Clinical Study of Disposition and Biological Activity of d-Limonene

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DESCRIPTION (provided by applicant): d-Limonene, a monocyclic monoterpene, is a major component in the essential oils of citrus fruits. Oral feeding of d-limonene has been shown to prevent carcinogen-induced rat mammary carcinoma during the initiation and promotion stages as well as cause significant regression of advanced mammary carcinomas without any observable systemic toxicity. Most clinical development efforts of monocyclic monoterpenes have focused on a hydroxylated analog of limonene, perillyl alcohol. These trials, conducted in advanced cancer patients, suggested that the clinical antitumor activity of perillyl alcohol is not likely to occur at safe doses. There is only one reported clinical trial of d-limonene. This trial was also conducted in advanced cancer patients; one partial response in a breast cancer patient was maintained for 11 months and three patients with colorectal carcinoma showed stabilization of disease for longer than 6 months. Despite of their structural similarities, perillyl alcohol and limonene exhibited distinct in vivo disposition pattern. Perillyl alcohol is not bioavailable after oral administration. It undergoes significant first-pass metabolism and is converted almost completely to two polar metabolites, perillic acid and dihydroperillic acid. Due to their polarity, the tissue distribution of these metabolites is likely to be limited, thus limiting their in vivo tissue activities. Unlike perillyl alcohol, d-limonene is bioavailable in humans after oral administration. Because of its high lipophilicity, d-limonene has been shown to distribute favorably to adipose and mammary tissues in rodents. New preliminary data generated from our research group showed that d-limonene distributes extensively to adipose tissue in humans. We propose to conduct a pilot clinical study to determine the breast tissue bioavailability of d- limonene and its associated biological activities in women with a recent diagnosis of ductal carcinoma in situ, lobular carcinoma in situ, or atypical ductal hyperplasia elected to undergo excision surgery. The overall objective of the study is to determine the breast tissue distribution of d-limonene and its associated effects on breast tissue and serum surrogate endpoint biomarkers. We hypothesize that d- limonene will distribute extensively to human breast tissue and exert biological activities that would lead to breast cancer prevention. Specifically, we plan to 1) to determine whether d-limonene will distribute extensively to the breast tissue and reach a breast tissue drug concentration range found effectively in previous pre-clinical studies and 2) to determine the modulating effects of 2-6 weeks of daily d-limonene administration on surrogate endpoint biomarkers in the breast tissue and serum. The proposed trial is important in order to determine whether d-limonene should be further evaluated as a breast cancer preventive agent. The long-term goals are to conduct long-term intervention trials to determine the breast cancer preventive activity of d-limonene and to conduct translational clinical research in understanding the effect of d-limonene on arresting/inhibiting/reversing the breast cancer carcinogenesis process. PUBLIC HEALTH RELEVANCE: Project Narrative Limonene is a major component in the essential oils of citrus fruits. It has demonstrated promising breast cancer preventive and therapeutic effects in preclinical model systems. This grant application proposes to conduct an early phase clinical study to evaluate the distribution of limonene to the breast tissue and its associated biological activities after 2 to 6 weeks of limonene dosing in women with a recent diagnosis of breast carcinoma in situ or atypical ductal hyperplasia scheduled to undergo definitive surgery. This study will help evaluate the potentials of developing limonene as a breast cancer preventive agent.