Therapeutic use of radiolabelled peptides

Abstract

The inhibitory effect of somatostatin (SS) on hormone secretion led to its use in the treatment of diseases. SS itself is unsuitable for this purpose because of its very short half-life in plasma after intravenous injection and because of its diversity of actions, such as lowering insulin levels. Therefore, more stable analogues have been synthesized, e.g. octreotide [D-Phe-c(Cys-Phe-D-Trp-Lys-Thr-Cys)-Thr(ol)]. Somatostatin receptors are integral membrane glycoproteins. Five different human somatostatin receptor types have been cloned. All subtypes bind SS14 with high affinity, while octreotide binds with high affinity to the somatostatin receptor subtype 2 (sst2), with lower affinity to sst3 and sst5 and it shows no binding to ssti and ssU [1-4]. Peptide receptor scintigraphy with the radioactive somatostatin-analogue [In-DTPA°]octreotide is a sensitive and specific technique to show in vivo the presence and abundance of somatostatin receptors on various tumours [5,6]. A new and most promising application is the use of radiolabeled peptides for peptide receptor radionuclide therapy. The success of the therapeutic strategy relies upon the amount of radioligand that can be concentrated within tumour cells and the rates of internalisation, degradation and recycling of both ligand and receptor will among other things determine this. Binding of peptide hormones to specific surface receptors is generally followed by internalisation of the ligand-receptor complex, for radiolabeled [DTPA°]octreotide this process appeared to be receptor-specific and temperature dependent [7,8]. Internalisation of [In-DTPA°]octreotide results in degradation to In-DTPA-D-Phe [9], this metabolite is not capable of passing the lysosomal membrane, thereby explaining the long retention time of radioactivity in target cells (see below). Since n i I n emits not only gamma-rays, but also short-ranged Auger electrons, an effect on tumour cell proliferation could be expected, as the radiotoxicity of Auger electrons is very high if the DNA of the cell is within the particle range [10]. m I n emits Auger and conversion electrons having a tissue penetration of 0.02 to 10 \im and 200 to 500 \x.m, respectively, and therefore we started to investigate the antiproliferative effect in cancer. We reported a biological half-life for m I n of >700 h in human tumour tissue [5], so In-labeled [DTPA°]octreotide has an appropriate distribution profile in humans for both scintigraphy and radionuclide therapy [11]. Earlier we reported [12] that high radioactive doses with [In-DTPA°]octreotide for radionuclide therapy inhibited the growth of somatostatin receptor-positive liver metastases in rats, radionuclide therapy efficacy was dependent on receptor presence. For radiotherapeuu'c applications also other radionuclides have been proposed and investigated for coupling to octreotide analogues. ^ Y is a (J-particle emitter, the maximum energy of the electrons is 2.3 MeV, their mean range is a few mm in tissue. ^ Y shows dissociation from DTPA-conjugated peptides in serum, resulting in haematopoietic toxicity in vivo, therefore, Tyr-octreotide [D-Phec(Cys-Tyr-D-Trp-Lys-Thr-Cys)-Thr(ol)], which has a higher binding affinity for sst2 than octreotide itself, has been derivatised with the chelator DOTA enabling stable radiolabeling with both ^ Y and m I n . Preclinical and clinical studies with [DOTA°,Tyr]octreotide showed favourable biodistribution and tumour uptake [13,14].