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© 2003 Memorial Sloar-Kettering Cancer Center (Monograph)
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Full Text |
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Barrie Cassileth
and K. Simon Yeung
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D-Limonene
(p-mentha-1,8-diene)
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| Clinical Summary |
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Derived
from the peels of citrus fruits. Patients use this supplement to prevent
and treat cancer. D-Limonene is a cyclic monoterpene that causes G1 cell
cycle arrest, induces apoptosis, and inhibits posttranslational
modification of signal transduction proteins. Following oral
administration, D-limonene is rapidly metabolized to limonene-1,2-diol,
perillic acid, dihydroperillic acid, and uroterpenol. D-Limonene has a
biologic half-life of approximately 24 hours, while its metabolites
exhibit relatively short biologic half-lives of approximately 2 hours.
Side effects include nausea, vomiting, and diarrhea. In vitro and animal
data suggest potential efficacy of D-limonene in treating cancer, but
human data are lacking. Further research is necessary to determine if
D-limonene has a role in the prevention or treatment of cancer.
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| Scientific Name |
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p-mentha-1,8-diene
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| Also Known As |
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R-limonene,
orange peel oil, citrus peel oil, citrene
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| Purported Uses |
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• Cancer
prevention
• Cancer
treatment
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| Constituents
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• Monocyclic
monoterpene
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Mechanism Of Action
[1], [2], [3], [4], [5], [6], [7], [8], [9], [11] |
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The
exact mechanism of action is unknown. D-Limonene and its metabolites,
perillic acid, dihydroperillic acid, uroterpenol, and limonene1,2-diol,
may inhibit tumor growth via inhibition of p21-dependent signaling and
apoptosis resulting from induction of the transforming growth factor
beta-signaling pathway. D-Limonene metabolites also cause G1 cell
cycle arrest, inhibit posttranslational modification of signal
transduction proteins, and cause differential expression of cell cycle-
and apoptosis-related genes. Animal studies show activity of D-limonene
against pancreatic, stomach, colon, skin, and liver cancers. Data also
indicate that D-limonene slows the promotion/progression stage of
carcinogen-induced tumors in rats.
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Pharmacokinetics
[1], [2], [10] |
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Following
oral administration, D-limonene is absorbed rapidly and metabolized to
perillic acid (PA), dihydroperillic acid (DPA), limonene1,2-diol, and
uroterpenol. D-Limonene metabolites distribute throughout the body to all
sites, including adipose tissue, and are eliminated as glucuronide
metabolites in the urine.
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Adverse Reactions
[1] |
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Reported:
Nausea, vomiting, diarrhea
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Drug Interactions
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None
known
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| Literature Summary And Critique |
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Vigushin
DM, et al. Phase
I and pharmacokinetic study of d-limonene in patients with advanced
cancer. Cancer Research Campaign Phase I/II Clinical Trials Committee. Cancer
Chemother Pharmacol
1998;42:111-7.
A
phase I pharmacokinetic study was conducted with doses ranging from
500-12000 mg/m2/day. A single tumor response was documented in
a breast cancer patient at the 8000 mg/m2/day dose level. The
investigators conducted a small phase II study with 10 additional breast
cancer patients but no additional tumor response was noted. Side effects
include nausea, vomiting, and diarrhea. Additional studies are necessary
to establish efficacy of D-limonene.
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| References |
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[1] Vigushin
DM, et al. Phase I and pharmacokinetic study of d-limonene in patients
with advanced cancer. Cancer Chemother Pharmacol 1998;42:111-7.
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[2] Hardcastle
IR, et al. Inhibition
of protein prenylation by metabolites of limonene. Biochem
Pharmacol
1999;57:801-9.
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[3] Belanger
JT. Perillyl
alcohol: applications in oncology. Altern Med Rev 1998;3:448-57.
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[4] Hudes
GR, et al. Phase
I pharmacokinetic trial of perillyl alcohol (NSC 641066) in patients with
refractory solid malignancies. Clin Cancer Res 2000;6:3071-80.
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[5]
Ripple
GH. Phase I clinical and pharmacokinetic study of perillyl alcohol
administered four times a day. Clin
Cancer Res
2000;6:390-6.
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[6]
Reddy
BS, et al. Chemoprevention
of colon carcinogenesis by dietary perillyl alcohol. Cancer Res
1997;57:420-5.
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[7]
Low-Baselli
A, et al. Failure to demonstrate chemoprevention by the monoterpene
perillyl alcohol during early rat hepatocarcinogenesis: a cautionary note.
Carcinogenesis 2000;21:1869-77.
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[8]
Kaji
I, et al. Inhibition by
d-limonene of experimental hepatocarcinogenesis in Sprague-Dawley rats
does not involve p21(ras) plasma membrane association. Int
J Cancer
2001;93:441-4.
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[9]
Uedo
N, et al. Inhibition
by d-limonene of gastric carcinogenesis induced by
N-methyl-N'-nitro-N-nitrosoguanidine in Wistar rats. Cancer Lett
1999;137:131-6.
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[10]
Crowell
PL, et al. Human metabolism of the experimental cancer therapeutic agent
d-limonene. Cancer Chemother Pharmacol 1994;35:31-7.
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[11]
Asamoto
M, et al. Mammary carcinomas induced in human c-Ha-ras proto-oncogene
transgenic rats are estrogen-independent, but responsive to d-limonene
treatment. Jpn J Cancer Res 2002;93:32-5.
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| Written |
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03/08/2002 |
| Updated |
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12/20/2002
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Disclaimer: http://www.mskcc.org/mskcc/print/11790.cfm |
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Source:
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