The intratumoral aromatase model: Studies with aromatase inhibitors and antiestrogens

Angela H. Brodie, Danijela Jelovac, Brian Long

Research output: Contribution to journalArticle

Abstract

Aromatase inhibitors have now been approved as first-line treatment options for hormone-dependent advanced breast cancer. When compared to tamoxifen, these aromatase inhibitors provide significant survival and tolerability advantages. However, the optimal use of an aromatase inhibitor and tamoxifen remains to be established. To date, the intratumoral aromatase xenograft model has proved accurate in predicting the outcome of clinical trials. Utilizing this model, we performed long-term studies with tamoxifen and letrozole to determine time to disease progression with each of the treatment regimens. Aromatase-transfected MCF-7Ca human breast cancer cells were grown as tumor xenografts in female ovariectomized athymic nude mice in which androstenedione was converted to estrogen and stimulated tumor growth. When tumor volumes were approximately 300mm3, the animals were grouped for continued supplementation with androstenedione only (control) or for treatment with letrozole 10μg per day (long-term), tamoxifen 100μg per day (long-term), letrozole alternating to tamoxifen (4-week rotation), tamoxifen alternating to letrozole (4-week rotation), or a combination of the two drugs. Tumors of control mice had doubled in volume in 3-4 weeks. In mice treated with tamoxifen and the combination, tumor doubling time was significantly shorter (16 and 18 weeks, respectively) than with letrozole (34 weeks). Furthermore, alternating letrozole and tamoxifen treatment every 4 weeks was less effective than letrozole alone. Tumors doubled in 17-18 weeks when the starting treatment was tamoxifen and in 22 weeks when the starting treatment was letrozole. Tumors progressing on tamoxifen remained sensitive to second-line therapy with letrozole (10μg per day). However, when mice with letrozole-resistant tumors were switched to antiestrogen treatment, tumors did not respond to tamoxifen (100μg per day) or faslodex (1mg per day). This suggests that advanced breast cancers treated with letrozole may be insensitive to subsequent second-line hormonal agents. Thus, although letrozole was determined to be an effective second-line treatment option for tumors progressing on tamoxifen, antiestrogen therapy does not appear to be effective for tumors progressing on letrozole. However, response to second-line treatment was observed in a model where tumors that had progressed on letrozole were transplanted to new mice. These tumors had been allowed to grow in the presence of supplemented androstenedione but absence of letrozole. This suggests that resistance to letrozole may be reversible, allowing tumors to respond to subsequent antiestrogens and letrozole.

Original languageEnglish (US)
Pages (from-to)283-288
Number of pages6
JournalJournal of Steroid Biochemistry and Molecular Biology
Volume86
Issue number3-5
DOIs
StatePublished - Sep 2003
Externally publishedYes

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letrozole
Aromatase Inhibitors
Aromatase
Estrogen Receptor Modulators
Tamoxifen
Tumors
Neoplasms
Androstenedione
Breast Neoplasms

Keywords

  • Antiestrogen
  • Aromatase
  • Tamoxifen

ASJC Scopus subject areas

  • Biochemistry
  • Endocrinology

Cite this

The intratumoral aromatase model : Studies with aromatase inhibitors and antiestrogens. / Brodie, Angela H.; Jelovac, Danijela; Long, Brian.

In: Journal of Steroid Biochemistry and Molecular Biology, Vol. 86, No. 3-5, 09.2003, p. 283-288.

Research output: Contribution to journalArticle

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