CPT-11 sensitivity in relation to the expression of P170-glycoprotein and multidrug resistance-associated protein

W. J M Jansen, T. M. Hulscher, J. Van Ark-Otte, G. Giaccone, H. M. Pinedo, E. Boven

Research output: Contribution to journalArticlepeer-review

Abstract

The relevance of P170-glycoprotein (P-gp) and multidrug resistance-associated protein (MRP) for the sensitivity to CPT-11 was investigated in human malignant cell lines as well as in human tumour xenografts. In vitro, the P-gp-positive sublines BRO/mdr1.1 (transfected with MDR1) and 2780(AD) were slightly cross-resistant against carboxylesterase-activated CPT-11. Cross-resistance against SN-38 was present in 2780(AD) cells, but not in BRO/mdr1.1 cells. The P-gp modulators BIBW22BS, verapamil and dexniguldipine partly reversed the resistance against CPT-11 in the P-gp-positive sublines. BIBW22BS was the most effective modulator in the reversal of the resistance against carboxylesterase-activated CPT-11 as well as against SN-38 in the 2780(AD) subline. In contrast to doxorubicin and vincristine, the BRO/mdr1.1 xenografts were at least as sensitive to CPT-11 as the BRO xenografts. The 2780(AD) xenografts were slightly less sensitive than the parent tumours, but there was no difference in topoisomerase I DNA unwinding activity. Therefore, the high retention of the multidrug resistant phenotype of 2780(AD) cells in vivo may be the cause of the low cross-resistance against CPT-11. The MRP-positive subline GLC4/ADR was cross-resistant against carboxylesterase-activated CPT-11 and SN-38. GLC4/ADR cells, however, demonstrated a twofold lower topoisomerase I activity than GLC4 cells. Cross-resistance against the camptothecin derivatives was not apparent in the MRP-transfected subline of SW1573/S1. In conclusion, P-gp-positive cells show a low cross-resistance against CPT-11/SN38, which is only apparent with high P-gp expression in vivo. MRP does not seem to play a role in the sensitivity to CPT-11.

Original languageEnglish (US)
Pages (from-to)359-365
Number of pages7
JournalBritish Journal of Cancer
Volume77
Issue number3
StatePublished - 1998
Externally publishedYes

Keywords

  • CPT-11
  • Multidrug resistance-associated protein
  • P170-glycoprotein
  • Topoisomerase

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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