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Cancer Chemotherapy and Pharmacology

, Volume 42, Issue 2, pp 111–117 | Cite as

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

  • David M. Vigushin
  • Grace K. Poon
  • Alan Boddy
  • Jacqueline English
  • Gavin W. Halbert
  • Christos Pagonis
  • Michael Jarman
  • R. Charles Coombes
  • Cancer Research Campaign Phase I/II Clinical Trials Committee
ORIGINAL ARTICLE

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 (Cmax) for d-limonene ranged from 10.8 ± 6.7 to 20.5 ± 11.2 μM. Predominant circulating metabolites were perillic acid (Cmax 20.7 ± 13.2 to 71 ± 29.3 μM ), dihydroperillic acid (Cmax 16.6 ± 7.9 to 28.1 ± 3.1 μM ), limonene-1,2-diol (Cmax 10.1 ± 8 to 20.7 ± 8.6 μM ), uroterpenol (Cmax 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.

Key wordsd-Limonene Natural monoterpene Farnesyltransferase inhibitor Pharmacokinetics 

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Copyright information

© Springer-Verlag Berlin Heidelberg 1998

Authors and Affiliations

  • David M. Vigushin
    • 1
  • Grace K. Poon
    • 2
  • Alan Boddy
    • 3
  • Jacqueline English
    • 1
  • Gavin W. Halbert
    • 4
  • Christos Pagonis
    • 5
  • Michael Jarman
    • 2
  • R. Charles Coombes
    • 1
  • Cancer Research Campaign Phase I/II Clinical Trials Committee
  1. 1.Cancer Research Campaign Laboratories, Department of Medical Oncology, Charing Cross Hospital, Fulham Palace Road, London W6 8RF, UK Tel.: +44 181 846 1419; Fax +44 181 846 1443 E-mail: d.vigushin@cxwms.ac.ukGB
  2. 2.Cancer Research Campaign Centre for Cancer Therapeutics, Institute of Cancer Research, Sutton SM2 5NG, UKGB
  3. 3.Cancer Research Unit, The Medical School, University of Newcastle, Newcastle upon Tyne NE2 4HH, UKGB
  4. 4.Cancer Research Campaign Phase I/II Clinical Trials Committee Formulation Unit, University of Strathclyde, Glasgow G1 1XW, UKGB
  5. 5.Cancer Research Campaign Phase I/II Data Centre, 10 Cambridge Terrace, London NW1 4JL, UKGB

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