THROMBOSPONDIN-1 (TSP-1) ANALOGS ABT-510 AND ABT-898 INHIBIT PROLACTINOMA GROWTH AND RECOVER PITUITARY ACTIVE TRANSFORMING GROWTH FACTOR-b1 (TGF-b1)

RECOUVREUX MV; CAMILLETTI MA; RIFKIN DB; BECU-VILLALOBOS D; DÍAZ TORGA G

Houston

Congreso; ENDO 2012; 2012

The Endocrine Society

Prolactinomas are the most prevalent type of secreting pituitary tumors in humans, and generally respond well to a medical therapy with dopamine agonists. However, for patients exhibiting resistance to dopaminergic drugs, alternative treatments are desired. Antiangiogenic strategies might represent a potential therapy for these tumors. TSP-1 is a large multifunctional glycoprotein involved in multiple biological processes including angiogenesis, apoptosis, and activation of TGF-b1.  Since tumors that over-express TSP-1 grow slower, have fewer metastases and have decreased angiogenesis, TSP-1 provides a novel target for cancer treatment. ABT-510 and ABT-898 (Abbott Laboratories) are TSP-1 synthetic analogues that mimic its antiangiogenic action. The aim of the present study was to explore the potential therapeutic effect of ABT-510 and ABT-898, on experimental prolactinomas developed after 4 weeks of diethylstilbestrol (DES) treatment in female rats.  Two weeks after DES pellet (20mg) implant, rats were injected three times a week during two weeks with vehicle, ABT-510 or ABT-898 (100mg/kg ip). Both TSP1 analogues were effective in decreasing pituitary tumor size (p=0.03) and PRL serum levels (P=0.0002), induced by DES. PCNA protein expression evaluated by western blot, was as well reduced after treatment, indicating a decrease in tumor proliferation rate (P<0.03). In order to evaluate the antiangiogenic effect of the drugs, we analyzed the vasculature by immunohistochemical staining of pituitary sections with the endothelial cell marker CD31. Total vascular area, as well as the number of CD31 positive vessels per area, were increased in DES pituitaries compared with controls (P<0.03). Both ABT-510 and ABT-898 treatment significantly decreased microvessel density (P=0.01 and P=0.027).  Finally, we found that treatment with the TSP-1 mimetic peptides were able to recover pituitary active TGF-b1 content in DES-treated rats, without effect on total TGF-b1 levels (measured by ELISA) or in its mRNA synthesis. Accordingly, we found that PSMAD2/3 expression was enhanced after treatment, suggesting a recovery of TGF-b1 activity in the pituitary. Our results show that ABT-510 and ABT-898 decrease pituitary tumor angiogenesis, tumor size, proliferation rate, serum prolactin values, and restore pituitary TGF-b1 activity. These results, place these synthetic TSP-1 analogs as potential alternative or complementary treatments in dopamine agonist-resistant prolactinomas.