A phase I trial of Depsipeptide (FR901228) in patients with advanced cancer

Marshall, John L.; Rizvi, Naiyer A.; Kauh, John S.; Dahut, William L.; Figuera, Manuela; Kang, Min H.; Figg, William D.; Wainer, Irving W.; Chaissang, Christoff; Li, Megan Zhaoyang; Hawkins, Michael

doi:10.1046/j.1359-4117.2002.01039.x

Cited by 195 publications

(136 citation statements)

References 9 publications

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“…By contrast, DEP is a natural tetrapeptide HDAC inhibitor that is currently in phase I and II clinical trials for treating hematological malignancies and solid tumors (Piekarz et al, 2001;Marshall et al, 2002;Sandor et al, 2002;Piekarz and Bates, 2004;Byrd et al, 2005). DEP inhibits all the known Class I and Class II HDAC enzymes (Nakajima et al, 1998).…”

Section: Resultsmentioning

confidence: 99%

Histone deacetylase inhibitors induce the degradation of the t(8;21) fusion oncoprotein

et al. 2006

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The t(8;21) chromosomal translocation that generates the fusion oncoprotein RUNX1-ETO predominates in leukemia patients of the French-American-British (FAB) class M2 subtype. The oncoprotein has the capacity to promote expansion of hematopoietic stem/progenitor cells and induces leukemia in association with other genetic alterations. Here, we show that RUNX1-ETO undergoes degradation in response to treatment with histone deacetylase inhibitors, one of which, depsipeptide (DEP), is currently undergoing phase II clinical testing in a variety of malignancies. These compounds induce turnover of RUNX1-ETO without affecting the stability of RUNX1-ETO partner proteins. In addition, RUNX1-ETO physically interacts with heat shock protein 90 (HSP90). DEP treatment interrupts the association of RUNX1-ETO with HSP90 and induces proteasomal degradation of RUNX1-ETO. DEP and the HSP90 antagonist 17-allylamino-geldanamycin (17-AAG) both triggered RUNX1-ETO degradation, but without any additive or cooperative effects. These findings may stimulate the development of more rational and effective approaches for treating t(8;21) patients using histone deacetylase inhibitors or HSP90 inhibitors.

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Section: Resultsmentioning

confidence: 99%

Histone deacetylase inhibitors induce the degradation of the t(8;21) fusion oncoprotein

et al. 2006

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“…Although HDAC inhibitors have shown efficacy in haematological malignancies (Marshall et al, 2002;Sandor et al, 2002;Byrd et al, 2005;Kelly et al, 2005;Garcia-Manero et al, 2008), their singleagent activity in solid tumours has been limited (Reid et al, 2004;Luu et al, 2006;Stadler et al, 2006;Blumenschein et al, 2008). This study describes a sequenced combination with the HDAC inhibitor vorinostat given for 48 h followed by an anthracycline-type topo II inhibitor, doxorubicin (Table 1).…”

Section: Discussionmentioning

confidence: 99%

Phase I trial of vorinostat and doxorubicin in solid tumours: histone deacetylase 2 expression as a predictive marker

et al. 2009

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BACKGROUND: Histone deacetylase inhibitors (HDACi) can sensitise cancer cells to topoisomerase inhibitors by increasing their access and binding to DNA. METHODS: This phase I trial was designed to determine the toxicity profile, tolerability, and recommended phase II dose of escalating doses of the HDACi vorinostat, with weekly doxorubicin. RESULTS: In total, 32 patients were treated; vorinostat was dosed at 400, 600, 800, or 1000 mg day À1 on days 1 -3, followed by doxorubicin (20 mg m À2 ) on day 3 for 3 of 4 weeks. Maximal tolerated dose was determined to be 800 mg day À1 of vorinostat. Dose-limiting toxicities were grade 3 nausea/vomiting (two out of six) and fatigue (one out of six) at 1000 mg day À1 . Non-doselimiting grade 3/4 toxicities included haematological toxicity and venous thromboembolism. Antitumor activity in 24 evaluable patients included two partial responses (breast and prostate cancer). Two patients with melanoma had stable disease for X8 months. Histone hyperacetylation changes in peripheral blood mononuclear and tumour cells were comparable. Histone hyperacetylation seemed to correlate with pre-treatment HDAC2 expression. CONCLUSION: These findings suggest that vorinostat can be combined with weekly doxorubicin in this schedule at a dose of 800 mg day À1 . The HDAC2 expression may be a marker predictive of HDAC inhibition. Antitumor activity of this regimen in breast cancer, prostate cancer, and melanoma seems interesting.

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“…The relaxed chromatin structure allows these genes to be expressed, which finally inhibit tumor cell growth. It seems that the most advanced agents include constituents from the small-molecule hydroxamate (SAHA, phase II) and cyclic peptide (FK-228, phase II) structural classes (58,59). Promising results from these studies will continue to drive the exploration of HDAC function and inhibitor design.…”

Section: Valproic Acid -------------------------------------------------mentioning

confidence: 99%

Histone deacetylase inhibitors: A novel target of anticancer therapy (Review)

Kouraklis¹,

Theocharis²

2006

Oncol Rep

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Abstract. Accumulating evidence suggests that the acetylation and deacetylation of histones play significant roles in transcriptional regulation of eukaryotic cells. The balance between acetylation and deacetylation is an important factor in regulating gene expression and is thus linked to the control of cell fate. The histone deacetylase inhibitors (HDIs) including the hydroxamic acids, such as suberoylanilide hydroxamic acid and pyroxamide, the benzamides MS-275 and CI-994 and the butyrate derivative 4-PBA are a new class of anti-neoplastic agents currently being evaluated in clinical trials. Moreover, new synthetic HDIs have been used recently in phase I and II clinical trials. Over the next few years experts believe that as first generation HDIs produce clinical benefits and second generation inhibitors are rationally designed with improved specificity, this class of drugs will emerge as a new way of cancer treatment. The first clinical studies have shown that histone hyperacetylation can be achieved safely in humans and that treatment of cancer with such agents seems to become possible. The use of HDIs, probably in association with classical chemotherapy drugs or in combination with DNA-demethylating agents, could be promising for cancer patients. Further evaluation is needed to establish the clinical activity of combination therapy using HDIs with cytotoxic drugs or differentiation induced agents.

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A phase I trial of Depsipeptide (FR901228) in patients with advanced cancer

Cited by 195 publications

References 9 publications

Histone deacetylase inhibitors induce the degradation of the t(8;21) fusion oncoprotein

Histone deacetylase inhibitors induce the degradation of the t(8;21) fusion oncoprotein

Phase I trial of vorinostat and doxorubicin in solid tumours: histone deacetylase 2 expression as a predictive marker

Histone deacetylase inhibitors: A novel target of anticancer therapy (Review)

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