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Subcellular localization of the camptothecin analogues, topotecan and gimatecan.
Biochem Pharmacol. 2004 Mar 15; 67(6):1035-45.BP

Abstract

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.

Authors+Show Affiliations

IGM-CNR, Sezione di Istochimica e Citometria, Dipartimento di Biologia Animale, Università di Pavia, 27100 Pavia, Italy.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

15006540

Citation

Croce, Anna Cleta, et al. "Subcellular Localization of the Camptothecin Analogues, Topotecan and Gimatecan." Biochemical Pharmacology, vol. 67, no. 6, 2004, pp. 1035-45.
Croce AC, Bottiroli G, Supino R, et al. Subcellular localization of the camptothecin analogues, topotecan and gimatecan. Biochem Pharmacol. 2004;67(6):1035-45.
Croce, A. C., Bottiroli, G., Supino, R., Favini, E., Zuco, V., & Zunino, F. (2004). Subcellular localization of the camptothecin analogues, topotecan and gimatecan. Biochemical Pharmacology, 67(6), 1035-45.
Croce AC, et al. Subcellular Localization of the Camptothecin Analogues, Topotecan and Gimatecan. Biochem Pharmacol. 2004 Mar 15;67(6):1035-45. PubMed PMID: 15006540.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Subcellular localization of the camptothecin analogues, topotecan and gimatecan. AU - Croce,Anna Cleta, AU - Bottiroli,Giovanni, AU - Supino,Rosanna, AU - Favini,Enrica, AU - Zuco,Valentina, AU - Zunino,Franco, PY - 2003/06/06/received PY - 2003/10/23/accepted PY - 2004/3/10/pubmed PY - 2004/4/13/medline PY - 2004/3/10/entrez SP - 1035 EP - 45 JF - Biochemical pharmacology JO - Biochem. Pharmacol. VL - 67 IS - 6 N2 - 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. SN - 0006-2952 UR - https://www.unboundmedicine.com/medline/citation/15006540/Subcellular_localization_of_the_camptothecin_analogues_topotecan_and_gimatecan_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0006295203008906 DB - PRIME DP - Unbound Medicine ER -