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

Lookup NU author(s): Professor Alan Boddy

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Abstract

Purpose: D-Limonene is a natural monoterpene with pronounced chemotherapeutic activity and minimal toxicity in preclinical studies. A phase I clinical trial to assess toxicity, the maximum tolerated dose (MTD) and pharmacokinetics in patients with advanced cancer was followed by a limited phase II evaluation in breast cancer. Methods: A group of 32 patients with refractory solid tumors completed 99 courses of D-limonene 0.5 to 12 g/m2 per day administered orally in 21-day cycles. Pharmacokinetics were analyzed by liquid chromatography-mass spectrometry. Ten additional breast cancer patients received 15 cycles of D-limonene at 8 g/m2 per day. Intratumoral monoterpene levels were measured in two patients. Results: The MTD was 8 g/m2 per day: nausea, vomiting and diarrhea were dose limiting. One partial response in a breast cancer patient on 8 g/m2 per day was maintained for 11 months; three patients with colorectal carcinoma had prolonged stable disease. There were no responses in the phase II study. Peak plasma concentration (C(max)) for D-limonene ranged from 10.8 ± 6.7 to 20.5 ± 11.2 μM. Predominant circulating metabolites were perillic acid (C(max) 20.7 ± 13.2 to 71 ± 29.3 μM), dihydroperillic acid (C(max) 16.6 ± 7.9 to 28.1 ± 3.1 μM), limonene-1,2-diol (C(max) 10.1 ± 8 to 20.7 ± 8.6 μM), uroterpenol (C(max) 14.3 ± 1.5 to 45.1 ± 1.8 μM), and an isomer of perillic acid. Both isomers of perillic acid, and cis and trans isomers of dihydroperillic acid were in urine hydrolysates. Intratumoral levels of D- limonene and uroterpenol exceeded the corresponding plasma levels. Other metabolites were trace constituents in tissue. Conclusions: D-Limonene is well tolerated in cancer patients at doses which may have clinical activity. The favorable toxicity profile supports further clinical evaluation.

Publication metadata

Author(s): Vigushin, D., Poon, G., Boddy, A. V., English, J., Halbert, G., Pagonis, C., Jarman, M., Coombes, R.

Publication type: Article

Publication status: Published

Journal: Cancer Chemotherapy and Pharmacology

Year: 1998

Volume: 42

Issue: 2

Pages: 111-117

Print publication date: 01/06/1998

ISSN (print): 0344-5704

ISSN (electronic): 1432-0843

URL: http://dx.doi.org/10.1007/s002800050793

DOI: 10.1007/s002800050793

PubMed id: 9654110

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