Adenocarcinoma cells are targeted by the new GnRH-PE66 chimeric toxin through specific gonadotropin-releasing hormone binding sites.
Luteinizing hormone-releasing hormone, also termed gonadotropin-releasing hormone (GnRH), accounts for the hypothalamic-pituitary gonadal control of human reproduction. The involvement of GnRH has been demonstrated in several carcinomas of hormone-responsive tissues. Exploiting this common feature, we constructed a Pseudomonas exotoxin (PE)-based chimeric toxin (GnRH-PE66) aimed at targeting those cancer cells bearing GnRH binding sites. We report here the strong growth inhibition and killing of a surprisingly wide variety of cancers, confined to the adenocarcinoma type. These cancer cells arising from hormone-responsive tissues, as well as non-responsive ones, express specific GnRH binding sites as indicated by the marked killing of ovarian, breast, endometrial, cervical, colon, lung, hepatic, and renal adenocarcinoma. This cytotoxicity is specific as it could be blocked upon addition of excess GnRH. The specificity of GnRH-PE66 chimeric toxin was also confirmed by GnRH binding assays, and its ability to prevent the formation of colon cancer xenografts in nude mice is presented. Although the functional role of specific GnRH binding sites in human carcinomas remains obscure, GnRH-PE66 displays considerable targeting potential and its use as a therapeutic agent for cancer should be considered.
Nechushtan
A
A
Department of Cellular Biochemistry, Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel.
Yarkoni
S
S
Marianovsky
I
I
Lorberboum-Galski
H
H
D036002:ADP Ribose Transferases; D000230:Adenocarcinoma; D000818:Animals; D001427:Bacterial Toxins / Q000494:pharmacology*; D001943:Breast Neoplasms; D004067:Digestive System Neoplasms; D005098:Exotoxins / Q000494:pharmacology*; D005260:Female; D007987:Gonadotropin-Releasing Hormone / Q000494:pharmacology; D006801:Humans; D000922:Immunotoxins / Q000494:pharmacology*; D008175:Lung Neoplasms; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D010051:Ovarian Neoplasms; D011065:Poly(ADP-ribose) Polymerases / Q000494:pharmacology*; D011550:Pseudomonas aeruginosa; D018675:Toxicity Tests; D014407:Tumor Cells, Cultured; D014594:Uterine Neoplasms; D037521:Virulence Factors; D000097668:Pseudomonas aeruginosa Exotoxin A
D036002:ADP Ribose Transferases; D001427:Bacterial Toxins; D005098:Exotoxins; D007987:Gonadotropin-Releasing Hormone; D000922:Immunotoxins; D011065:Poly(ADP-ribose) Polymerases; D037521:Virulence Factors; D000097668:Pseudomonas aeruginosa Exotoxin A