Induction of breast cancer resistance protein by the camptothecin derivative DX-8951f is associated with minor reduction of antitumour activity.
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, MRP1, 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.
van Hattum
A H
AH
Department of Medical Oncology, Vrije Universiteit Medical Center, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands.
Hoogsteen
I J
IJ
Schlüper
H M M
HM
Maliepaard
M
M
Scheffer
G L
GL
Scheper
R J
RJ
Kohlhagen
G
G
Pommier
Y
Y
Pinedo
H M
HM
Boven
E
E
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D000166:Acridines / Q000494:pharmacology; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000627:therapeutic use*; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D004264:DNA Topoisomerases, Type I / Q000235:genetics / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D007124:Immunoenzyme Techniques; D007546:Isoquinolines / Q000494:pharmacology; D008562:Membrane Glycoproteins; D051379:Mice; D008819:Mice, Nude; D009154:Mutation; D009363:Neoplasm Proteins / Q000378:metabolism; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000473:pathology; D010051:Ovarian Neoplasms / Q000188:drug therapy*; D044005:Tetrahydroisoquinolines; D060245:Tetraspanin 29; D013778:Tetrazolium Salts; D013844:Thiazoles; D059004:Topoisomerase I Inhibitors; D014407:Tumor Cells, Cultured / Q000166:cytology / Q000187:drug effects
C116614:ABCG2 protein, human; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000166:Acridines; D015703:Antigens, CD; D000972:Antineoplastic Agents, Phytogenic; C554869:CD9 protein, human; C554870:Cd9 protein, mouse; D007546:Isoquinolines; D008562:Membrane Glycoproteins; D009363:Neoplasm Proteins; D044005:Tetrahydroisoquinolines; D060245:Tetraspanin 29; D013778:Tetrazolium Salts; D013844:Thiazoles; D059004:Topoisomerase I Inhibitors; D004264:DNA Topoisomerases, Type I; C022616:thiazolyl blue; C083501:Elacridar; C095887:exatecan; D002166:Camptothecin