Lactandrate: a D-homo-aza-androsterone alkylator in the treatment of breast cancer

  • Dimitrios T.P. Trafalis
  • George D. Geromichalos
  • Catherine Koukoulitsa
  • Athanasios Papageorgiou
  • Panayiotis Karamanakos
  • and Charalambos Camoutsis
Preclinical study


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 3β-hydroxy-13α-amino-13,17-seco- 5α-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 (ERα) 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.


breast cancer docking estrogen receptor homo-aza-steroids human cell lines human breast xenograft lactam murine breast tumors steroid alkylators 



activation function 2


average mice weight change


complete tumor regression rate


dimethyl sulfoxide


estrogen receptor


50% growth inhibition


human estrogen receptor alpha


50% in vitro cytotoxicity




ligand-binding domain


maximum tolerated dose


protein kinase C


partial tumor regression rate


total growth inhibition


tumor-free survivors


tumor inhibition


tumor weight


% median lifespan change of treated animals (T) over the control (C)


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Copyright information

© Springer Science+Business Media, Inc. 2005

Authors and Affiliations

  • Dimitrios T.P. Trafalis
    • 1
    • 2
    • 6
  • George D. Geromichalos
    • 3
  • Catherine Koukoulitsa
    • 4
  • Athanasios Papageorgiou
    • 3
  • Panayiotis Karamanakos
    • 5
  • and Charalambos Camoutsis
    • 1
  1. 1.Laboratory of Medicinal Chemistry, Faculty of PharmacyUniversity of PatrasPatrasGreece
  2. 2.1st Department of Medical Oncology“Metaxa” Cancer HospitalPiraeusGreece
  3. 3.Symeonidio Research CenterTheagenio Cancer HospitalThessalonikiGreece
  4. 4.Department of Pharmacognosy and Chemistry of Natural Products, School of PharmacyUniversity of AthensAthensGreece
  5. 5.1st Department of SurgeryMedical School, University of AthensAthensGreece
  6. 6.AthensGreece

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