Publications (2)0 Total impact
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Article: Determination of 9-nitrocamptothecin and its metabolite 9-aminocamptothecin in human plasma using high-performance liquid chromatography with ultraviolet and fluorescence detection
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ABSTRACT: A high-performance liquid chromatography assay is described for the determination of the investigational anti-cancer drug 9-nitrocamptothecin (9-NC) and its metabolite 9-aminocamptothecin (9-AC) as the total of their lactone and carboxylate forms. The sample pre-treatment consisted of a deproteinisation step and a quantitative acid-catalyzed conversion of all 9-NC and 9-AC into their lactone forms and a subsequent solid-phase extraction. Redissolved extracts were analyzed on a Prodigy analytical column, using a mixture of methanol–phosphate buffer (pH 2.5). Detection was concomitantly performed with UV for 9-NC and fluorimetrically for 9-AC. The lower limit of quantifications were 10 ng/ml and 2.5 ng/ml for the determination of 9-NC and 9-AC, respectively, using 500 μl of plasma. The presented method was successfully applied to a clinical pharmacokinetic study.Journal of Chromatography B. -
Article: DNA repair mechanisms involved in gemcitabine cytotoxicity and in the interaction between gemcitabine and cisplatin
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ABSTRACT: The influence of DNA repair mechanisms on the interaction between gemcitabine and cisplatin was studied using a panel of Chinese hamster ovary (CHO) cell lines each deficient in one of the following repair pathways: base excision repair (BER), nucleotide excision repair (NER), homologous recombination (HR) and non-homologous end joining (NHEJ). NER and HR are known to be involved in platinum-DNA adduct repair. Single agent experiments demonstrated that each of the repair deficient cell lines had a similar sensitivity towards gemcitabine as the parental cell lines, whereas the NER- and HR-deficient lines showed increased sensitivity towards cisplatin. Furthermore, in the parental cell lines, the administration sequence cisplatin followed by gemcitabine was synergistic, whereas the reversed schedule showed additivity and simultaneous administration revealed antagonistic cytotoxicity. In the repair deficient cell lines, using this synergistic schedule of cisplatin followed by gemcitabine, loss of synergy was observed in the NER- and HR-deficient cell lines. However, the magnitude of the effect in the NER-deficient cells was small. The sensitivity to the combination of cisplatin and gemcitabine shown by the BER- and NHEJ-deficient cell lines did not differ significantly from that of the parental cell line. Cellular accumulation of platinum as well as the formation of GG- and AG-intrastrand adducts in the parental line and in the HR-deficient line were not affected by gemcitabine.In conclusion, our results indicate that BER, NER, HR, and NHEJ are most likely incapable of modulating the cytotoxicity of gemcitabine, and that HR is involved in the synergistic interaction between cisplatin and gemcitabine in our cell system.Biochemical Pharmacology.
