
90
Y-DOTALAN O10,000 (3) 23G5 (4) 290G105 (4) O10,000 (4) 16G3.4 (4)
DOTA-OC O10,000 (3) 14G3 (4) 27G9 (4) O1,000 (4) 103G39 (3)
90
Y-DOTA-OC O10,000 (5) 20G2 (5) 27G8 (4) O10,000 (4) 57G22 (4)
DTPA-Tyr
3
-
octreotate
O10,000 (4) 3.9G1 (4) O10,000 (4) O1,000 (4) O1,000 (4)
111
In-DTPA-Tyr
3
-
octreotate
O10,000 (3) 1.3G0.2 (3) O10,000 (3) 433G16 (3) O1,000 (3)
DOTA-Tyr
3
-
octreotate
O10,000 (3) 1.5G0.4 (3) O1,000 (3) 453G176 (3) 547G160 (3)
90
Y-DOTA-Tyr
3
-
octreotate
O10,000 (3) 1.6G0.4 (3) O1,000 (3) 523G239 (3) 187G50 (3)
Modified from Reubi et al.
26
a
All values are IC
50
GSEM in nM. The number of experiments is in parentheses.
Peptide receptor radionuclide therapy 599

Citations
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Journal ArticleDOI
TL;DR: This research presents a meta-analyses of the immune system’s response to chemotherapy, which shows clear patterns of decline in the immune systems of patients with symptomatic oncologists and patients with a history of liver disease.
Abstract: a Department of Digestive and Liver Disease, Ospedale Sant’Andrea, Rome , Italy; b Department of Oncology, Royal Free University UFR Bichat-Beaujon-Louis Mourier, Colombes , France; c Digestive Oncology, University Hospital Gasthuisberg/Leuven, Leuven , Belgium; d Institute of Pathology, Catholic University – Policlinic A. Gemelli, Rome , Italy; e Department of Endocrinology, Medical University of Silesia, Katowice , Poland; f Department of Surgery, Rigshospitalet, Copenhagen University Hospital, Copenhagen , Denmark; g Department of Pathology, Tohoku University Graduate School of Medicine, Sendai , Japan; h Department of Internal Medicine and Gastroenterology, St. Orsola Hospital, University of Bologna, Bologna , Italy; i Institut Catala d’Oncologia (IDIBELL), Barcelona , Spain; j Department of Gastroenterology, Beaujon Hospital, Clichy , France

266 citations

Journal Article
TL;DR: The high density of GLP-1 receptors in insulinomas as well as the high specific uptake of [Lys(40)(Ahx-DTPA-(111)In)NH(2)]exendin-4 in the tumor of Rip1Tag2 mice indicate that targeting of GLp-1 receptor in insulinoma may become a useful imaging method to localize insulinomas in patients, either preoperatively or intraoperatively.
Abstract: High levels of glucagon-like peptide-1 (GLP-1) receptor expression in human insulinomas and gastrinomas provide an attractive target for imaging, therapy, and intraoperative tumor localization, using receptor-avid radioligands. The goal of this study was to establish a tumor model for GLP-1 receptor targeting and to use a newly designed exendin-4-DTPA (DTPA is diethylenetriaminepentaacetic acid) conjugate for GLP-1 receptor targeting. METHODS: Exendin-4 was modified C-terminally with Lys(40)-NH(2), whereby the lysine side chain was conjugated with Ahx-DTPA (Ahx is aminohexanoic acid). The GLP-1 receptor affinity (50% inhibitory concentration [IC(50)] value) of [Lys(40)(Ahx-DTPA)NH(2)]exendin-4 as well as the GLP-1 receptor density in tumors and different organs of Rip1Tag2 mice were determined. Rip1Tag2 mice are transgenic mice that develop insulinomas in a well-defined multistage tumorigenesis pathway. This animal model was used for biodistribution studies, pinhole SPECT/MRI, and SPECT/CT. Peptide stability, internalization, and efflux studies were performed in cultured beta-tumor cells established from tumors of Rip1Tag2 mice. RESULTS: The GLP-1 receptor affinity of [Lys(40)(Ahx-DTPA)NH(2)]exendin-4 was found to be 2.1 +/- 1.1 nmol/L (mean +/- SEM). Because the GLP-1 receptor density in tumors of Rip1Tag2 mice was very high, a remarkably high tumor uptake of 287 +/- 62 %IA/g (% injected activity per gram tissue) was found 4 h after injection. This resulted in excellent tumor visualization by pinhole SPECT/MRI and SPECT/CT. In accordance with in vitro data, [Lys(40)(Ahx-DTPA-(111)In)NH(2)]exendin-4 uptake in Rip1Tag2 mice was also found in nonneoplastic tissues such as pancreas and lung. However, lung and pancreas uptake was distinctly lower compared with that of tumors, resulting in a tumor-to-pancreas ratio of 13.6 and in a tumor-to-lung ratio of 4.4 at 4 h after injection. Furthermore, in vitro studies in cultured beta-tumor cells demonstrated a specific internalization of [Lys(40)(Ahx-DTPA-(111)In)NH(2)]exendin-4, whereas peptide stability studies indicated a high metabolic stability of the radiopeptide in beta-tumor cells and human blood serum. CONCLUSION: The high density of GLP-1 receptors in insulinomas as well as the high specific uptake of [Lys(40)(Ahx-DTPA-(111)In)NH(2)]exendin-4 in the tumor of Rip1Tag2 mice indicate that targeting of GLP-1 receptors in insulinomas may become a useful imaging method to localize insulinomas in patients, either preoperatively or intraoperatively. In addition, Rip1Tag2 transgenic mice represent a suitable animal tumor model for GLP-1 receptor targeting.

