Article

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: 2.57). 02/1998; 42(2):111-7.
Source: PubMed

ABSTRACT 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.

5 Followers
 · 
223 Views
  • Source
    • "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. "
    Senescence, 02/2012; , ISBN: 978-953-51-0144-4
  • Source
    • "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). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Breast cancer is one of the main causes of death by cancer in women, with an alarming year-by-year increase in incidence. Conventional cancer therapies, including surgery, radiotherapy, chemotherapy, endocrine therapy, and targeted therapy, play an important role in the treatment of breast cancer; however, drug resistance, severe side effect, and high recurrent rate significantly limit the effectiveness of current clinical treatments. Plant-based system has been used for treatment or prevention of various human diseases throughout history. The pressing need for development of new therapeutic or preventive agents for breast cancer has spurred the search for bioactive phytocompounds with novel modes of action. In this chapter, we review the current limitation of conventional chemo- or targeted-therapeutic drugs for breast cancer, and summarize some potential novel phytoagents discovered from dietary vegetables or traditional herbal medicines as alternative options or future medicine for breast cancer. We explore the mechanistic insights of these natural phytoagents against various types of breast cancer and discuss their therapeutic potential, alone or in combination, with current clinical drugs.
    10/2011: pages 47-67;
  • Source
    • "Potent AD/immunostimulant via inhalation (Komori et al., 1995) CBD Anxiolytic (Carvalho-Freitas and Costa, 2002; Pultrini Ade et al., 2006) via 5-HT1A (Komiya et al., 2006) CBD Apoptosis of breast cancer cells (Vigushin et al., 1998) CBD, CBG Active against acne bacteria (Kim et al., 2008) CBD Dermatophytes (Sanguinetti et al., 2007; Singh et al., 2010) CBG Gastro-oesophageal reflux (Harris, 2010) THC a-Pinene "
    [Show abstract] [Hide abstract]
    ABSTRACT: Tetrahydrocannabinol (THC) has been the primary focus of cannabis research since 1964, when Raphael Mechoulam isolated and synthesized it. More recently, the synergistic contributions of cannabidiol to cannabis pharmacology and analgesia have been scientifically demonstrated. Other phytocannabinoids, including tetrahydrocannabivarin, cannabigerol and cannabichromene, exert additional effects of therapeutic interest. Innovative conventional plant breeding has yielded cannabis chemotypes expressing high titres of each component for future study. This review will explore another echelon of phytotherapeutic agents, the cannabis terpenoids: limonene, myrcene, α-pinene, linalool, β-caryophyllene, caryophyllene oxide, nerolidol and phytol. Terpenoids share a precursor with phytocannabinoids, and are all flavour and fragrance components common to human diets that have been designated Generally Recognized as Safe by the US Food and Drug Administration and other regulatory agencies. Terpenoids are quite potent, and affect animal and even human behaviour when inhaled from ambient air at serum levels in the single digits ng·mL -1. They display unique therapeutic effects that may contribute meaningfully to the entourage effects of cannabis-based medicinal extracts. Particular focus will be placed on phytocannabinoid-terpenoid interactions that could produce synergy with respect to treatment of pain, inflammation, depression, anxiety, addiction, epilepsy, cancer, fungal and bacterial infections (including methicillin-resistant Staphylococcus aureus). Scientific evidence is presented for non-cannabinoid plant components as putative antidotes to intoxicating effects of THC that could increase its therapeutic index. Methods for investigating entourage effects in future experiments will be proposed. Phytocannabinoid-terpenoid synergy, if proven, increases the likelihood that an extensive pipeline of new therapeutic products is possible from this venerable plant.
    British Journal of Pharmacology 08/2011; 163(7):1344-64. DOI:10.1111/j.1476-5381.2011.01238.x · 4.99 Impact Factor
Show more