Abstract A79: Human breast tissue bioavailability of topically applied limonene

Abstract

Abstract Purpose: Limonene is a monocyclic monoterpene found at high concentration in citrus peel oil and has demonstrated anti-cancer effects in preclinical studies of mammary carcinogenesis. However, the effective oral dose determined in rodents extrapolates to a human dose that may not be feasible for long-term consumption. Limonene is highly lipophilic and has been long explored as an enhancer for percutaneous absorption of pharmaceutical drugs, including tamoxifen. Preliminary work from our group demonstrated that topically applied limonene is absorbed through the mouse skin and accumulates in the mammary glands. Methods: We conducted a pilot clinical study to determine whether limonene would be bioavailable in the breast following topical application. In the first study phase, we recruited 19 healthy women to apply limonene containing massage oil to the breast daily or 3x/wk. Nipple aspirate fluid (NAF) and plasma samples were collected before and after 4 weeks of limonene massage application. Sample limonene concentrations were determined using gas chromatography-mass spectrometry. In the second study phase, we recruited 25 healthy women to undergo 4 weeks of daily limonene massage oil application to the breast. Potential agent effect biomarkers were determined in NAF and plasma collected before and after the limonene massage application. Results: In samples collected from the first study phase, no significant increase in NAF and plasma limonene levels was observed following the limonene massage application, possibly because limonene deposits in the fatty breast tissue with minimal secretion to NAF or systemic circulation. Changes in agent effect biomarkers in NAF, including TGF-beta, EGF, and adiponectin, were evaluated in the second study phase for determination of the breast tissue limonene bioavailability. There were no consistent changes in the agent effect biomarkers overall or in pre-menopausal women following the limonene massage application. However, among the post-menopausal women (n =8), there were significant increases in NAF levels of TGF-beta (p = 0.005) and EGF (p = 0.032), and there was an increasing trend in adiponectin (p = 0.164, n=5 due to limited NAF volume). Conclusions: We conclude that breast massage application of limonene containing massage oil did not result in consistent changes in limonene secretion to the NAF and the potential drug effect biomarkers in NAF. However, limonene massage application increased the NAF expression of TGF-beta and EGF in post-menopausal women, indicative of the intervention effects in the breast tissue. Further studies are needed to explore the potential effects of topical limonene massage intervention on carcinogenesis biomarkers in a larger cohort of post-menopausal women. Supported by Department of Defense, BCRP Idea Award, BC061529 Citation Information: Cancer Prev Res 2010;3(1 Suppl):A79.