Abstract
Purpose: The primary objective of this study was to determine the recommended phase II doses of the new histone deacetylase inhibitor vorinostat when administered in combination with carboplatin and paclitaxel. Experimental design: Patients (N = 28) with advanced solid malignancies were treated with vorinostat, administered orally once daily for 2 weeks or twice daily for 1 week, every 3 weeks. Carboplatin and paclitaxel were administered i.v. once every 3 weeks. Vorinostat and paclitaxel doses were escalated in sequential cohorts of three patients. The pharmacokinetics of vorinostat, its metabolites, and paclitaxel are described. Results: Vorinostat was safely administered up to 400 mg once daily or 300 mg twice daily with carboplatin and paclitaxel. Two of 12 patients on the 400 mg once daily schedule experienced the dose-limiting toxicities of Grade 3 vomiting and Grade 4 neutropenia with fever. Non-dose-limiting toxicities included nausea, diarrhea, fatigue, neuropathy, thrombocytopenia, and anemia. Of the 25 patients in whom response could be assessed, partial responses occurred in 11 (10 with non-small cell lung cancer and 1 with head and neck cancer), and stable disease occurred in 7. The pharmacokinetics of vorinostat was linear over the dose range studied. The area under the concentration-time curve and the half-life of vorinostat were increased when vorinostat was co-administered with carboplatin and paclitaxel, but vorinostat did not alter the pharmacokinetics of paclitaxel. Conclusions: Both vorinostat regimens (400 mg orally once daily × 14 days or 300 mg twice daily × 7 days) were well tolerated in combination with carboplatin (AUC = 6 mg/mL × min) and paclitaxel ( 200mg/m2).2). Encouraging antitumor activity was observed in patients with previously untreated non-small cell lung cancer.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 3605-3610 |
| Number of pages | 6 |
| Magazine | clinical cancer research |
| Volume | 13 |
| issue number | 12 |
| Of the | |
| state | Published -June 15, 2007 |
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- Oncology
- cancer research
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Ramalingam , SS , Parise , RA , Ramananthan , RK , Lagattuta , TF , Musguire , LA , Stoller , RG , Potter , DM , Argiris , AE , Zwiebel , JA , Egorin , MJ .(2007).A Phase I Pharmacokinetic Study of the Histone Deacetylase Inhibitor Vorinostat in Combination with Carboplatin and Paclitaxel for Advanced Solid Malignancies.clinical cancer research,13(12), 3605-3610.https://doi.org/10.1158/1078-0432.CCR-07-0162
Ramalingam, Suresh S.; Parise, Robert A.; Ramananthan, Ramesh K. et al. /A Phase I Pharmacokinetic Study of the Histone Deacetylase Inhibitor Vorinostat in Combination with Carboplatin and Paclitaxel for Advanced Solid Malignancies. tu:clinical cancer research. 2007; Volume 13, number 12. p. 3605-3610.
@artículo{714a2fbf1c6a41c9a5863c3454b4ff45,
title = "Phase I and pharmacokinetic study of vorinostat, a histone deacetylase inhibitor, in combination with carboplatin and paclitaxel for advanced solid malignancies",
abstract = "Purpose: The primary objective of this study was to determine the recommended Phase II doses of the novel histone deacetylase inhibitor vorinostat when administered in combination with carboplatin and paclitaxel. Experimental Design: Patients (N = 28) were treated with advanced solid malignancies with vorinostat, given orally once daily for 2 weeks or twice daily for 1 week, every 3 weeks Carboplatin and paclitaxel given intravenously once every 3 weeks Doses of vorinostat and paclitaxel was escalated into sequential cohorts of three patients.Vorinostat pharmacokinetics, its metabolites and paclitaxel were characterized Results: Vorinostat was safely administered up to 400 mg once daily or 300 mg once daily with carboplatin and paclitaxel. Limiting doses include nausea, diarrhea, fatigue, neuropathy, thrombocytopenia, and anemia.Of the 25 patients in whom response could be assessed, partial responses occurred in 11 (10 with non-small cell lung cancer and 1 with lung cancer). head and neck), and stable disease occurred in 7. The pharmacokinetics of vorinostat was linear over the dose range studied. The area under the concentration-time curve and the half-life of vorinostat were increased when vorinostat was co-administered with carboplatin and paclitaxel, but vorinostat did not alter the pharmacokinetics of paclitaxel. Conclusions: Both vorinostat regimens (400 mg orally once daily × 14 days or 300 mg twice daily × 7 days) were well tolerated in combination with carboplatin (AUC = 6 mg/mL × min) and paclitaxel ( 200mg/m2). Encouraging anticancer activity was observed in patients with previously untreated non-small cell lung cancer."
