title: Lactandrate: a D-homo-aza-androsterone alkylator in the treatment of breast cancer.
abstract: The sensitivity of breast neoplasms to hormonal control provides the basis of novel investigational treatments with steroidal alkylators. An androsterone D-lactam steroidal ester, the 3beta-hydroxy-13alpha-amino-13,17-seco- 5alpha-androstan-17-oic-13,17-lactam, p-bis(2-chloroethyl)amino phenyl acetate (lactandrate) was synthesized and tested for antitumor activity against six human breast cancer cell lines in vitro and against two murine and one xenograft mammary tumors in vivo. A docking study on the binding interactions of lactandrate with the ligand-binding domain (LBD) of estrogen receptor-alpha (ERalpha) was inquired. In vitro testing of lactandrate cytostatic and cytotoxic activity was performed on T47D, MCF7, MDA-MB-231, BT-549, Hs578T, MDA-MB-435 breast adenocarcinoma human cell lines. In vivo testing was performed on two murine mammary tumors, the MXT tumor and CD8F1 adenocarcinoma, as well as on human mammary carcinoma MX-1 xenograft. Molecular modeling techniques were adopted to predict a possible location and interaction mode of the molecule into LBD. Lactandrate induced significantly high antitumor effect against all tested in vitro and in vivo models. The cell lines with positive ER expression found to be significantly more sensitive to lactandrate. Moreover, lactandrate found to be positioned inside the binding cavity with its steroidal moiety, whilst the alkylating moiety protrudes out of receptor's pocket. Lactandrate produced important anticancer activity on breast cancer in vitro and in vivo. Some correlation between ER and lactandrate effect was demonstrated. Docking studies provide the basis for the structure-based design of improved steroidal alkylating esters for the treatment of estrogen-related cancers.
authors.affiliation: Laboratory of Medicinal Chemistry, Faculty of Pharmacy, University of Patras, Patras, Greece. dtrafalis@yahoo.com
authors.forename: Dimitrios T P
authors.initials: DT
authors.lastname: Trafalis
authors.forename: George D
authors.initials: GD
authors.lastname: Geromichalos
authors.forename: Catherine
authors.initials: C
authors.lastname: Koukoulitsa
authors.forename: Athanasios
authors.initials: A
authors.lastname: Papageorgiou
authors.forename: Panayiotis
authors.initials: P
authors.lastname: Karamanakos
authors.forename: Charalambos
authors.initials: C
authors.lastname: Camoutsis
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy; D000477:Alkylating Agents / Q000627:therapeutic use*; D000738:Androsterone / Q000627:therapeutic use; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001378:Azasteroids / Q000627:therapeutic use*; D049109:Cell Proliferation / Q000187:drug effects; D047628:Estrogen Receptor alpha / Q000378:metabolism; D005260:Female; D006718:Homosteroids / Q000627:therapeutic use*; D006801:Humans; D008297:Male; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D015394:Molecular Structure; D012632:Secosteroids / Q000627:therapeutic use*; D014407:Tumor Cells, Cultured / Q000187:drug effects
chemical_list: C515329:3-hydroxy-13-amino-13,17-secoandrostan-17-oic-13,17-lactam p-bis(2-chloroethyl)amino phenyl acetate; D000477:Alkylating Agents; D000970:Antineoplastic Agents; D001378:Azasteroids; D047628:Estrogen Receptor alpha; D006718:Homosteroids; D012632:Secosteroids; D000738:Androsterone