A lymphoma cell line resistant to 4-piperidinopiperidine was less sensitive to CPT-11

CPT-11 is a promising new anticancer drug in which 4-piperidinopiperidine is a side-chain structure. In the present studies, we examined the role played by 4-piperidinopiperidine in the pharmacological activity of CPT-11. When T-cell lymphoma RVC cells were incubated with 4-piperidinopiperidine at c...

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Bibliographic Details
Published in:Cancer chemotherapy and pharmacology 1997, Vol.39 (6), p.473-478
Main Authors: ONISHI, Y, OGURO, M, KIZAKI, H
Format: Article
Language:English
Subjects:
Antineoplastic agents
Antineoplastic Agents - pharmacology
Biological and medical sciences
Camptothecin - analogs & derivatives
Camptothecin - pharmacology
Cell Division - drug effects
DNA Topoisomerases, Type I - metabolism
DNA Topoisomerases, Type II - metabolism
Drug Resistance, Neoplasm
Etoposide - pharmacology
General aspects
Humans
Lymphoma, T-Cell - enzymology
Lymphoma, T-Cell - pathology
Medical sciences
Pharmacology. Drug treatments
Piperidines - pharmacology
Tumor Cells, Cultured
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Summary:CPT-11 is a promising new anticancer drug in which 4-piperidinopiperidine is a side-chain structure. In the present studies, we examined the role played by 4-piperidinopiperidine in the pharmacological activity of CPT-11. When T-cell lymphoma RVC cells were incubated with 4-piperidinopiperidine at concentrations higher than 50 micrograms/ml, the cells underwent apoptosis with a nucleosomal ladder of chromosomal DNA on agarose gels in a dose-dependent manner. We then established a cell line resistant to 4-piperidinopiperidine (4-pp-R), which was about 20-fold more resistant to 4-piperidinopiperidine than the parent RVC cells. Moreover, 4-pp-R cells showed coresistance to CPT-11. However, the growth rate and cell cycle population of 4-pp-R cells were not different from those of the parent RVC cells, and there were no differences between the two cells lines with regard to their drug transport system. CPT-11-metabolizing activity, their activity and amount of topoisomerase I, or their sensitivity to either SN-38 or etoposide, suggesting that the cytotoxicity of CPT-11 is not a consequence of the activity of its metabolite SN-38. The present studies suggested that resistance to CPT-11 is in part due to insensitivity to 4-piperidinopiperidine and its metabolites, since 4-piperidinopiperidine was cytotoxic and 4-pp-R cells were less sensitive to CPT-11.
ISSN:0344-5704
1432-0843
DOI:10.1007/s002800050601