Hecate-CG beta conjugate and gonadotropin suppression shows two distinct mechanisms of action in the treatment of adrenocortical tumors in transgenic mice expressing Simian Virus 40 T antigen under inhibin-alpha promoter

Lytic peptide Hecate (23-amino acid (AA)) fused with a 15-AA fragment of human chorionic gonadotropin-beta (CG-beta), Hecate-CG beta conjugate (H-CG beta-c) selectively binds to and destroys tumor cells expressing LH/chorionic gonadotropin receptor (Lhcgr). Transgenic mice (6.5 month old) expressing SV40 T-antigen under the inhibin-alpha promoter (inh alpha/Tag) presenting with Lhcgr expressing adrenal tumors were treated either with H-CG beta-c, GnRH antagonist (GnRH-a), estradiol (E-2, only females) or their combinations for 1 month. We expected that GnRH-a or E-2 in combination with H-CG beta-c could improve the treatment efficacy especially in females by decreasing circulating LH and eliminating the potential competition of serum LH with the H-CG beta-c. GnRH-a and H-CG beta-c treatments were successful in males (adrenal weights 14 +/- 2 8 mg and 60 +/- 26 vs 237 +/- 59 mg in controls, P < 0.05). Histopathologically, GnRH-a apparently destroyed the adrenal parenchyma leaving only the fibrotic capsule with few necrotic foci. In females, H-CG beta-c was totally ineffective, whereas GnRH-a (19 +/- 5 mg) or E-2 (77 +/- 50 mg) significantly reduced the adrenal weights compared with controls (330 +/- 70 mg). Adrenal morphometry, cell proliferation markers, post-treatment suppression of serum progesterone, and quantitative RT-PCR of GATA-4, Lhcgr, and GATA-6 further supported the positive outcome. H-CG beta-c selectively killed the Lhcgr expressing tumor cells, whereas GnRH-a blocked tumor progression through gonadotropin suppression, emphasizing the gonadotropin dependency of these adrenocortical tumors. If extrapolated to humans, H-CG beta-c could be considered for the treatment of gonadotropin-dependent adrenal tumors in males, whereas in females gonadotropin suppression, but not H-CG beta-c, would work better.