| Autor: |
D M, Vigushin, G K, Poon, A, Boddy, J, English, G W, Halbert, C, Pagonis, M, Jarman, R C, Coombes |
| Rok vydání: |
1998 |
| Předmět: |
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| Zdroj: |
Cancer chemotherapy and pharmacology. 42(2) |
| ISSN: |
0344-5704 |
| Popis: |
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. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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