Suberoylanilide hydroxamic acid is effective in preclinical studies of medulloblastoma.
OBJECTIVE
Suberoylanilide hydroxamic acid (SAHA) has been studied in adult solid and hematologic malignancies. However, little information has been reported on the effects of SAHA on central nervous system (CNS) tumors including medulloblastoma, the most common malignant brain tumor in children. We investigated SAHA in preclinical medulloblastoma models to determine its anti-cancer efficacy as well as its ability to affect intracranial lesions when administered systemically.


RESULTS
Tissue culture studies were performed treating primary human fibroblasts, established medulloblastoma cell lines, and primary human medulloblastoma tumors with SAHA. At 10 microM concentration, SAHA had little effect on normal fibroblasts but caused >90% apoptosis in cultured medulloblastoma cells. Primary medulloblastomas from patients were sensitive to SAHA compared to vehicle alone in ex vivo studies. In athymic mice with medulloblastoma xenograft tumors, oral SAHA resulted in apoptosis of tumor tissue and significantly slowed tumor growth. In the ND2:Smo transgenic mouse medulloblastoma model, SAHA treatment caused significant apoptosis in these cerebellar tumors.


CONCLUSIONS
SAHA effectively induces cell death in established medulloblastoma cell lines, human patient primary tumor cultures, medulloblastoma xenografts and intracranial spontaneous medulloblastomas. Fibroblasts in culture and mice treated with SAHA did not reveal prohibitive toxicity profiles. These findings support the advancement of SAHA to pediatric clinical trials.
Spiller
Susan E
SE
Fred Hutchinson Cancer Research Center, 1100 Fairview Ave. N., Seattle, WA 98109, USA.
Ravanpay
Ali C
AC
Hahn
Andrew W
AW
Olson
James M
JM
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002478:Cells, Cultured; D002528:Cerebellar Neoplasms / Q000188:drug therapy*; D002648:Child; D005347:Fibroblasts / Q000187:drug effects; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D020287:In Situ Nick-End Labeling; D008527:Medulloblastoma / Q000188:drug therapy*; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000188:drug therapy; D000077337:Vorinostat
D000970:Antineoplastic Agents; D006877:Hydroxamic Acids; D000077337:Vorinostat