Lipophilicity of camptothecins derivatives has been reported to improve the stability of the
lactone ring and to favor rapid uptake and intracellular accumulation. Recently, a novel series of lipophilic camptothecins substituted at position 7 was developed, and
gimatecan (
ST1481) was selected for clinical development on the basis of some favorable features, including potent cytotoxicity and the unique feature of the lack of recognition by
breast cancer resistance-associated
protein (BCRP). In this work the intrinsic fluorescence properties of this compound were exploited to investigate its intracellular disposition in comparison with the water-soluble
camptothecin,
topotecan (
TPT), in HT-29 colon
carcinoma cells and in a subline, HT-29/Mit, selected for resistance to
mitoxantrone and overexpressing BCRP. The study was performed at single-cell level by means of microspectrofluorometry and fluorescence image analysis. The results indicated a quite different subcellular localization of
TPT ST1481, since
TPT localized mainly in mitochondria, whereas
gimatecan exhibited a lysosomal localization. An increased persistence of DNA damage in
gimatecan-treated cells was consistent with the interpretation that lysosomes represent a store of active
drug. In contrast to
gimatecan, which showed a similar localization in HT-29 cells and in the
mitoxantrone-resistant subline, the cellular pharmacokinetic of
TPT was markedly influenced by overexpression of BCRP
protein in the resistant subline. In conclusion, the present results indicating a quite different behavior of the two camptothecins suggest that, apart from intracellular accumulation, subcellular distribution plays a role in their cytotoxic potency and contributes to their pharmacological features.