Subcellular localization of the camptothecin analogues, topotecan and gimatecan

Anna Cleta Croce, Giovanni Bottiroli, Rosanna Supino, Enrica Favini, Valentina Zuco, Franco Zunino

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)1035-1045
Number of pages11
JournalBiochemical Pharmacology
Issue number6
Publication statusPublished - Mar 15 2004


  • A.u.
  • Arbitrary units
  • BCRP
  • Breast cancer resistance-associate protein
  • Camptothecins
  • Colon carcinoma cells
  • F.I.
  • Fluorescence intensity
  • Resistance
  • Subcellular localization
  • Topotecan
  • TPT

ASJC Scopus subject areas

  • Pharmacology


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