172 citations


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Journal ArticleDOI
TL;DR: The basic principles of Auger electron therapy as compared with vector-guided α and β radiation are discussed and some radioprotection issues are reviewed.
Abstract: Background Auger electron emitters that can be targeted into DNA of tumour cells represent an attractive systemic radiation therapy goal. In the situation of DNA-associated decay, the high linear energy transfer (LET) of Auger electrons gives a high relative biological efficacy similar to that of α particles. In contrast to α radiation, however, Auger radiation is of low toxicity when decaying outside the cell nucleus, as in cytoplasm or outside cells during blood transport. The challenge for such therapies is the requirement to target a high percentage of all cancer cells. An overview of Auger radiation therapy approaches of the past decade shows several research directions and various targeting vehicles. The latter include hormones, peptides, halogenated nucleotides, oligonucleotides and internalising antibodies.

163 citations

01 Jan 2006
TL;DR: In this article, a newly designed exendin-4-DTPA conjugate was used for GLP-1 receptor targeting in human insulinomas and gastrinomas using receptor-avid radioligands.
Abstract: High levels of glucagon-like peptide-1 (GLP-1) receptor expression in human insulinomas and gastrinomas provide an attractive target for imaging, therapy, and intraoperative tumor localization, using receptor-avid radioligands. The goal of this study was to establish a tumor model for GLP-1 receptor targeting and to use a newly designed exendin-4–DTPA (DTPA is diethylenetriaminepentaacetic acid) conjugate for GLP-1 receptor targeting. Methods: Exendin-4 was modified C-terminally with Lys 40 NH2, whereby the lysine side chain was conjugated with AhxDTPA (Ahx is aminohexanoic acid). The GLP-1 receptor affinity (50% inhibitory concentration [IC50] value) of [Lys 40 (Ahx-DTPA) NH2]exendin-4 as well as the GLP-1 receptor density in tumors and different organs of Rip1Tag2 mice were determined. Rip1Tag2 mice are transgenic mice that develop insulinomas in a well-defined multistage tumorigenesis pathway. This animal model was used for biodistribution studies, pinhole SPECT/MRI, and SPECT/ CT. Peptide stability, internalization, and efflux studies were performed in cultured b-tumor cells established from tumors of Rip1Tag2 mice. Results: The GLP-1 receptor affinity of [Lys 40 (Ahx-DTPA)NH2]exendin-4 was found to be 2.1 6

154 citations

Journal ArticleDOI
TL;DR: Treatment with radiolabelled somatostatin analogues presents a promising tool for the management of patients with inoperable or disseminated NETs, and particularly GEP tumours.
Abstract: Neuroendocrine tumours (NETs) constitute a heterogeneous group of tumours that frequently express cell membrane-specific peptide receptors, such as somatostatin receptors (SSTRs), and of which gastroenteropancreatic (GEP), carcinoid and pancreatic islet cell tumours exhibit the highest expression of SSTRs. Radiolabelled receptor-binding somatostatin analogues (octreotide and lanreotide) act as vehicles to guide radioactivity to tissues expressing SSTRs, and can thus be used for their diagnosis and treatment. After the localization of NETs bearing SSTRs with (111)In-octreotide (OctreoScan), a number of radioisotopes with different physical properties have been used for their treatment. The administration of high doses of the Auger electron and gamma-emitter (111)In-diethylenetriaminepenta-acetic acid (DTPA)(0),octreotide in patients with metastatic tumours has been associated with considerable symptomatic improvement but relatively few and short-lived objective tumour responses. The use of another radiolabelled somatostatin analogue coupled with (90)Y, a pure beta-emitter, (90)Y-1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid (DOTA)(0),Tyr(3),octreotide ((90)Y-DOTATOC, OctreoTher), was associated with 10-30% objective tumour response rates, and appears to be particularly effective in larger tumours. (111)In- and (90)Y-DOTA-lanreotide has also been used for the treatment of NETs although its therapeutic efficacy is probably inferior to that of octreotide-based radiopharmaceuticals. More recently, treatment with (177)Lu-DOTA(0),Tyr(3)octreotate ((177)Lu-DOTATATE), which has a higher affinity for the SSTR subtype 2, resulted in approximately 30% complete or partial tumour responses; this radiopharmaceutical is particularly effective in smaller tumours. Furthermore, treatment using both (90)Y-DOTATOC and (177)Lu-DOTA(0),Tyr(3)octreotate seems promising, as the combination of these radiopharmaceuticals could be effective in tumours bearing both small and large lesions. Tumour regression is positively correlated with a high level of uptake on (111)In-octreotide scintigraphy, limited tumour mass and good performance status. In general, better responses have been obtained in GEP tumours than other NETs. The side effects of this form of therapy are relatively few and mild, particularly when kidney-protective agents are used. Treatment with radiolabelled somatostatin analogues presents a promising tool for the management of patients with inoperable or disseminated NETs, and particularly GEP tumours.

154 citations

References
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Journal ArticleDOI
TL;DR: The successful application of radiolabelled octreotide in scintigraphy indicates the possible usefulness of other radiolABelled peptides, either native peptides or derivatives of these, in, for example, nuclear oncology.
Abstract: Various tumours, classically specified as either neuroendocrine or non-neuroendocrine, contain high numbers of somatostatin receptors, which enable in vivo localization of the primary tumour and its metastases by scintigraphy with the radiolabelled somatostatin analogue octreotide. In addition granulomas and autoimmune processes can be visualized because of local accumulation of somatostatin receptor-positive activated mononuclear leucocytes. In many instances a positive scintigram predicts a favourable response to treatment with octreotide. It is tempting to speculate that octreotide labelled with an appropriate radionuclide might be used in cancer therapy. The successful application of radiolabelled octreotide in scintigraphy indicates the possible usefulness of other radiolabelled peptides, either native peptides or derivatives of these, in, for example, nuclear oncology. The small size of these peptides, e.g. bombesin and substance P, is of the utmost importance for a relatively fast blood clearance, thus leading to low background radioactivity. In this way peptides are powerful alternatives to (fragments of) monoclonal antibodies, the application of which to scintigraphic localization of specific cell surface antigen-bearing tumours is plagued by slow blood clearance and, hence, high background levels.

