Hecate-CGbeta 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-CGbeta conjugate (H-CGbeta-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 (inhalpha/Tag) presenting with Lhcgr expressing adrenal tumors were treated either with H-CGbeta-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-CGbeta-c could improve the treatment efficacy especially in females by decreasing circulating LH and eliminating the potential competition of serum LH with the H-CGbeta-c. GnRH-a and H-CGbeta-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-CGbeta-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-CGbeta-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-CGbeta-c could be considered for the treatment of gonadotropin-dependent adrenal tumors in males, whereas in females gonadotropin suppression, but not H-CGbeta-c, would work better.
Vuorenoja
Susanna
S
Department of Physiology, University of Turku, FIN-20520 Turku, Finland.
Mohanty
Bidut Prava
BP
Arola
Johanna
J
Huhtaniemi
Ilpo
I
Toppari
Jorma
J
Rahman
Nafis A
NA
D000306:Adrenal Cortex Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D000818:Animals; D000957:Antigens, Viral, Tumor / Q000378:metabolism*; D049109:Cell Proliferation; D018997:Chorionic Gonadotropin, beta Subunit, Human / Q000627:therapeutic use; D005260:Female; D007987:Gonadotropin-Releasing Hormone / Q000378:metabolism; D006062:Gonadotropins / Q000378:metabolism*; D006801:Humans; D007124:Immunoenzyme Techniques; D007265:Inhibins / Q000235:genetics*; D008297:Male; D008555:Melitten / Q000031:analogs & derivatives* / Q000627:therapeutic use; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011374:Progesterone / Q000097:blood; D011401:Promoter Regions, Genetic / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013539:Simian virus 40 / Q000235:genetics
D000957:Antigens, Viral, Tumor; D018997:Chorionic Gonadotropin, beta Subunit, Human; D006062:Gonadotropins; D012333:RNA, Messenger; C480619:hecate-chorionic gonadotropin beta-subunit conjugate; C094377:inhibin-alpha subunit; D008555:Melitten; D007987:Gonadotropin-Releasing Hormone; D011374:Progesterone; D007265:Inhibins