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Cellosaurus publication CLPUB00418

Publication number CLPUB00418
Authors Xu J.-Y., Erdreich-Epstein A., Biegel J.A., Reynolds C.P.
Title Fenretinide combined with thiotepa is active against 3 newly established atypical teratoid rhabdoid tumor cell lines that manifest high-level multidrug resistance.
Citation Cancer Res. 68 Suppl. 9:3743-3743(2008)
Web pages https://aacrjournals.org/cancerres/article/68/9_Supplement/3743/548720/
Abstract Malignant rhabdoid tumors of kidney (MRT)) and brain (atypical teratoid rhabdoid tumors (AT/RT)) are very aggressive pediatric malignancies, typically have a poor prognosis, manifest a high level of de novo multidrug resistance. We have established 3 new AT/RT and MRT cell lines: CHLA-266 (AT/RT, with supratentorial metastasis at diagnosis), COG-AR-359 (brain AT/RT at diagnosis), and COG-AR-382 (abdominal malignant rhabdoid tumor at diagnosis from the same patient as COG-AR-359). All 3 cell lines lack expression of the INI1 tumor suppressor gene and have INI1 gene mutations in chromosome band 22q11.2. Cell line identity to the patient was verified by short tandem repeat assay. CHLA-266 and COG-AR-382 grow as adherent cultures with doubling times of 40hrs and 82hrs, respectively, whereas COG-AR-359 has a mixed adherent/suspension phenotype with a doubling time of 53hrs. CHLA-266 and COG-AR-359 were tumorgenic in NOD/SCID mice, but COG-AR-382 was not tumorgenic to date. Drug cytotoxicity for etoposide (ETOP), cyclophosphamide (4-HC), temozolomide (TMZ), thiotepa, topotecan (TPT), and fenretinide (4-HPR) employed fluorescein diacetate and digital image microcopy (DIMSCAN). All 3 new lines showed multi-drug resistance, with the concentration lethal for 90% of cells (LC90) well above clinically achievable plasMA levels for all drugs tested except for 4-HPR. However, 4-HPR as a single agent had only modest activity. Interestingly, we observed synergistic cytotoxicity when 4-HPR was combined with thiotepa (Combination index at LC90 = 0.60 for COG-AR-359 and 0.1 for CHLA-266). Thiotepa as a single agent achieved a mean of 1.45 logs kill activity, 4-HPR < 1 log, but thiotepa + 4-HPR produced a mean of 3.4 logs of cell kill. Thus, we have used newly established AT/RT cell lines that are resistant to commonly- used cytotoxic drugs to identify a synergistic combination of drugs with activity against AT/RT cell lines.
Cell lines CVCL_M149; CHLA-266
CVCL_RS25; COG-AR-359
CVCL_RS26; COG-AR-382