1,498 citations

Journal ArticleDOI
TL;DR: In vivo somatostatin receptor scintigraphy using Octreoscan is a valuable method for the visualisation of human endocrine tumours and their metastases and small structural modifications, chelator substitution or metal replacement were shown to considerably affect the binding affinity.
Abstract: In vivo somatostatin receptor scintigraphy using Octreoscan is a valuable method for the visualisation of human endocrine tumours and their metastases. Recently, several new, alternative somatostatin radioligands have been synthesised for diagnostic and radiotherapeutic use in vivo. Since human tumours are known to express various somatostatin receptor subtypes, it is mandatory to assess the receptor subtype affinity profile of such somatostatin radiotracers. Using cell lines transfected with somatostatin receptor subtypes sst1, sst2, sst3, sst4 and sst5, we have evaluated the in vitro binding characteristics of labelled (indium, yttrium, gallium) and unlabelled DOTA-[Tyr3]-octreotide, DOTA-octreotide, DOTA-lanreotide, DOTA-vapreotide, DTPA-[Tyr3]-octreotate and DOTA-[Tyr3]-octreotate. Small structural modifications, chelator substitution or metal replacement were shown to considerably affect the binding affinity. A marked improvement of sst2 affinity was found for Ga-DOTA-[Tyr3]-octreotide (IC50 2.5 nM) compared with the Y-labelled compound and Octreoscan. An excellent binding affinity for sst2 in the same range was also found for In-DTPA-[Tyr3]-octreotate (IC50 1.3 nM) and for Y-DOTA-[Tyr3]-octreotate (IC50 1.6 nM). Remarkably, Ga-DOTA-[Tyr3]-octreotate bound at sst2 with a considerably higher affinity (IC50 0.2 nM). An up to 30-fold improvement in sst3 affinity was observed for unlabelled or Y-labelled DOTA-octreotide compared with their Tyr3-containing analogue, suggesting that replacement of Tyr3 by Phe is crucial for high sst3 affinity. Substitution in the octreotide molecule of the DTPA by DOTA improved the sst3 binding affinity 14-fold. Whereas Y-DOTA-lanreotide had only low affinity for sst3 and sst4, it had the highest affinity for sst5 among the tested compounds (IC50 16 nM). Increased binding affinity for sst3 and sst5 was observed for DOTA-[Tyr3]-octreotide, DOTA-lanreotide and DOTA-vapreotide when they were labelled with yttrium. These marked changes in subtype affinity profiles are due not only to the different chemical structures but also to the different charges and hydrophilicity of these compounds. Interestingly, even the coordination geometry of the radiometal complex remote from the pharmacophoric amino acids has a significant influence on affinity profiles as shown with Y-DOTA versus Ga-DOTA in either [Tyr3]-octreotide or [Tyr3]-octreotate. Such changes in sst affinity profiles must be identified in newly designed radiotracers used for somatostatin receptor scintigraphy in order to correctly interpret in vivo scintigraphic data. These observations may represent basic principles relevant to the development of other peptide radioligands.

1,022 citations

Journal ArticleDOI
TL;DR: Radioiodinated tyr-3-octreotide can label somatostatin receptors in endocrine-related tumours in vivo and can therefore be used for tumour localisation.

591 citations

Journal Article
TL;DR: A massive GRP receptor overexpression in prostate tissues that are neoplastically transformed or, like prostatic intraepithelial neoplasias, are in the process of malignant transformation is demonstrated.
Abstract: Bombesin-like peptides such as gastrin-releasing peptide (GRP) have been shown to play a role in cancer as autocrine growth factors that stimulate tumor growth through specific receptors. To search for potential clinical indications for GRP analogues, it is important to identify human tumor types expressing sufficient amounts of the respective receptors. In the present study, we have evaluated the expression of GRP receptors in human nonneoplastic and neoplastic prostate tissues using in vitro receptor autoradiography on tissue sections with 125I-Tyr4-bombesin as radio-ligand. GRP receptors were detected, often in high density, in 30 of 30 invasive prostatic carcinomas and also in 26 of 26 cases of prostatic intraepithelial proliferative lesions, corresponding mostly to prostatic intraepithelial neoplasias. Well-differentiated carcinomas had a higher receptor density than poorly differentiated ones. Bone metastases of androgen-independent prostate cancers were GRP receptor-positive in 4 of 7 cases. Conversely, GRP receptors were identified in only a few hyperplastic prostates and were localized in very low density in glandular tissue and, focally, in some stromal tissue. In all of the cases, the receptors corresponded to the GRP receptor subtype of bombesin receptors, having high affinity for GRP and bombesin and lower affinity for neuromedin B. These data demonstrate a massive GRP receptor overexpression in prostate tissues that are neoplastically transformed or, like prostatic intraepithelial neoplasias, are in the process of malignant transformation. GRP receptors may be markers for early molecular events in prostate carcinogenesis and useful in differentiating prostate hyperplasia from prostate neoplasia Such data may not only be of biological significance but may also provide a molecular basis for potential clinical applications such as GRP-receptor scintigraphy for early tumor diagnosis, radiotherapy with radiolabeled bombesin-like peptide analogues, and chemotherapy with cytotoxic bombesin analogues.

