HPMA copolymer-aminoglutethimide conjugates inhibit aromatase in MCF-7 cell lines.

Abstract

N-(2-Hydroxypropyl)methacrylamide (HPMA) copolymer-doxorubicin (Dox) has already shown clinical activity in breast cancer patients. Moreover, we have recently found that an HPMA conjugate containing a combination of both Dox and the aromatase inhibitor aminoglutethimide (AGM) shows significantly increased anti-tumour activity in vitro. To better understand the mechanism of action of HPMA copolymer-AGM conjugates several models were used here to investigate their effect on cell growth and aromatase inhibition. Cytotoxicity of HPMA copolymer conjugates containing AGM, Dox and also the combination AGM-Dox was determined by MTT assay in MCF-7 and MCF-7ca cells. Androstenedione (5 x 10(- 8) M) stimulates the growth of MCF-7ca cells. Both free AGM and polymer-bound AGM (0.2-0.4 mg/ml) were shown to block this mitogenic activity. When MCF-7ca cells were incubated [(3)H]androstenedione both AGM and HPMA copolymer-GFLG-AGM (0.2 mg/ml AGM-equiv.) showed the ability to inhibit aromatase. Although, free AGM was able to inhibit isolated human placental microsomal aromatase in a concentration dependent manner, polymer-bound AGM was not, suggesting that drug release is essential for activity of the conjugate. HPMA copolymer conjugates containing aromatase inhibitors have potential for the treatment of hormone-dependant cancers, and it would be particularly interesting to explore further as potential therapies in post-menopausal women as components of combination therapy.

• Authors: Francesca Greco, María J Vicent, Neal A Penning, Robert I Nicholson, Ruth Duncan
• Journal: Journal of drug targeting (J Drug Target) 2005 Sep-Nov Vol. 13 Issue 8-9 Pg. 459-70 ISSN: 1061-186X [Print] England
• PMID: 16332571 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Acrylamides
• Aromatase Inhibitors
• Aminoglutethimide
• Androstenedione
• Doxorubicin
• Aromatase
• N-(2-hydroxypropyl)methacrylamide

Topics

• Acrylamides (chemical synthesis, chemistry, pharmacology)
• Aminoglutethimide (chemical synthesis, chemistry, pharmacology)
• Androstenedione (pharmacology)
• Aromatase (drug effects, metabolism)
• Aromatase Inhibitors (chemical synthesis, chemistry, pharmacology)
• Breast Neoplasms (drug therapy)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Chromatography, High Pressure Liquid
• Doxorubicin (chemical synthesis, chemistry, pharmacology)
• Drug Screening Assays, Antitumor
• Female
• Humans
• In Vitro Techniques
• Microsomes (drug effects, enzymology)
• Molecular Structure
• Structure-Activity Relationship