Phase I Study of Oral CI-994 in Combination with Gemcitabine in Treatment of Patients with Advanced Cancer

Nemunaitis, John; Orr, Douglas W.; Eager, Rob; Cunningham, Casey; Williams, A. S.; Mennel, Robert G.; Grove, William R.; Olson, Stephen C.

doi:10.1097/00130404-200301000-00010

Cited by 54 publications

(24 citation statements)

References 34 publications

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“…[7][8][9][10][11][12] In the present study, we describe prodrugs of BA that are HDACIs. These prodrugs inhibit proliferation and induce histone acetylation, differentiation and cell death of human prostate carcinoma cells in vitro and in vivo.…”

Section: Discussionmentioning

confidence: 99%

“…A number of substances that display HDACI properties are in preclinical and clinical development, including AN-9 (a derivative of BA), the hydroxamic acid SAHA, trichostatin A, the benzamides MS-275 and CI-994 and the cyclic peptides trapoxin and depsipeptide. [7][8][9][10][11][12] For over a decade, we have studied prodrugs of low m.w. aliphatic acids, primarily BA, as potential anticancer agents.…”

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confidence: 99%

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In vivo and in vitro antitumor activity of butyroyloxymethyl‐diethyl phosphate (AN‐7), a histone deacetylase inhibitor, in human prostate cancer

Rephaeli

Blank-Porat

Tarasenko

et al. 2005

Intl Journal of Cancer

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AN-7, a prodrug of butyric acid, induced histone hyperacetylation and differentiation and inhibited proliferation of human prostate 22Rv1 cancer cells in vitro and in vivo. In nude mice implanted with these cells, 50 mg/kg AN-7 given orally thrice a week led to inhibition of tumor growth and metastasis, tumor regression in >25% of animals and increased survival. Median time to the experimental end point (tumor volume 2 cm 3 or death) in the untreated was 52 days, and average tumor volume was 0.8 6 0.18 cm 3 . At the same time, 94.4% of AN-7-treated mice survived and had average tumor volumes of 0.37 6 0.1 cm 3 . PSA expression was a useful marker for 22Rv1 lung metastasis detection. Sizeable metastases positively stained for PSA and limited air gaps were found in lungs of untreated mice. In animals treated with AN-7, lung morphology appeared normal. Primary tumors of treated animals were highly positive for PSA and had an elevated level of p21 and the proapoptotic protein Bax. Sections taken from AN-7-treated animals, examined under an electron microscope, exhibited condensed chromatin and apoptotic bodies. PSA serum levels were higher in untreated compared to treated animals and correlated with tumor volume. Since prolonged oral administration with 50 mg/kg or a single oral dose of 1.2 g/kg AN-7 did not cause adverse effects and the former exhibited significant anticancer activity, AN-7 is likely to display a high therapeutic index and may be beneficial for prostate cancer patients. ' 2005 Wiley-Liss, Inc.Key words: AN-7; histone deacetylase inhibitor; prostate-specific antigen; prodrug; lung metastasis; prostate carcinoma Modification of histones as molecular targets for disease therapy in general, and for cancer therapy in particular, is the subject of intense investigations.1-4 The steady-state level of core histone acetylation, maintained by a dynamic balance between the activity of HATs and HDACs, provides a molecular communication link between chromatin and signal transduction. 5,6 In general, increased levels of histone acetylation lead to relaxation of the chromatin structure, allowing access of transcription factors and increased transcription, while decreased levels of acetylation are associated with repressed transcription.Considerable attention has been focused on developing HDACIs as potential anticancer agents. [1][2][3][4] In cancer cells, HDACIs affect the regulation of gene expression, cell growth, differentiation and apoptosis. A number of substances that display HDACI properties are in preclinical and clinical development, including AN-9 (a derivative of BA), the hydroxamic acid SAHA, trichostatin A, the benzamides MS-275 and CI-994 and the cyclic peptides trapoxin and depsipeptide. [7][8][9][10][11][12] For over a decade, we have studied prodrugs of low m.w. aliphatic acids, primarily BA, as potential anticancer agents. 13-15These compounds undergo esterase-dependent intracellular hydrolysis to release acids and aldehydes. The intracellular metabolic degradation is supported by the observat...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

