Therapeutic Efficacy Evaluation of 177Lu-DOTA-NT and 177Lu-DOTA-SR48692 in Murine RS-1 Hepatoma

Neurotensin (NT) is a peptide with biological affinity to neurotensin receptors (NTR), while SR48692 is a non-peptide molecule with competitive/inhibitory activity to the same receptors. This paper aims to bring a scientific contribution to elucidate the paradigm concerning the capture of NT agonist or antagonist (SR48692) by tumor cells, depending on the competition between NT and SR48692 for identical receptors. For this reason, we have tested the therapeutic efficacy of a single dose of both 177Lu-DOTA-NT and 177Lu-DOTA-SR48692 administered to positive NTR malignant hepatoma bearing rats. Additionally, in order to evaluate the competition between NT and SR we have studied under similar circumstances, the therapeutic effects of the following combinations: 177Lu-DOTA-NT/DOTA-SR48692 and 177Lu-DOTA-SR48692/DOTA-NT. Male Wistar rats inoculated with RS1 hepatoma cells were divided in four treatment groups and one control group and treated intraperitoneally with a dose of 74-GBq (specific activity of 2 Ci/mg) per compound. At different time after compounds administration, five animals from each group were sacrificed, and removed several specimens: blood, tumor, liver, pancreas, spleen, kidney, bone marrow and small intestine. The radiobiological effects of these different regimens were evaluated by biochemistry (thiols, malonaldialdehyde and total antioxidant status) and flow cytometry (DNA ploidy, cell proliferation status, proliferative index). Treatment with the aforementioned compounds resulted in the tumor regression and the increased density of cells in G1 corresponding to a decrease of S and G2 that indicate the arrest in G1. Redox parameters recorded a proportional increase subsequently to radiotherapy induction. Our data evidenced in vivo a therapeutic potential of the two radiolabeled compounds in radionuclide therapy of murine RS-1 hepatoma. In addition, the combination between the radiolabeled compound and its unlabeled counterpart may become a promising strategy to improve the therapeutic effects.