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Phase
I and pharmacokinetic study of D-limonene in patients with advanced cancer.
Cancer Research Campaign Phase I/II Clinical Trials Committee
Vigushin
DM, Poon GK, Boddy A, English J, Halbert GW, Pagonis C, Jarman M, Coombes RC
Department
of Medical Oncology, Charing Cross Hospital, London, UK.
d.vigushin@cxwms.ac.uk
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 (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.
Conclusions.
D-Limonene is well tolerated in cancer patients at doses which may have clinical
activity.
The favorable toxicity profile supports further clinical evaluation.
PMID:
9654110 [PubMed - indexed for MEDLINE]
Source:
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9654110&dopt=Abstract
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