In vivo and in vitro antitumor activity of butyroyloxymethyl‐diethyl phosphate (AN‐7), a histone deacetylase inhibitor, in human prostate cancer

Rephaeli

Blank-Porat

Tarasenko

et al. 2005

Intl Journal of Cancer

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“…In this context, forward chemogenomics strategies are used to initially examine the phenotypic effect of a compound or a panel of compounds on a Applications Chemogenomics strategies are increasingly being harnessed by various fields of medical research -for example, those related to cancer or immune, inflammatory and hormone disease -in attempts to develop new targeted therapies as rapidly as possible (BOX 3). Several advances have been made by chemogenomics in understanding the molecular biology of various diseases and in identifying potential pharmacological and MYELODYSPLASTIC SYNDROME [40][41][42][43][44][45][46] . In turn, phenotypic screening of compounds that have been recently discovered by reverse chemogenomics to inhibit a certain biological pathway can be used to identify the immediate target of compound action in this pathway.…”

Section: Ligand and Target Selectionmentioning

confidence: 99%

Chemogenomics: an emerging strategy for rapid target and drug discovery

2004

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“…116 A phase I trial of CI-994 in combination with known anti-cancer drugs such as capecitabine, paclitaxel, carboplatin, or gemcitabine demonstrated that CI-994 was well tolerated in combination therapy. 19,117,118 In the case of hydroxamic acids, a phase I trial of oral SAHA has shown that it is well tolerated, induces histone acetylation, and has anti-tumor activity in solid and hematological tumors. Non-specific constitutional symptoms, including fatigue, anorexia, diarrhea, and dehydration were observed, while myelosuppression and thrombocytopenia were common in IV formulation.…”

Section: Hdacis In Clinical Trialsmentioning

confidence: 99%

Histone Deacetylase Inhibitors for Cancer Therapy

Kim¹,

Bang²,

Robertson³

2006

Epigenetics

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The epigenome of cancer cells is determined by DNA methylation and an array of post-translational modifications of the core histones. Epigenetic abnormalities are commonly found in human tumors and importantly, they can be reversed by pharmacologic inhibitors. Histone deacetylase inhibitors (HDACIs) represent one of the most promising epigenetic treatments for cancer. HDACIs have emerged as promising targets for cancer therapy because they reactivate the transcription of multiple genes that are silenced in human tumors and they show pleiotropic anti-tumor effects selectively in cancer cells. HDACIs are well-tolerated and several show promising anti-tumor activity. While gene transcription has been considered to be the major target of HDACIs, inhibition of acetylation of non-histone proteins is now emerging as a novel basis for their anti-tumor effects. In this review, we discuss new insights into the molecular mechanism of HDACIs, their current status of clinical development, and possible future uses in cancer therapy.

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Phase I Study of Oral CI-994 in Combination with Gemcitabine in Treatment of Patients with Advanced Cancer

Abstract: The 6-mg/m2 dose of CI-994 (p.o. x 21 days) was defined as the maximum tolerated dose that could safely be administered in combination with gemcitabine (1,000 mg/m2 i.v. on days 1, 8, and 15) during a 28-day cycle.

Cited by 54 publications

References 34 publications

In vivo and in vitro antitumor activity of butyroyloxymethyl‐diethyl phosphate (AN‐7), a histone deacetylase inhibitor, in human prostate cancer

In vivo and in vitro antitumor activity of butyroyloxymethyl‐diethyl phosphate (AN‐7), a histone deacetylase inhibitor, in human prostate cancer

Chemogenomics: an emerging strategy for rapid target and drug discovery

Histone Deacetylase Inhibitors for Cancer Therapy

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