Abstract
The antitumor efficacy of the synthetic benzamide derivative MS-27-275 (MS-275), an inhibitor of histone deacetylation [T. Suzuki et al., J. Med. Chem., 42: 3001-3003, 1999], was evaluated in a series of pediatric solid tumor cell lines, including neuroblastoma, rhabdomyosarcoma, Ewing's sarcoma (EWS), retinoblastoma, medulloblastoma, undifferentiated sarcoma (US), osteosarcoma, and malignant rhabdoid tumors. Treatment with MS-275 results in an increase in acetylation of histones within 4 h of drug exposure. The cell lines were treated with various concentrations of MS-275 for 3 days and incubated with [ 3H]thymidine for 20 h before cell harvest. MS-275 inhibited [ 3H]thymidine uptake in a dose-dependent manner in all tumor cell lines examined. The IC 50 ranged from 50 nm in the D283 medulloblastoma cell line to 1.3 μM in the US. A common feature of MS-275 treatment of pediatric tumor cell lines was induction of p21mRNA. However, the effects on cell cycle were diverse because in some cases MS-275 induced an increase in G 1 or G 2, whereas in others, there was an induction of apoptosis. In EWS, the EWS/fli chimeric transcription factor created by the t(11;22) suppresses transforming growth factor (TGF) βRII transcription, however, MS-275 was able to induce an increase in TGF-βRII mRNA and restore TGF-β signaling. Using xenograft orthotopic models of US, EWS, and neuroblastoma, we find that the growth of established tumors is inhibited in mice treated with MS-275.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 6108-6115 |
| Number of pages | 8 |
| Journal | Cancer Research |
| Volume | 62 |
| Issue number | 21 |
| State | Published - Nov 1 2002 |
| Externally published | Yes |
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ASJC Scopus subject areas
- Cancer Research
- Oncology
Cite this
MS-27-275, an inhibitor of histone deacetylase, has marked in vitro and in vivo antitumor activity against pediatric solid tumors. / Jaboin, Jerry; Wild, Jason; Hamidi, Habib; Khanna, Chand; Kim, Chong Jai; Robey, Robert; Bates, Susan E.; Thiele, Carol J.
In: Cancer Research, Vol. 62, No. 21, 01.11.2002, p. 6108-6115.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - MS-27-275, an inhibitor of histone deacetylase, has marked in vitro and in vivo antitumor activity against pediatric solid tumors
AU - Jaboin, Jerry
AU - Wild, Jason
AU - Hamidi, Habib
AU - Khanna, Chand
AU - Kim, Chong Jai
AU - Robey, Robert
AU - Bates, Susan E.
AU - Thiele, Carol J.
PY - 2002/11/1
Y1 - 2002/11/1
N2 - The antitumor efficacy of the synthetic benzamide derivative MS-27-275 (MS-275), an inhibitor of histone deacetylation [T. Suzuki et al., J. Med. Chem., 42: 3001-3003, 1999], was evaluated in a series of pediatric solid tumor cell lines, including neuroblastoma, rhabdomyosarcoma, Ewing's sarcoma (EWS), retinoblastoma, medulloblastoma, undifferentiated sarcoma (US), osteosarcoma, and malignant rhabdoid tumors. Treatment with MS-275 results in an increase in acetylation of histones within 4 h of drug exposure. The cell lines were treated with various concentrations of MS-275 for 3 days and incubated with [ 3H]thymidine for 20 h before cell harvest. MS-275 inhibited [ 3H]thymidine uptake in a dose-dependent manner in all tumor cell lines examined. The IC 50 ranged from 50 nm in the D283 medulloblastoma cell line to 1.3 μM in the US. A common feature of MS-275 treatment of pediatric tumor cell lines was induction of p21mRNA. However, the effects on cell cycle were diverse because in some cases MS-275 induced an increase in G 1 or G 2, whereas in others, there was an induction of apoptosis. In EWS, the EWS/fli chimeric transcription factor created by the t(11;22) suppresses transforming growth factor (TGF) βRII transcription, however, MS-275 was able to induce an increase in TGF-βRII mRNA and restore TGF-β signaling. Using xenograft orthotopic models of US, EWS, and neuroblastoma, we find that the growth of established tumors is inhibited in mice treated with MS-275.
AB - The antitumor efficacy of the synthetic benzamide derivative MS-27-275 (MS-275), an inhibitor of histone deacetylation [T. Suzuki et al., J. Med. Chem., 42: 3001-3003, 1999], was evaluated in a series of pediatric solid tumor cell lines, including neuroblastoma, rhabdomyosarcoma, Ewing's sarcoma (EWS), retinoblastoma, medulloblastoma, undifferentiated sarcoma (US), osteosarcoma, and malignant rhabdoid tumors. Treatment with MS-275 results in an increase in acetylation of histones within 4 h of drug exposure. The cell lines were treated with various concentrations of MS-275 for 3 days and incubated with [ 3H]thymidine for 20 h before cell harvest. MS-275 inhibited [ 3H]thymidine uptake in a dose-dependent manner in all tumor cell lines examined. The IC 50 ranged from 50 nm in the D283 medulloblastoma cell line to 1.3 μM in the US. A common feature of MS-275 treatment of pediatric tumor cell lines was induction of p21mRNA. However, the effects on cell cycle were diverse because in some cases MS-275 induced an increase in G 1 or G 2, whereas in others, there was an induction of apoptosis. In EWS, the EWS/fli chimeric transcription factor created by the t(11;22) suppresses transforming growth factor (TGF) βRII transcription, however, MS-275 was able to induce an increase in TGF-βRII mRNA and restore TGF-β signaling. Using xenograft orthotopic models of US, EWS, and neuroblastoma, we find that the growth of established tumors is inhibited in mice treated with MS-275.
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UR - http://www.scopus.com/inward/citedby.url?scp=0036828101&partnerID=8YFLogxK
M3 - Article
VL - 62
SP - 6108
EP - 6115
JO - Journal of Cancer Research
JF - Journal of Cancer Research
SN - 0099-7013
IS - 21
ER -