Endocrine Abstracts

Vaptans are nonpeptide vasopressin receptors antagonists, developed for the treatment of euvolemic or hypervolemic hyponatremia. Among them, tolvaptan, a selective V₂receptors antagonist, approved for the treatment of hyponatremia secondary to the syndrome of inappropriate antidiuresis, was also approved for the treatment of polycystic kidney disease. Here, tolvaptan is able to reduce the growth of renal cysts and the rate of estimated glomerular filtration decrease. This unpredicted antiproliferative effect has been related to its inhibitory effect on the intracellular cAMP/PKA pathway in kidney epithelial cells. Noteworthy, there is in vitro evidence showing that tolvaptan reduces cell proliferation and invasion, and triggers apoptosis in different human cancer cell lines. To study this effect in vivo, a xenograft model of small cell lung cancer in Fox1^nu/nu nude mice (n=10) was developed through subcutaneous inoculation of H69 cells transfected with a plasmid containing the luciferase gene. When masses of about 100 mm³ were formed, mice were divided into two groups, a control group and a treatment group, which received tolvaptan at 0.15% daily. During the 60-day experimental period (T0-T60), tumor volume was assessed at different time points, both by using a digital caliper and by the IVIS Lumina system, which exploits the bioluminescence emitted by transfected cells. Through these observations, the size of the lesions appeared significantly greater in the control group compared with the treatment group at T60 (4271±1915 mm³ and 2307±463 mm³,respectively, P≤0.05). Interestingly, there was a trend toward a longer survival in the treatment group compared to the control group (59+1 vs 50.4+4.7 days, mean+SE, respectively). The expression of PCNA, a proliferative marker, and of caspase 3, a marker of apoptosis, were evaluated on explanted tumors. The level of expression of PCNA was significantly lower in the masses of tolvaptan-treated mice compared to control ones, whereas caspase 3 was more abundantly expressed in the treatment group. In conclusion, these findings confirm also in vivo an effective role of tolvaptan in counteracting tumor progression. Overall, these results suggest a possible dual role of this drug in cancer patients with hyponatremia, which is a frequent finding in this condition and is most often related to the syndrome of inappropriate antidiuresis.