Camptothecin Analogue Efficacy In Vitro: Effect of Liposomal Encapsulation of GI147211C (NX211)

Topoisomerase I inhibitors, including camptothecin and topote- can (TP), have demonstrated chemotherapeutic utility in vivo. Solubility limitations of camptothecins have led to a search for more soluble camptothecin analogues, including GI147211C (GlaxoWellcome). Alternative means of delivery that i...

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Bibliographic Details
Published in:	Xenobiotica Vol. 6; no. 1; pp. 51 - 62
Main Author:	Eric Lynam, Darla J. Landfair, Marc E. Wiles
Format:	Journal Article
Language:	English
Published:	Informa UK Ltd 1999
Online Access:	Get full text
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Summary:	Topoisomerase I inhibitors, including camptothecin and topote- can (TP), have demonstrated chemotherapeutic utility in vivo. Solubility limitations of camptothecins have led to a search for more soluble camptothecin analogues, including GI147211C (GlaxoWellcome). Alternative means of delivery that improve tumor targeting of these agents have also been sought. In these studies, we used GI147211C and liposomally encapsulated GI147211C (NX211) for comparison of in vitro cytotoxicity relative to TP. Standard 3H-thymidine-based cytotoxicity assays were performed with IC50 (50% inhibitory concentration) values determined for these agents across a broad range of tumor cell types. Our results indicate that GI147211C and NX211 are significantly more effective as cytotoxic agents than TP (p < 0.05) for several tumor cell types. For example, MDA-MB-468 (human breast adenocarcinoma) tumor cells exhibited median IC50 values of 2.85, 6.42, and 47.3 ng/ml for NX211, GI147211C, and TP, respectively. Some cell types, such as DU-145 (human prostate carcinoma) exhibited greater sensitivity to NX211 than to GI147211C (i.e., median IC50 values of 0.44 and 1.61 ng/ml,respectively).Interestingly,fluorescence assessment of cellular uptake of GI147211C and NX211 suggests differential uptake of GI147211C relative to NX211 (i.e., = 3-4 fold greater uptake of GI147211C on an equivalently administered concentration basis). Together, these observations suggest that GI147211C and NX211 demonstrated greater cytotoxicity in vitro compared to TP and raise the possibility that liposomal encapsulation may alter activity of GI147211C at the cellular level.
ISSN:	0049-8254 1366-5928
DOI:	10.1080/107175499267165