Pharmacokinetics and dosimetry of radiolabelled octreotide for tumour therapy

Somatostatin (SS) receptors (sstr) are usually highly expressed on neuroendocrine (NE) tumours. The radiolabelled SS analogue 111In-DTPA-D-Phe1-octreotide is today widely used to scintigraphically visualise NE tumours, and high 111In activity concentrations are obtained in tumour vs. normal tissues. The main aim was to investigate the possibility to use radiolabelled SS analogues for systemic therapy.Binding and internalisation of 111In was demonstrated in primary NE tumour cell cultures after incubation with 111In-DTPA-D-Phe1-octreotide. After pulse incubation a rapid release of 50 % of 111In from the cells occurred and the remaining 111In was maintained within the cells over time, mainly located in the cytoplasm and to some extent also in the cell nucleus. The pharmacokinetics of different amounts of i.v. injected 111In-DTPA-D-Phe-octreotide in a patient with disseminated midgut carcinoid tumour was followed by scintigraphy up to 550 h. The uptake in the tumours were long-lasting and the uptake in tumour and most tissues was lower when higher amounts were administered. The pharmacokinetics of i.v. injected 111In-DTPA-D-Phe1-octreotide in nude mice transplanted with tumour cells from the patient (GOT1) was similar to that for the patient, indicating that the animal model could be useful for experimental therapeutic studies.A mathematical model was constructed to calculate the tumour-to-normal-tissue mean absorbed dose ratios (TND) for different radionuclides and tumour sizes. Using the pharmacokinetics of 111In-DTPA-D-Phe1-octreotide from the patient and the mice, the TND was calculated for radionuclides proposed for therapy. 161Tb obtained the highest TND values both in the human and in the mouse model. For therapy of small tumours (< 1 g), suitable electron emitters should, e.g., emit few photons (photon-to-electron energy ratio < 2) and many electrons with low energy (< 40 keV). Five radionuclides fulfilled the criteria: 103mRh, 189mOs, 119Sb, 161Ho and 58mCo.The technique of radiolabelled SS analogues for tumour therapy has great potential for future development. Factors that could increase TND values should be optimised. The major advantage of this type of therapy is that unknown tumours and micrometastases, e.g. in disseminated cancers, may be treated