title: 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.affiliation: Welsh School of Pharmacy, Redwood Building, Cardiff University, Tenovus Centre for Cancer Research, King Edward VII Avenue, UK.
authors.forename: Francesca
authors.initials: F
authors.lastname: Greco
authors.forename: María J
authors.initials: MJ
authors.lastname: Vicent
authors.forename: Neal A
authors.initials: NA
authors.lastname: Penning
authors.forename: Robert I
authors.initials: RI
authors.lastname: Nicholson
authors.forename: Ruth
authors.initials: R
authors.lastname: Duncan
mesh_terms: D000178:Acrylamides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000616:Aminoglutethimide / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000735:Androstenedione / Q000494:pharmacology; D001141:Aromatase / Q000187:drug effects* / Q000378:metabolism; D047072:Aromatase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D004317:Doxorubicin / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D008861:Microsomes / Q000187:drug effects / Q000201:enzymology; D015394:Molecular Structure; D013329:Structure-Activity Relationship
chemical_list: D000178:Acrylamides; D047072:Aromatase Inhibitors; D000616:Aminoglutethimide; D000735:Androstenedione; D004317:Doxorubicin; D001141:Aromatase; C032976:N-(2-hydroxypropyl)methacrylamide