author = "Ramalingam, {Suresh S.} i Parise, {Robert A.} i Ramananthan, {Ramesh K.} i Lagattuta, {Theodore F.} i Musguire, {Lori A.} i Stoller, {Ronald G.} i Potter , Douglas M. , Argiris , Athanasios E. , Zwiebel , James A. , Egorin , Merrill J. , Belani , Chandra P .
year = "2007",
month = June,
y = "15",
dva = "10.1158/1078-0432.CCR-07-0162",
language = "English (US)",
volume = "13",
pages = "3605--3610",
journal = "Clinical Cancer Research",
issn = "1078-0432",
editor = "American Association for Cancer Research Inc.",
number = "12",
}
Ramalingam , SS , Parise , RA , Ramananthan , RK , Lagattuta , TF , Musguire , LA , Stoller , RG , Potter , DM , Argiris , AE , Zwiebel , JA , Egorin , MJ2007, 'A Phase I Pharmacokinetic Study of the Histone Deacetylase Inhibitor Vorinostat in Combination with Carboplatin and Paclitaxel for Advanced Solid Malignancies',clinical cancer research, sv. 13, br. 12, calle. 3605-3610.https://doi.org/10.1158/1078-0432.CCR-07-0162
A phase I pharmacokinetic study of vorinostat, a histone deacetylase inhibitor, in combination with carboplatin and paclitaxel for advanced solid malignancies./ Ramalingam, Suresh S.; Parise, Robert A.; Ramananthan, Ramesh K. et al.
tu:clinical cancer research, Vol.13, Number 12, 06.15.2007, p. 3605-3610.
Results of the investigation:Contribution to the magazine.›Article›Peer Review
TY-DAN
T1: Phase I Pharmacokinetic Study of Histone Deacetylase Inhibitor Vorinostat in Combination with Carboplatin and Paclitaxel for Advanced Solid Malignancies
Australia - Ramalingam, Suresh S.
AU-Paris, Robert A.
Australia - Ramananthan, Ramesh K.
AU - Lagattuta, Theodore F.
AU - Musguire, Lori A.
AU - Stoller, Ronald G.
AU - Potter, Douglas M.
AU - Argiris, Athanassios E.
AU - Zwiebel, James A.
AU - Egorin, Merrill J.
AU - Belani, Chandra P.
PY - 15.6.2007
Y1 - 15.6.2007
N2 - Purpose: The primary objective of this study was to determine the recommended Phase II doses of the novel histone deacetylase inhibitor vorinostat when administered in combination with carboplatin and paclitaxel. Experimental design: Patients (N = 28) with advanced solid malignancies were treated with vorinostat, administered orally once daily for 2 weeks or twice daily for 1 week, every 3 weeks. Carboplatin and paclitaxel were administered i.v. once every 3 weeks. Vorinostat and paclitaxel doses were escalated in sequential cohorts of three patients. The pharmacokinetics of vorinostat, its metabolites, and paclitaxel are described. Results: Vorinostat was safely administered up to 400 mg once daily or 300 mg twice daily with carboplatin and paclitaxel. Two of 12 patients on the 400 mg once daily schedule experienced the dose-limiting toxicities of Grade 3 vomiting and Grade 4 neutropenia with fever. Non-dose-limiting toxicities included nausea, diarrhea, fatigue, neuropathy, thrombocytopenia, and anemia. Of the 25 patients in whom response could be assessed, partial responses occurred in 11 (10 with non-small cell lung cancer and 1 with head and neck cancer), and stable disease occurred in 7. The pharmacokinetics of vorinostat was linear over the dose range studied. The area under the concentration-time curve and the half-life of vorinostat were increased when vorinostat was co-administered with carboplatin and paclitaxel, but vorinostat did not alter the pharmacokinetics of paclitaxel. Conclusions: Both vorinostat regimens (400 mg orally once daily × 14 days or 300 mg twice daily × 7 days) were well tolerated in combination with carboplatin (AUC = 6 mg/mL × min) and paclitaxel ( 200mg/m2). Encouraging antitumor activity was observed in patients with previously untreated non-small cell lung cancer.
