Phase I and pharmacokinetic study of D-limonene in patients with advanced cancer. Cancer Research Campaign Phase I/II Clinical Trials Committee.

Department of Medical Oncology, Charing Cross Hospital, London, UK.
Cancer Chemotherapy and Pharmacology (Impact Factor: 2.77). 02/1998; 42(2):111-7.
Source: PubMed


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.
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.
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 (Cmax) for D-limonene ranged from 10.8+/-6.7 to 20.5+/-11.2 microM. Predominant circulating metabolites were perillic acid (Cmax 20.7+/-13.2 to 71+/-29.3 microM), dihydroperillic acid (Cmax 16.6+/-7.9 to 28.1+/-3.1 microM), limonene-1,2-diol (Cmax 10.1+/-8 to 20.7+/-8.6 microM), uroterpenol (Cmax 14.3+/-1.5 to 45.1+/-1.8 microM), 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.
D-Limonene is well tolerated in cancer patients at doses which may have clinical activity. The favorable toxicity profile supports further clinical evaluation.

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    • "In the past, monoterpens, sesquiterpenes, diterpens and triterpens (Zhang et al., 2006) have been characterized by several authors (Vigushin et al., 1998; Crowell et al., 1992; Hardcastle et al., 1999) as potential anti-cancer drugs on the basis of in vitro and in vivo studies, but their role as anti-inflammatory drugs has remained elusive. "
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    • "Limonene and limonene-related monoterpenes inhibit cancer cell growth by decreasing the level of cyclin D1, which led to cell cycle arrest in breast cancer cell lines T-47D, MCF-7, and MDA-MB-231 (Bardon et al. 1998). A Phase I pharmacokinetics study showed that patients with advanced cancer tolerated d-limonene doses well, which suggests its clinical efficacy (Vigushin et al. 1998). Retinoids, a group of diterpenes including vitamin A (retinol) and its active metabolite retinoic acid (RA), have potent effects on tumor cell growth, differentiation , and apoptosis (Liby et al. 2007). "
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