| 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.
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