AB - Purpose: The primary objective of this study was to determine the recommended phase II doses of the new histone deacetylase inhibitor vorinostat when administered in combination with carboplatin and paclitaxel. Experimental design: Patients (N = 28) with advanced solid malignancies were treated with vorinostat, administered orally once daily for 2 weeks or twice daily for 1 week, every 3 weeks. Carboplatin and paclitaxel were administered i.v. once every 3 weeks. Vorinostat and paclitaxel doses were escalated in sequential cohorts of three patients. The pharmacokinetics of vorinostat, its metabolites, and paclitaxel are described. Results: Vorinostat was safely administered up to 400 mg once daily or 300 mg once daily with carboplatin and paclitaxel. Two of 12 patients on the 400 mg once daily schedule experienced Grade 3 dose-limiting toxicity vomiting and Grade 4 neutropenia with fever. Non-dose-limiting toxicities included nausea, diarrhea, fatigue, neuropathy, thrombocytopenia, and anemia. Of the 25 patients in whom response could be assessed, partial responses occurred in 11 (10 with non-small cell lung cancer and 1 with head and neck cancer), and stable disease occurred in 7. The pharmacokinetics of vorinostat was linear over the dose range studied. The area under the concentration-time curve and the half-life of vorinostat were increased when vorinostat was co-administered with carboplatin and paclitaxel, but vorinostat did not alter the pharmacokinetics of paclitaxel. Conclusions: Both vorinostat regimens (400 mg orally once daily × 14 days or 300 mg twice daily × 7 days) were well tolerated in combination with carboplatin (AUC = 6 mg/mL × min) and paclitaxel ( 200mg/m2). Encouraging antitumor activity was observed in patients with previously untreated non-small cell lung cancer.
URL: http://www.scopus.com/inward/record.url?scp=34250696097&partnerID=8YFLogxK
URL: http://www.scopus.com/inward/citedby.url?scp=34250696097&partnerID=8YFLogxK
U2 - 10.1158/1078-0432.CCR-07-0162
DO - 10.1158/1078-0432.CCR-07-0162
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Serial number - 1078-0432
VL-13
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JO - Clinical Cancer Research
JF - Clinical Cancer Research
JE - 12
ES -
Ramalingam SS, Parise RA, Ramananthan RK, Lagattuta TF, Musguire LA, Stoller RG et al.A Phase I Pharmacokinetic Study of the Histone Deacetylase Inhibitor Vorinostat in Combination with Carboplatin and Paclitaxel for Advanced Solid Malignancies.clinical cancer research. June 15, 2007; 13(12): 3605-3610. two: 10.1158/1078-0432.CCR-07-0162
FAQs
What happens when you inhibit histone deacetylase? ›
HDAC inhibition leads to the loss of HSP90 chaperone function and enhanced degradation of client proteins, such as Bcr-Abl, ErbB2/neu, and FLT3.
What class Hdac inhibitor is Vorinostat? ›Vorinostat also known as suberoylanilide hydroxamic acid (SAHA) is an orally bioavailable inhibitor of class I and II HDACs. It is a small-molecular-weight linear hydroxamic acid compound, with an empirical formula of C14H20N2O3 and a molecular weight of 264.32 g/mol.
How do HDAC inhibitors work in cancer? ›HDAC inhibitors induce cancer cell cycle arrest, differentiation and cell death, reduce angiogenesis and modulate immune response. Mechanisms of anticancer effects of HDAC inhibitors are not uniform; they may be different and depend on the cancer type, HDAC inhibitors, doses, etc.
Is Vorinostat a histone deacetylase inhibitor? ›Vorinostat, a histone deacetylase (HDAC) inhibitor, promotes cell cycle arrest and re-sensitizes rituximab- and chemo-resistant lymphoma cells to chemotherapy agents.
