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Naturally Occurring Histone Deacetylase (HDAC) Inhibitors in the Treatment of Cancers
Published in Namrita Lall, Medicinal Plants for Cosmetics, Health and Diseases, 2022
Sujatha Puttalingaiah, Murthy V. Greeshma, Mahadevaswamy G. Kuruburu, Venugopal R. