In vitro prevention of the emergence of multidrug resistance in a pediatric rhabdomyosarcoma cell line

Citation
Ha. Cocker et al., In vitro prevention of the emergence of multidrug resistance in a pediatric rhabdomyosarcoma cell line, CLIN CANC R, 7(10), 2001, pp. 3193-3198
Citations number
24
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Oncology
Journal title
CLINICAL CANCER RESEARCH
ISSN journal
1078-0432 → ACNP
Volume
7
Issue
10
Year of publication
2001
Pages
3193 - 3198
Database
ISI
SICI code
1078-0432(200110)7:10<3193:IVPOTE>2.0.ZU;2-8
Abstract
We have established preclinical models for the development of drug resistan ce to vincristine (a major drug used in the treatment of pediatric rhabdomy osarcoma) using cell lines. The RD cell line has a mutant P53 phenotype and does not have detectable P-glycoprotein (P-gp) or multidrug resistance-rel ated protein (MRP) despite expressing low levels of mdr-1 mRNA, which encod es P-gp and mrp1 mRNA. Resistant variants of RD were derived by exposure to increasing concentrations of vincristine. This was repeated on six occasio ns, resulting in three cell lines which could tolerate 64 X the IC50 concen tration. Six independent agents were tested for their ability to prevent th e development of resistance in this model. Despite at least 10 attempts, re sistance did not develop in the presence of the multidrug resistance (MDR) modulators PSC833, VX710, and XR9576. This strongly suggests that these age nts may delay or even prevent the development of resistance to vincristine. This was also confirmed in a second rhabdomyosarcoma cell line, Rh30. In c ontrast, the agents indomethacin (MRP1 modulator), CGP41251 (protein kinase C inhibitor), and dexrazoxane (putative MDR prevention agent) did not affe ct the development of resistance in the RD model. Characterization of the r esistant cell lines indicated the presence of increased mdr-1 and P-gp expr ession, which resulted in resistance to the agents doxorubicin, etoposide, and vincristine but not cisplatin. The resistance could be modulated using PSC833 or VX710, confirming that functional P-gp is present. No apparent di fferences were seen between the resistant cell lines derived in the absence and presence of the various agents. These experiments strongly suggest tha t the development of MDR may be preventable using modulators of MDR and mer it clinical studies to test this hypothesis.