Phase I and pharmacokinetic study of d -limonene in patients with advanced cancer

Abstract

D-Limonene is well tolerated in cancer patients at doses which may have clinical activity. The favorable toxicity profile supports further clinical evaluation.

Antileukemia activity of perillyl alcohol (POH): uncoupling apoptosis from G0/G1 arrest suggests that the primary effect of POH on Bcr/Abl-transformed cells is to induce growth arrest

“…Thus, dietary administration of the monoterpenes, limonene or perillyl alcohol (POH) can cure advanced mammary, stomach, lung, skin and liver cancers in rats, mice or hamsters [42][43][44][45][46][47][48][49][50][51] and they do not cause significant toxicity in rats, dogs or humans. [42][43][44][45][52][53][54][55][56] The anticancer activities of these monoter-penes are associated with a selective induction of apoptosis in the neoplastic tissue but not in adjacent normal tissues. 43,50 Although the specific anticancer mechanisms are poorly understood, the broad anticancer activity of monoterpenes, coupled with their negligible toxicity prompted us to test limonene and its hydroxylated derivative, POH, against Bcr/Abltransformed and nontransformed cell lines.…”

Phase I Study of Perillyl Alcohol in Patients with Refractory Malignancies

“…20,33 In the first clinical study of a monoterpene, d-limonene was administered on a three times daily schedule. 27 Dose-related gastrointestinal toxicity was observed and the recommended dose for phase II testing was 8 gm/m 2 . Among the 42 patients treated, one of 26 patients with breast cancer achieved a partial response of soft tissue disease that was sustained for 11 months.…”

“…Four of the patients treated with limonene discontinued treatment within 21 days because of non-DLT. 27 In the other published studies of perillyl alcohol, 17% of patients discontinued treatment because of toxicity. 8,35,36 Traditional criteria that are used to define acceptable toxicity for agents given intermittently and produce significant toxicity for only a limited period every 3-4 weeks may not be appropriate for defining the optimal dose of an agent which is given chronically.…”

“…Tumor tissue concentrations were measured in 2 patients with breast cancer and the total monoterpene concentrations were 1.9-and 5.5-fold greater than in plasma. 27 Structure-activity studies of limonene-derived monoterpenes have demonstrated that monohydroxyl, ester, and aldehyde substitutions at the C7 position enhance the potency for both inhibition of protein prenylation and cellular proliferation. 14 Perillyl alcohol is a hydroxylated analog of limonene which is 5-fold more potent than limonene in producing tumor regression in an advanced mammary carcinoma model.…”

“…26 A dose-finding study of the monoterpene limonene was recently reported. 27 The dose-limiting toxicities were nausea, vomiting and diarrhea. Although plasma concentrations comparable to the concentrations effective in vitro could not be achieved, intratumoral monoterpene concentrations were as much as 5.5 fold greater than the concentration achieved in plasma.…”