What does histone deacetylation usually result in? ›By deacetylating the histone tails, the DNA becomes more tightly wrapped around the histone cores, making it harder for transcription factors to bind to the DNA. This leads to decreased levels of gene expression and is known as gene silencing.
What would you expect to happen in a cell treated with an HDAC inhibitor drug? ›HDAC inhibitors promote growth arrest, differentiation, and apoptosis of tumor cells, with minimal effects on normal tissue. In addition to decompaction of the histone/DNA complex, HDAC inhibition also affects acetylation status and function of nonhistone proteins.
What is the target of vorinostat? ›Vorinostat is a hydroxymate HDAC inhibitor that targets class I, II, and IV HDACs. Vorinostat was approved as a therapeutic agent for patients who had undergone at least two systemic therapies for recurrent, progressive, or persistent cutaneous T-cell lymphoma (CTCL).
What is the metabolism of vorinostat? ›Metabolism/Elimination
Vorinostat is eliminated primarily through metabolism via glucuronidation and hydrolysis (major pathways), followed by β-oxidation. CYP enzymes have a negligible role in vorinostat metabolism.
Mechanism of action
Vorinostat's inhibition of histone deacetylases results in the accumulation of acetylated histones and acetylated proteins, including transcription factors crucial for the expression of genes needed to induce cell differentiation. It acts on class I, II and IV of histone deacetylase.
Histone deacetylase inhibitors (HDACi) might be able to reverse the activation of tumor suppressor genes (TSG), and in this way inhibit the viability and malignant proliferation of tumor cells (Glozak and Seto, 2007). The efficacy of HDACi treatment has been demonstrated in numerous clinical studies.
What are the side effects of HDAC chemotherapy? ›
In general, the side effects of HDAC inhibitors are reversible with drug cessation and primarily include fatigue, nausea, dehydration, diarrhea, prolonged QT, thrombocytopenia, lymphopenia, and neutropenia.
Is HDAC a therapeutic target? ›Histone deacetylases (HDACs) are key regulators of gene expression that act as transcriptional repressors by removing acetyl groups from histones. HDACs are dysregulated in many cancers, making them a therapeutic target for the treatment of cancer.
What is the mechanism of action of HDAC inhibitors? ›Reversible modification of the terminal tails of core histones constitutes the major epigenetic mechanism for remodeling higher-order chromatin structure and controlling gene expression. HDAC inhibitors (HDI) block this action and can result in hyperacetylation of histones, thereby affecting gene expression.
What are the benefits of vorinostat? ›Vorinostat is used to treat a certain type of cancer (CTCL-cutaneous T-cell lymphoma). It works by slowing or stopping the growth of cancer cells.
How do HDAC inhibitors affect gene expression? ›HDACi can interact with the catalytic domain of histone deacetylase. Thus, HDACi change the balance between the deacetylating activity of HDACs and the acetylating activity of HATs, which lead to increased histone acetylation and up-regulated gene expression.
How would a HDAC1 work? ›HDAC1 is known to promote proliferation of breast cancers by repressing ER transcription. Loss of HDAC1/2 causes arrest in G1 or in G2/M and reduces proliferation in breast cancer.
What is the purpose of deacetylation? ›The acetylation and deacetylation of lysine residues in both histones and nonhistone proteins play a role in controlling the expression of genes. Acetylation typically results in the activation of genes, while deacetylation results in the silencing of genes.
How does histone acetylation leads to gene expression? ›Histone acetylation is a critical epigenetic modification that changes chromatin architecture and regulates gene expression by opening or closing the chromatin structure. It plays an essential role in cell cycle progression and differentiation.
What disorders have HDAC? ›HDAC proteins are vital regulators of fundamental cellular events, such as cell cycle progression, differentiation, and tumorigenesis. Abnormal HDACs can contribute to many different human diseases including cancer, neurodegenerative disorders, cardiac hypertrophy, and pulmonary diseases.
What effect would inhibitors of histone deacetylases have upon transcription? ›Inhibition of HDAC activity results in transcriptional reprogramming, which is believed to contribute largely to the therapeutic benefits of HDAC inhibitors on cancers, cardiovascular diseases, neurodegenerative disorders and pulmonary diseases [24].
