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Ref Type | Journal Article | ||||||||||||
PMID | (18483379) | ||||||||||||
Authors | Dalgard CL, Van Quill KR, O'Brien JM | ||||||||||||
Title | Evaluation of the in vitro and in vivo antitumor activity of histone deacetylase inhibitors for the therapy of retinoblastoma. | ||||||||||||
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Abstract Text | To evaluate the potential utility of histone deacetylase inhibitors (HDACi) for treatment of retinoblastoma (RB).Growth-inhibitory effects of HDACi [trichostatin A (TSA), suberoylanilide hydroxamic acid (SAHA), or MS-275] were assessed in human and transgenic murine RB cells. Effects of TSA and MS-275 were also assessed in combination with standard therapeutic agents for RB. Proapoptotic effects of MS-275 and TSA were evaluated by caspase-3/7 activity, Annexin V translocation, and/or Bim expression analyses. Effects of MS-275 on cell cycle distribution and reactive oxygen species levels were determined by flow cytometry. Retinal tissue morphology was evaluated in mice after local administration of MS-275. Analysis of retinal acetyl-histone levels was used to assess MS-275 delivery after systemic administration. Therapeutic effects of MS-275 were determined in transgenic mouse and rat ocular xenograft models of RB after i.p. injection of 20 mg/kg every other day for 21 or 13 days, respectively.TSA, SAHA, and MS-275 dose dependently reduced RB cell survival. TSA and MS-275 showed additive growth-inhibitory effects in combination with carboplatin, etoposide, or vincristine. TSA and MS-275 increased caspase-3/7 activity. MS-275 increased Annexin V membrane translocation and induced G1 arrest. Cytotoxicity of MS-275 was dependent on increased reactive oxygen species levels and was reversed by antioxidant pretreatment. Intraocular administration of 1 microL of 10 micromol/L MS-275 did not alter ocular tissue morphology. Increased acetyl-histone levels confirmed MS-275 delivery to retinal tissue after systemic administration. MS-275 significantly reduced tumor burden in both mouse and rat models of RB.HDACi should be considered for clinical trials in children with RB. |
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Therapy Name | Drugs | Efficacy Evidence | Clinical Trials |
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Gene | Variant | Impact | Protein Effect | Variant Description | Associated with drug Resistance |
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Molecular Profile | Indication/Tumor Type | Response Type | Therapy Name | Approval Status | Evidence Type | Efficacy Evidence | References |
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RB1 loss | retinoblastoma | sensitive | Vorinostat | Preclinical - Cell culture | Actionable | In a preclinical study, Zolinza (vorinostat) inhibited growth of retinoblastoma cell lines in culture (PMID: 18483379), which have been demonstrated to be deficient in RB1 (PMID: 23498719). | 23498719 18483379 |
RB1 loss | retinoblastoma | sensitive | Entinostat | Preclinical - Cell line xenograft | Actionable | In a preclinical study, Entinostat (MS-275) inhibited growth of retinoblastoma cell lines in culture and inhibited tumor growth in a retinoblastoma cell line xenograft model (PMID: 18483379), which have been demonstrated to be deficient in RB1 (PMID: 23498719). | 23498719 18483379 |
RB1 loss | retinoblastoma | sensitive | Trichostatin A | Preclinical - Cell culture | Actionable | In a preclinical study, Trichostatin A (TSA) inhibited growth of retinoblastoma cell lines in culture (PMID: 18483379), which have been demonstrated to be deficient in RB1 (PMID: 23498719). | 23498719 18483379 |