491 citations

Journal Article
TL;DR: High-dose targeted radiotherapy with 7.4 GBq/m(2) of the radiolabeled somatostatin analog (90)Y-DOTATOC is a well-tolerated treatment for neuroendocrine tumors, with remarkable clinical benefit and objective response.
Abstract: The aim of this prospective phase II study was to evaluate the tumor response of neuroendocrine tumors to high-dose targeted irradiation with 7.4 GBq/m2 of the radiolabeled somatostatin analog 90Y-1,4,7,10-tetra-azacyclododecan-4,7,10-tricarboxy-methyl-1-yl-acetyl-d-Phe-Tyr3-octreotide (DOTATOC). In addition, we investigated the clinical benefit of 90Y-DOTATOC regarding the malignant carcinoid syndrome and tumor-associated pain. Methods: Thirty-nine patients (mean age, 55 y) with progressive neuroendocrine gastroenteropancreatic and bronchial tumors were included. The treatment consisted of 4 equal intravenous injections of a total of 7.4 GBq/m290Y-DOTATOC, administered at intervals of 6 wk. After each treatment cycle, a standardized clinical benefit assessment using the National Cancer Institute grading criteria (NCI-CTC) was performed. Results: The objective response rate according to World Health Organization (WHO) criteria was 23%. For endocrine pancreatic tumors (13 patients), the objective response rate was 38%. Complete remissions were found in 5% (2/39), partial remissions in 18% (7/39), stable disease in 69% (27/39), and progressive disease in 8% (3/39). A significant reduction of clinical symptoms could be found in 83% of patients with diarrhea, in 46% of patients with flush, in 63% of patients with wheezing, and in 75% of patients with pellagra. The overall clinical benefit was 63%. All responses (both clinical benefit and WHO response) were ongoing for the duration of follow-up (median, 6 mo; range, 2–12 mo). Side effects were grade 3 or 4 (NCI-CTC) lymphocytopenia in 23%, grade 3 anemia in 3%, and grade 2 renal insufficiency in 3%. Conclusion: High-dose targeted radiotherapy with 7.4 GBq/m290Y-DOTATOC is a well-tolerated treatment for neuroendocrine tumors, with remarkable clinical benefit and objective response.

464 citations

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This article reviews the effectiveness of the different radiolabelled somatostatin analogues used, the currently known side-effects and the survival data available. Furthermore, clinical issues, including indication and timing of therapy, are discussed. Finally, important directions for future research are briefly mentioned to illustrate that, although the currently available results already suggest a favourable outcome compared with other systemic therapies, new strategies are being developed to increase efficacy. 

A direction of future research to improve current PRRT for GEP tumours includes the development of new stable somatostatin analogues with a high affinity for the different SSTR subtypes. 69 The concomitant expression of these receptors could be used in the future in a multireceptor PRRT to target more efficiently GEP tumours in each patient individually. 70 Although the patients were treated with external radiotherapy, gemcitabine and other radiosensitising agents with concurrent PRRT might prove effective in the future. It might therefore be a promising analogue to be used for treatment of patients with tumours that not bear only SSTR2, but also express SSTR3 and/or SSTR5.