Breast Cancer Research and Treatment

, 97:17

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

DOI: 10.1007/s10549-005-9083-x

Cite this article as:
Trafalis, D.T., Geromichalos, G.D., Koukoulitsa, C. et al. Breast Cancer Res Treat (2006) 97: 17. doi:10.1007/s10549-005-9083-x

Summary

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.

Keywords

breast cancerdockingestrogen receptorhomo-aza-steroidshuman cell lineshuman breast xenograftlactammurine breast tumorssteroid alkylators

Abbreviations

AF-2

activation function 2

AWC

average mice weight change

CR

complete tumor regression rate

DMSO

dimethyl sulfoxide

ER

estrogen receptor

GI50

50% growth inhibition

hERα

human estrogen receptor alpha

IC50

50% in vitro cytotoxicity

i.p.

intra-peritoneal

LBD

ligand-binding domain

MTD

maximum tolerated dose

PKC

protein kinase C

PR

partial tumor regression rate

TGI

total growth inhibition

TFS

tumor-free survivors

TI

tumor inhibition

TW

tumor weight

%T/C

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

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