TY - JOUR
T1 - Induction of breast cancer resistance protein by the camptothecin derivative DX-8951f is associated with minor reduction of antitumour activity
AU - Van Hattum, A. H.
AU - Hoogsteen, I. J.
AU - Schlüper, H. M M
AU - Maliepaard, M.
AU - Scheffer, G. L.
AU - Scheper, R. J.
AU - Kohlhagen, G.
AU - Pommier, Y.
AU - Pinedo, H. M.
AU - Boven, E.
PY - 2002/9/9
Y1 - 2002/9/9
N2 - DX-8951f (exatecan mesylate), a new water-soluble derivative of camptothecin, is currently being evaluated in phase II clinical trials. Resistance may be acquired when treating cancer patients with DX-8951f. Therefore, we selected a subline of the human ovarian cancer cell line A2780 for resistance against DX-8951f to investigate possible mechanisms of resistance. This DX-8951f-resistant subline, designated 2780DX8 (resistance factor = 9.3), displayed a typical cross-resistance pattern including compounds, such as topotecan (resistance factor = 34), SN-38 (resistance factor = 47), mitoxantrone (resistance factor = 59) and doxorubicin (resistance factor = 2.9), which have previously been associated with the expression of breast cancer resistance protein. 2780DX8 cells did not show changes in the topoisomerase I gene, in topoisomerase I protein levels or catalytic activity. Overexpression of breast cancer resistance protein could be detected, both at the mRNA and protein level, while staining for Pgp, MRPI, or LRP was negative. GF120918, an inhibitor of breast cancer resistance protein, was able to reverse the DX-8951f-induced resistance in 2780DX8 cells. In vivo experiments in well-established 2780DX8 human tumour xenografts demonstrated that the growth inhibition induced by CPT-11 was more affected by breast cancer resistance protein expression than that of DX-8951f. These data indicate for the first time that DX-8951f is able to induce breast cancer resistance protein as a mechanism of resistance. Breast cancer resistance protein, however, results in only minor reduction of antitumour activity of DX-8951f which is an advantage over topotecan and CPT-11/SN-38.
AB - DX-8951f (exatecan mesylate), a new water-soluble derivative of camptothecin, is currently being evaluated in phase II clinical trials. Resistance may be acquired when treating cancer patients with DX-8951f. Therefore, we selected a subline of the human ovarian cancer cell line A2780 for resistance against DX-8951f to investigate possible mechanisms of resistance. This DX-8951f-resistant subline, designated 2780DX8 (resistance factor = 9.3), displayed a typical cross-resistance pattern including compounds, such as topotecan (resistance factor = 34), SN-38 (resistance factor = 47), mitoxantrone (resistance factor = 59) and doxorubicin (resistance factor = 2.9), which have previously been associated with the expression of breast cancer resistance protein. 2780DX8 cells did not show changes in the topoisomerase I gene, in topoisomerase I protein levels or catalytic activity. Overexpression of breast cancer resistance protein could be detected, both at the mRNA and protein level, while staining for Pgp, MRPI, or LRP was negative. GF120918, an inhibitor of breast cancer resistance protein, was able to reverse the DX-8951f-induced resistance in 2780DX8 cells. In vivo experiments in well-established 2780DX8 human tumour xenografts demonstrated that the growth inhibition induced by CPT-11 was more affected by breast cancer resistance protein expression than that of DX-8951f. These data indicate for the first time that DX-8951f is able to induce breast cancer resistance protein as a mechanism of resistance. Breast cancer resistance protein, however, results in only minor reduction of antitumour activity of DX-8951f which is an advantage over topotecan and CPT-11/SN-38.
KW - BCRP
KW - Camptothecins
KW - DX-8951f
KW - GF 120918
KW - Multidrug resistance
KW - Ovarian cancer xenografts
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UR - http://www.scopus.com/inward/citedby.url?scp=18544375425&partnerID=8YFLogxK
U2 - 10.1038/sj.bjc.6600508
DO - 10.1038/sj.bjc.6600508
M3 - Article
C2 - 12237778
AN - SCOPUS:18544375425
SN - 0007-0920
VL - 87
SP - 665
EP - 672
JO - British Journal of Cancer
JF - British Journal of Cancer
IS - 6
ER -