How would treatment with histone deacetylase inhibitors change chromatin conformation? ›
By deacetylating the core histones, HDACs neutralize the positive charges on histones tails and consequently compact the chromatin structure into a conformation that is repressive to most cellular processes (4).
What is the success rate of vorinostat? ›Vorinostat is under clinical development by Merck and currently in Phase II for Follicular Lymphoma. According to GlobalData, Phase II drugs for Follicular Lymphoma have a 46% phase transition success rate (PTSR) indication benchmark for progressing into Phase III.
Does vorinostat cross the blood brain barrier? ›The number of rotatable bonds showed an unfavorable profile for regorafenib and vorinostat which where both found to cross the BBB.
Does vorinostat increase transcription? ›Together with our kinetics data, these data suggest that vorinostat increases the efficiency of viral postentry events, including reverse transcription, nuclear import, and integration. Efficiency of postentry viral events, including reverse transcription and nuclear import, is improved by vorinostat.
What is the role of histone deacetylase in cell cycle? ›Histone deacetylases (HDACs) catalyze the deacetylation of lysine residues on histones and non-histone proteins. HDACs have been shown to control the functions of key cell cycle proteins.
What is the IC50 of vorinostat HDAC? ›Vorinostat (SAHA,MK0683, Suberoylanilide hydroxamic acid, Zolinza) is an HDAC inhibitor with IC50 of ~10 nM in a cell-free assay. Vorinostat abrogates productive HPV-18 DNA amplification. Vorinostat inhibits the activities of HDAC1 and HDAC3 with IC50 of 10 nM and 20 nM, respectively.
What is the half life of vorinostat? ›The mean terminal half-life (t½) was ~2.0 hours for both vorinostat and the O-glucuronide metabolite, while that of the 4-anilino-4-oxobutanoic acid metabolite was 11 hours.
What type of drug is vorinostat? ›Vorinostat is in a class of medications called histone deacetylase (HDAC) inhibitors. It works by killing or stopping the growth of cancer cells.
How would a histone deacetylase inhibitor activate transcription? ›HDAC inhibition blocks elongation of RNAP2. HDACIs repress transcription by blocking elongation, as we have shown previously in human breast cancer (BT474) and non-cancerous breast epithelial (MCF10A) cell lines using GRO-seq (Kim et al., 2013).
What is another name for vorinostat? ›Vorinostat is a drug that has been approved by the U.S. Food and Drug Administration (FDA) under the brand name Zolinza for the treatment of cancer.
How does histone deacetylation cause cancer? ›
Altered expression and mutations of genes that encode HDACs have been linked to tumor development since they both induce the aberrant transcription of key genes regulating important cellular functions such as cell proliferation, cell‐cycle regulation and apoptosis.
Can heart damage from chemo be reversed? ›Can cardiotoxicity be reversed? Cardiotoxicity may be reversible. Research has shown that cardiotoxicity that arises after using trastuzumab may be reversible. Cardiotoxicity that arises from anthracycline use is often not reversible and requires long-term treatment.
What are the side effects of hidac chemotherapy? ›- You may get a fever, skin rash, aches and pains or increased sweating.
- These symptoms are caused by the drug cytarabine.
- Symptoms usually happen 6 to 12 hours after your dose, and may last until 24 hours after your treatment has finished.
- To reduce any pain or fever, take paracetamol, if needed.
| Phytochemical Class | Compound | Dietary Source |
|---|---|---|
| Flavonol | Myricitrin/Myricetin | Bayberry tree components, wine, berries, vegetables |
| Flavone | Apigenin | Citrus, onions, celery, chamomile tea |
| Luteolin | Celery, parsley, broccoli, onions, carrots, peppers, cabbages, apples | |
| Baicalein/Baicalin | Scutellaria baicalensis |
A neurodegenerative disease that has received great attention for therapeutic HDAC inhibition is the polyglutamine disorder Huntington's disease. This movement disorder is characterized by degeneration of neurons of the basal ganglia as a result of an expanded polyglutamine stretch on the huntingtin protein.
What drugs are HDAC inhibitors? ›To date, four HDAC inhibitors, Vorinostat, Romidepsin, Panobinostat, and Belinostat, have been approved by the United States Food and Drug Administration. Principally, these HDAC inhibitors are used for hematologic cancers in clinic with less severe side effects.
