Determinants of CPT-11 and SN-38 activities in human lung cancer cells

J. Van Ark-Otte, M. A. Kedde, W. J F Van der Vijgh, A. M C Dingemans, W. J M Jansen, H. M. Pinedo, E. Boven, G. Giaccone

Research output: Contribution to journalArticle

Abstract

Irinotecan (CPT-11) is a semisynthetic camptothecin derivative with a broad spectrum of anti-tumour activity. Carboxylesterase (CE) catalyses the conversion of CPT-11 to SN-38 (7-ethyl-10-hydroxycamptothecin), the active form of CPT-11. The antiproliferative effects of CPT-11 and SN-38, CE-activity and topoisomerase I protein expression were investigated in five human small-cell lung cancer (SCLC) cell lines and four human non-small-cell lung cancer (NSCLC) cell lines. Antiproliferative activity, expressed as IC50 values, was determined using the MTT assay. CPT-11 was significantly more active in SCLC than in NSCLC cell lines (P = 0.0036), whereas no significant difference between histological types was observed with SN-38. A significant correlation (r2 = 0.52, P = 0.028) was observed between CE activity and chemosensitivity to CPT-11 but not to SN-38, and significantly higher CE activity was observed in SCLC compared with NSCLC cell lines (P = 0.025). Western blotting experiments showed topoisomerase I protein expressions within a factor of 2, and a granular nuclear staining was detectable in all cell lines by immunocytochemistry of cytospins. No correlation was observed between protein expression and sensitivity to CPT-11 or SN-38. Cellular and medium concentrations of CPT-11 and SN-38 were measured by high-performance liquid chromatography (HPLC) in one SCLC cell line with high CE activity and high sensitivity to CPT-11, and one NSCLC cell line with low sensitivity to CPT-11 and CE activity. Intracellular concentrations of CPT-11 and SN-38 were higher in the SCLC cell line, and this was associated with an increase in cellular uptake of CPT-11 compared with the medium, and an increased intracellular formation of SN-38. In conclusion, CE activity appears to be associated with higher sensitivity to CPT-11 in human lung cancer cell lines and may partly explain the difference in the in vitro sensitivity to CPT-11 between SCLC and NSCLC cells. The assessment of CE activity in clinical material of lung cancer patients undergoing treatment with CPT-11 may be warranted. However, other mechanisms may influence sensitivity to CPT-11, possibly including drug transport.

Original languageEnglish (US)
Pages (from-to)2171-2176
Number of pages6
JournalBritish Journal of Cancer
Volume77
Issue number12
StatePublished - 1998
Externally publishedYes

Fingerprint

irinotecan
Human Activities
Lung Neoplasms
Carboxylesterase
Small Cell Lung Carcinoma
Cell Line
Non-Small Cell Lung Carcinoma

Keywords

  • Carboxylesterase
  • CPT-11
  • Non-small-cell lung cancer
  • Small-cell lung cancer
  • SN-38
  • Topoisomerase I

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Van Ark-Otte, J., Kedde, M. A., Van der Vijgh, W. J. F., Dingemans, A. M. C., Jansen, W. J. M., Pinedo, H. M., ... Giaccone, G. (1998). Determinants of CPT-11 and SN-38 activities in human lung cancer cells. British Journal of Cancer, 77(12), 2171-2176.

Determinants of CPT-11 and SN-38 activities in human lung cancer cells. / Van Ark-Otte, J.; Kedde, M. A.; Van der Vijgh, W. J F; Dingemans, A. M C; Jansen, W. J M; Pinedo, H. M.; Boven, E.; Giaccone, G.

In: British Journal of Cancer, Vol. 77, No. 12, 1998, p. 2171-2176.

Research output: Contribution to journalArticle

Van Ark-Otte, J, Kedde, MA, Van der Vijgh, WJF, Dingemans, AMC, Jansen, WJM, Pinedo, HM, Boven, E & Giaccone, G 1998, 'Determinants of CPT-11 and SN-38 activities in human lung cancer cells', British Journal of Cancer, vol. 77, no. 12, pp. 2171-2176.
Van Ark-Otte J, Kedde MA, Van der Vijgh WJF, Dingemans AMC, Jansen WJM, Pinedo HM et al. Determinants of CPT-11 and SN-38 activities in human lung cancer cells. British Journal of Cancer. 1998;77(12):2171-2176.
Van Ark-Otte, J. ; Kedde, M. A. ; Van der Vijgh, W. J F ; Dingemans, A. M C ; Jansen, W. J M ; Pinedo, H. M. ; Boven, E. ; Giaccone, G. / Determinants of CPT-11 and SN-38 activities in human lung cancer cells. In: British Journal of Cancer. 1998 ; Vol. 77, No. 12. pp. 2171-2176.
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