Local transdermal therapy to the breast for breast cancer prevention and DCIS therapy: Preclinical and clinical evaluation

Oukseub Lee, David Ivancic, Subhashini Allu, Ali Shidfar, Kara Kenney, Irene Helenowski, Megan E Sullivan, Miguel Muzzio, Denise Scholtens, Robert T. Chatterton, Kevin P. Bethke, Nora M. Hansen, Seema A. Khan*

*Corresponding author for this work

Research output: Contribution to journalArticle

10 Scopus citations

Abstract

Purpose: Women at high risk of breast cancer and those with carcinoma in situ need non-toxic, well-tolerated preventive interventions. One promising approach is drug delivery through the breast skin (local transdermal therapy, LTT). Our goal was to test novel drugs for LTT, to establish that LTT is applicable to non-steroidal drugs. Methods: Athymic nude rats were treated with oral tamoxifen, transdermal 4-hydroxytamoxifen (4-OHT) or endoxifen gel applied daily to the axillary mammary gland for 6 weeks (Study 1). Study 2 was identical to Study 1, testing transdermal telapristone acetate (telapristone) gel versus subcutaneous implant. At euthanasia, mammary glands and blood were collected. In Study 3, consenting women requiring mastectomy were randomized to diclofenac patch applied to the abdomen or the breast for 3 days preoperatively. At surgery, eight tissue samples per breast were collected from predetermined locations, along with venous blood. Drug concentrations were measured using liquid chromatography-tandem mass spectroscopy. Results: Mammary tissue concentrations of 4-OHT, endoxifen, and telapristone were significantly higher in the axillary glands of the gel-treated animals, compared to inguinal glands or to systemically treated animals. Plasma concentrations were similar in gel and systemically treated animals. The clinical trial showed significantly higher mammary concentrations when diclofenac was applied to the breast skin versus the abdominal skin, but concentrations were variable. Conclusions: These results demonstrate that lipophilic drugs can be developed for LTT; although the nude rat is suitable for testing drug permeability, delivery is systemic. In human, however, transdermal application to the breast skin provides local delivery.

Original languageEnglish (US)
Pages (from-to)1235-1246
Number of pages12
JournalCancer Chemotherapy and Pharmacology
Volume76
Issue number6
DOIs
StatePublished - Dec 1 2015

Keywords

  • 4-Hydroxytamoxifen
  • Breast
  • Diclofenac
  • Endoxifen
  • Telapristone
  • Transdermal therapy

ASJC Scopus subject areas

  • Oncology
  • Toxicology
  • Pharmacology
  • Cancer Research
  • Pharmacology (medical)

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