What effect would a HDAC inhibitor have on the target cells? ›Effect of HDAC inhibitors and their antitumor pathways: Dysregulated expression of HDAC aids in cell proliferation, angiogenesis and escape from autophagy, apoptosis of cancer cells. After treatment with HDAC inhibitor multiple anti-tumor pathways get activated and results in the destruction of cancer cells.
What effect does HDAC have on DNA? ›The histone hyperacetylation induced by HDACi causes structural alterations in chromatin, which may expose portions of DNA that are normally protected by heterochromatin to DNA-damaging agents such as: UV, x-ray, cytotoxic drugs, or reactive oxygen species (ROS).
What enzyme is inhibited by vorinostat? ›Vorinostat is a histone deacetylase inhibitor. It is an FDA approved drug for the treatment of cutaneous T cell lymphoma.
What are the disadvantages of HDAC inhibitors? ›Toxicity in clinical trials
Inhibitors of HDAC also have some adverse effects like any class of anticancer agents. The inhibitors (grades III and IV) cause certain side effects like thrombocytopenia, neutropenia, anemia, fatigue, and diarrhea.
How do tumor cells respond to Hdac inhibition? ›
The predominant responses include induction of tumor cell death and inhibition of proliferation that in experimental models have been linked to therapeutic efficacy.
What does histone deacetylase do? ›Histone deacetylases (HDACs) are enzymes that catalyze the removal of acetyl functional groups from the lysine residues of both histone and nonhistone proteins.
How will blocking histone deacetylases affect gene expression? ›HDAC inhibitors (HDI) block this action and can result in hyperacetylation of histones, thereby affecting gene expression. The open chromatin resulting from inhibition of histone deacetylases can result in either the up-regulation or the repression of genes.
What are the effects of histone acetylation deacetylation? ›Histone acetylation results in charge neutralization and separation of DNA from the histones allowing nucleosomal DNA to become more accessible to transcription factors.
What occurs in histone acetylation and how does it affect gene expression? ›Histone acetylation occurs at lysine residues and it increases gene expression in general. (B) Histone methylation: Methylation is catalyzed by histone methyltransferase. Histone demethylase reverses methylation. Methylation activates or represses gene expression depending on which residue is methylated.
How does histone acetylation and deacetylation control gene regulation? ›Abstract. Histone acetylation is a critical epigenetic modification that changes chromatin architecture and regulates gene expression by opening or closing the chromatin structure. It plays an essential role in cell cycle progression and differentiation.
What is the function of Vorinostat? ›Vorinostat is in a class of medications called histone deacetylase (HDAC) inhibitors. It works by killing or stopping the growth of cancer cells.
What does histone deacetylase do to transcription? ›Histone deacetylation represses transcription by different mechanisms. On the one hand, this process increases the charge density on the N-termini of the core histones thereby strengthening histone tail-DNA interactions and blocking access of the transcriptional machinery to the DNA template.
What is the importance of histone acetylation and deacetylation? ›Histone acetylation also regulates the formation of heterochromatin; deacetylation of H4 lysine 16 is important for spreading of heterochromatin components, whereas acetylation of this site serves as a barrier to this spreading.
Does deacetylation decrease gene expression? ›In contrast, the formation of a tight chromatin structure due to the deacetylation of histone lysine residues on the surface by histone deacetylases enforces the interaction between the histones and DNA, which minimizes the chance of RNA polymerases contacting DNA, resulting in decreased gene expression.
What is the significance of deacetylation? ›
The acetylation and deacetylation of lysine residues in both histones and nonhistone proteins play a role in controlling the expression of genes. Acetylation typically results in the activation of genes, while deacetylation results in the silencing of genes.
Does histone deacetylation activate gene expression? ›Histone acetylation is a major modification that affects gene transcription and is controlled by histone acetyltransferases (HATs) and histone deacetylases (HDAC). HATs acetylate lysines of histone proteins, resulting in relaxation of chromatin structure, and they also facilitate gene activation.
Does histone deacetylation increase transcription? ›Acetylation removes positive charges thereby reducing the affinity between histones and DNA. Thus, in most cases, histone acetylation enhances transcription while histone deacetylation represses transcription, but the reverse is seen as well (Reamon-Buettner and Borlak, 2007).