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The human liver metabolism of paclitaxel (Taxol), an anticancer drug, leads to three metabolites: 6alpha-hydroxypaclitaxel, 3'-p-hydroxypaclitaxel and 6alpha,3'-p-dihydroxypaclitaxel. The inter-individual variability of paclitaxel metabolism was investigated first in vitro using 22 human liver microsomes. Three metabolites have been detected by HPLC. This preliminary work revealed marked inter-individual differences in paclitaxel metabolism. The amount of major metabolite 6alpha-hydroxypaclitaxel formed varied 16-fold (0.7 to 11.5 nmol/mg/h). We next studied the effect of 29 compounds (antineoplastics, antiemetics, histamine-2 receptor antagonist, antalgics, antifungals, antivirals, psychotropics, antibiotic, corticoid, antiarrhythmic, calcium channel blocker) on paclitaxel metabolism in human liver microsomes. Among the compounds studied, quercetin, antifungal drugs such as ketoconazole and miconazole, and the antineoplastic drug doxorubicin inhibited formation of 6alpha-hydroxypaclitaxel. Dixon plots indicated that quercetin and doxorubicin inhibited 6alpha-hydroxypaclitaxel formation through a competitive mechanism with a Ki of 10.1 microM and 64.8 microM, respectively. The inhibition of this metabolite by ketoconazole was through a noncompetitive mechanism with a Ki of 11.8 microM. Our data thus suggest that special attention should be paid when these drugs are combined in clinical practice.

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Three major alkaloids: cepharanthine (1), tetrahydropalmatine (2) and xylopinine (3) isolated from Stephania rotunda tuber were investigated for their cytotoxic activity in a panel of human cancer cells (HT29, LS174T, SW620 and HepG2) using MTT assay. In the present study, cepharanthine (1) exerted potent cytotoxicity against colon and hepatoma cancer cell lines with IC(50) values between 2.4 and 5.3 microM while tetrahydropalmatine (2) and xylopinine (3) displayed weak cytotoxicity. In addition, the mutagenic activity of cepharanthine (1) was investigated using a modified liquid incubation technique of the Salmonella/microsomal assay. This alkaloid (1) was found to be non-mutagenic for doses up to 8.2 microM.

A reliable high-performance liquid chromatography (HPLC) method coupled with photodiode array detection has been developed and validated for the determination of three major alkaloids: cepharanthine, tetrahydropalmatine and xylopinine in Stephania rotunda Lour. (Menispermaceae) collected in Cambodia. The chromatographic separation was carried out on a Symmetry C8 column (250 mm x 4.6 mm, 5 µm, Waters), with an isocratic solvent system of 25 mM potassium phosphate buffer (pH 3.5) -acetonitrile. UV detection was performed at 282 nm. Good linear behavior over the investigated concentration ranges was observed with values of r 2 >0.9964 for all the analytes. The method was reproducible with intra-and inter-day variations of less than 3.91%. The mean recoveries of the analytes ranged from 95.7 to 104.6%. The proposed method was linear, accurate, precise and specific. The validated method was successfully applied to quantify the three alkaloids in various parts of Stephania rotunda and in tubers collected from different Cambodian regions. The results indicated that the developed HPLC method could be used for the quality control of S. rotunda.

The purpose of the present study was to screen 27 plant species used in the traditional medicine of Cambodia for in vitro antibacterial and antifungal activities. Thirty-three methanolic extracts were tested against Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, Mycobacterium smegmatis and Candida albicans. Screened by disk diffusion assay, the extracts showed antimicrobial activity especially on Gram-positive bacteria. None of the crude methanolic extracts showed activity against P. aeruginosa. Twenty-five selected extracts were evaluated using a micro-dilution test. Harrisonia perforata (roots) and Hymenodictyon excelsum (bark) exhibited a bactericidal effect against S. aureus at a concentration of 500 microg/ml. Azadirachta indica (bark), Harrisonia perforata (roots and stem) and Shorea obtusa (roots) exhibited a bactericidal effect against M. smegmatis at 250 microg/ml.

Context: The genus Cyclamen L. (Primulaceae) is rich in saponins known to have interesting biological activities. Objective: To isolate saxifragifolin B and cyclamin, two triterpene saponins, from Cyclamen libanoticum Hildebr and Cyclamen persicum Mill, and to assess their cytotoxic, clastogenic/ aneugenic, and anticlastogenic effects, as well as antioxidant potential. Materials and methods: Saxifragifolin B and cyclamin were tested for their cytotoxicity against SK-BR-3, HT-29, HepG2/3A, NCI-H1299, BXPC-3, 22RV1, and normal DMEM cell lines using WST-1 assay. Their clastogenic/aneugenic activities and anticlastogenic effects against the anticancer drug mitomycin C were assessed by the in vitro micronucleus assay in CHO cells. Their antioxidant capacities were determined using Fe 2+ -chelating and 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging assays. Results: Both saponins were described for the first time in Cyclamen libanoticum. They showed strong cytotoxic activities against the tested cancer cell lines. Saxifragifolin B was found to be 56-and 37-times more active than mitomycin C against breast adenocarcinoma (SK-BR-3) and lung carcinoma (NCI-H1299), respectively. Also, saxifragifolin B did not induce micronuclei formation and prevented cells from mitomycin C clastogenic effect. Cyclamin induced a significant increase of micronucleated cells after metabolic activation with S9 mix, and did not possess any anticlastogenic activity. Both molecules exhibited low antioxidant activities as compared to reference compounds. Discussion and conclusions: This study showed the remarkable cytotoxic activity of saxifragifolin B, especially against breast adenocarcinoma and lung carcinoma and its chemoprotective activity against mitomycin C. Thus, saxifragifolin B could be suggested as a potential cytotoxic drug with a preventive effect against possible exposures to genotoxic agents.