Dimethyl sulfoxide to vorinostat: Development of this histone deacetylase inhibitor as an anticancer drug Journal Article
| Authors: | Marks, P. A.; Breslow, R. |
| Article Title: | Dimethyl sulfoxide to vorinostat: Development of this histone deacetylase inhibitor as an anticancer drug |
| Abstract: | In our quest to understand why dimethyl sulfoxide (DMSO) can cause growth arrest and terminal differentiation of transformed cells, we followed a path that led us to discover suberoylanilide hydroxamic acid (SAHA; vorinostat (Zolinza)), which is a histone deacetylase inhibitor. SAHA reacts with and blocks the catalytic site of these enzymes. Extensive structure-activity studies were done along the path from DMSO to SAHA. SAHA can cause growth arrest and death of a broad variety of transformed cells both in vitro and in tumor-bearing animals at concentrations not toxic to normal cells. SAHA has many protein targets whose structure and function are altered by acetylation, including chromatin-associated histones, nonhistone gene transcription factors and proteins involved in regulation of cell proliferation, migration and death. In clinical trials, SAHA has shown significant anticancer activity against both hematologic and solid tumors at doses well tolerated by patients. A new drug application was approved by the US Food and Drug Administration for vorinostat for treatment of cutaneous T-cell lymphoma. More potent analogs of SAHA have shown unacceptable toxicity. © 2007 Nature Publishing Group. |
| Keywords: | treatment outcome; unclassified drug; acute granulocytic leukemia; fludarabine; histone deacetylase inhibitor; clinical trial; drug tolerability; fatigue; neutropenia; review; larynx carcinoma; angiogenesis inhibitor; fluorouracil; diarrhea; dose response; monotherapy; nonhuman; solid tumor; unspecified side effect; antineoplastic agents; united states; drug targeting; capecitabine; adjuvant therapy; cancer patient; cancer radiotherapy; antineoplastic agent; anorexia; neoplasms; cell proliferation; animals; cell death; imatinib; metastasis; bortezomib; enzyme inhibition; multiple myeloma; breast cancer; protein targeting; thrombocytopenia; dehydration; neoplasm proteins; combination chemotherapy; antineoplastic activity; food and drug administration; in vitro study; drug design; structure activity relation; experimental mouse; kidney carcinoma; animalia; drug receptor binding; cutaneous t cell lymphoma; dimethyl sulfoxide; hematologic malignancy; myelodysplastic syndrome; drug research; neuroblastoma; tumors; cell transformation; colon cancer; breast tumor; mesothelioma; vorinostat; patient compliance; hydroxamic acids; cell migration; cell cycle arrest; thyroid carcinoma; flavopiridol; alkylation; animal cell culture; isotretinoin; trastuzumab; anthracycline; x ray crystallography; cell cycle regulation; histone deacetylases; urinary tract carcinoma; clinical trials; cancer cell destruction; valproic acid; 3 phenylsulfamoylcinnamohydroxamic acid; arylbutyric acid derivative; n (2 aminophenyl) 4 (3 pyridinylmethoxycarbonylaminomethyl)benzamide; 4 [n (2 hydroxyethyl) n [2 (3 indolyl)ethyl]aminomethyl]cinnamohydroxamic acid; trichostatin a; leukemia remission; depsipeptide; hydroxamic acid derivative; drug acetylation; drug products; growth kinetics; fr 901228; lbh 589; fludarabine phosphate; drug application; potent analogs; tumor-bearing animals; hexamethylenebisacetamide; experimental rat |
| Journal Title: | Nature Biotechnology |
| Volume: | 25 |
| Issue: | 1 |
| ISSN: | 1087-0156 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2007-01-05 |
| Start Page: | 84 |
| End Page: | 90 |
| Language: | English |
| DOI: | 10.1038/nbt1272 |
| PUBMED: | 17211407 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 280" - "Export Date: 17 November 2011" - "CODEN: NABIF" - "Source: Scopus" |
