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-piperidinopiperid ine 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-piper idinopiperidine at concentrations higher than 50 mu g/ml, the cells un derwent apoptosis with a nucleosomal ladder of chromosomal DNA on agar ose gels in a dose-dependent manner. We then established a cell line r esistant to 4-piperidinopiperidine (4-pp-R), which was about 20-fold m ore resistant to 4-piperidinopiperidine than the parent RVC cells. Mor eover, 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 fro m those of the parent RVC cells, and there were no differences between the two cell lines with regard to their drug transport system, CPT-ll -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 me tabolite SN-38. The present studies suggested that resistance to CPT-1 1 is in part due to insensitivity to 4-piperidinopiperidine and its me tabolites, since 4-piperidinopiperidine was cytotoxic and 4-pp-R cells were less sensitive to CPT-11.