Speaker
Dr
Hafid BELHADJ-TAHAR
(Groupe Santé Recherche)
Description
Introduction
Cancer constitutes one of the first causes of mortality in the world. This
proliferative disease is characterised by two evolutionary components made of
regional extension and metastatic diffusion. The therapeutic success of cancer
treatment depends on precocity of the diagnosis, of extension assessment and initial
treatment of primitive tumour and its metastatic dissemination. The present work is
part of the French National Cancer Fighting Plan as illustrated in south France with
the founding of the “Cancéropôle”. For tumoral targeting, biomolecule vectors
complexed with two different isotopes (gamma- and beta-emitters) seem to be a
suitable strategy. Indeed, technetium-99m can be used for diagnosis and rhenium-
186/188 for radiotherapy and rhenium-185/187 for chemotherapy [1]. The tetragastrin
(CCK4), an effector related to gastrin, exhibits specific affinity for CCKb
receptors which are preferentially expressed by some tumoral cells in digestive
tract. The aims of this work are (i) synthesis of a beta-ala-CCK4 biovector coupled
to SN3 ligand and (ii)development of technetium and rhenium complexation method
using physiological pH and temperature conditions and (iii) pharmacological in vitro
and in vivo studies of these labelled vectors.
Methods
S-(1-ethoxyethyl)mercaptoacetyl-triglycyl-b-alanine-CCK4 vector was obtained by
successive condensations of activated amino acids on resin and characterised with
HPLC-UV, 1H-NMR. The labelled biovectors (185/187Rhenium and 99/99mTechnetium)
were (i) incubated with CCKB cell receptors and their affinity was tested by
tetragastrin competition and (ii) injected into healthy Wistar rats and nude mice
with pancreatic adenocarcinoma grafts (AR4-J). Pharmacokinetics and tissue
distribution were monitored by NaI gamma camera imaging.
Results
The biovectors were obtained with high chemical purity and were efficiently labelled
(>95%) in one step under pH 7-8 and 45°C conditions. These labelled biovectors
present remarkable pharmacokinetic properties related to low background noise
resulting from lack of hepatic uptake. Moreover, labelled CCK4 has a good affinity
for CCKB receptor (IC50 8. 10-8M). This result allows to conclude that linking the
SN3 chelating agent to CCK4 does not alter the conformation and biochemical
properties of this peptide and then may be proposed as radiopharmaceutical kit in
routine cancer treatment.
1- Belhadj-Tahar H. et Darbieu M.H. et coll. Med. Nucl. Imag. Fonct. Metab. 2004, 28
(3) : 101-9
Author
Dr
Hafid BELHADJ-TAHAR
(Groupe Santé Recherche)
Co-authors
Prof.
Jean-Paul ESQUERRE
(EA3033)
Dr
Yvon COULAIS
(EA3033)