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

Autor: Vigushin, David M., Poon, Grace K., Boddy, Alan, English, Jacqueline, Halbert, Gavin W., Pagonis, Christos, Jarman, Michael, Coombes, R. Charles, Vigushin, D M, Poon, G K, Boddy, A, English, J, Halbert, G W, Pagonis, C, Jarman, M, Coombes, R C
Zdroj: Cancer Chemotherapy & Pharmacology; Jun1998, Vol. 42 Issue 2, p111-117, 7p
Abstrakt: 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 μ M. Predominant circulating metabolites were perillic acid (Cmax 20.7 ± 13.2 to 71 ± 29.3 μ M ), dihydroperillic acid (Cmax 16.6 ± 7.9 to 28.1 ± 3.1 μ M ), limonene-1,2-diol (Cmax 10.1 ± 8 to 20.7 ± 8.6 μ M ), uroterpenol (Cmax 14.3 ± 1.5 to 45.1 ± 1.8 μ M ), 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. [ABSTRACT FROM AUTHOR]
Databáze: Complementary Index
Externí odkaz: