Clinical experience with the novel histone deacetylase inhibitor vorinostat (suberoylanilide hydroxamic acid) in patients with relapsed lymphoma Journal Article
| Authors: | O'Connor, O. A. |
| Article Title: | Clinical experience with the novel histone deacetylase inhibitor vorinostat (suberoylanilide hydroxamic acid) in patients with relapsed lymphoma |
| Abstract: | Preclinical studies indicate that vorinostat (suberoylanilide hydroxamic acid or SAHA) inhibits histone deacetylase (HDAC) activity, increases acetylated histones H2a, H2b, H3, and H4, and thereby induces differentiation and apoptosis in a variety of tumour cell lines, including murine erythroleukaemia, human bladder transitional cell carcinoma, and human breast adenocarcinoma. On the basis of these favourable preclinical findings, vorinostat has been selected as a candidate for clinical development with the potential to treat patients with selected malignances, including Hodgkin's disease and non-Hodgkin's lymphomas. Phase I clinical trials in patients with haematological malignances and solid tumours showed that both intravenous (i.v.) and oral formulations of vorinostat are well tolerated, can inhibit HDAC activity in peripheral blood mononuclear cells and tumour tissue biopsies, and produce objective tumour regression and symptomatic improvement with little clinical toxicity. The dose-limiting toxicities (DLT) of i.v. vorinostat were primarily haematologic and were rapidly reversible within 4-5 days of therapy cessation. In contrast, the DLT for oral vorinostat were primarily non-haematologic (including dehydration, anorexia, diarrhoea, fatigue) and were also rapidly reversible, usually within 3 days. Further research is warranted to optimise the dosing schedule for vorinostat, particularly with respect to dose, timing of administration, and duration of therapy, and to fully delineate the mechanism(s) of antitumour effect of vorinostat in various types of malignances. Several phase II studies are currently ongoing in patients with haematological malignances and solid tumours. © 2006 Cancer Research. |
| Keywords: | treatment outcome; histone deacetylase inhibitor; clinical trial; constipation; drug tolerability; fatigue; neutropenia; diarrhea; drug safety; hypophosphatemia; nonhuman; solid tumor; treatment duration; conference paper; cancer patient; anorexia; apoptosis; enzyme inhibition; infection; anemia; leukopenia; thrombocytopenia; dehydration; tumor biopsy; cell differentiation; antineoplastic activity; cancer cell culture; enzyme activity; hodgkin disease; drug dose escalation; dyspnea; hyperglycemia; hypokalemia; cancer regression; hematologic malignancy; nonhodgkin lymphoma; thorax pain; drug mechanism; non-hodgkin's lymphoma; thrombosis; histone h3; lymphoma; vorinostat; cancer relapse; drug bioavailability; protein bcl 6; cancer tissue; drug half life; breast adenocarcinoma; bladder carcinoma; histone h2a; histone h2b; transitional cell carcinoma; peripheral blood mononuclear cell; histone deacetylase; pleurisy; hypocalcemia; histone h4; guillain barre syndrome; saha; hodgkin's disease; erythroleukemia; bcl-6 |
| Journal Title: | British Journal of Cancer |
| Volume: | 95 |
| Issue: | Suppl.1 |
| ISSN: | 0007-0920 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2006-12-01 |
| Start Page: | S7 |
| End Page: | S12 |
| Language: | English |
| DOI: | 10.1038/sj.bjc.6603464 |
| PROVIDER: | scopus |
| PMCID: | PMC2360773 |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 22" - "Export Date: 4 June 2012" - "CODEN: BJCAA" - "Source: Scopus" |
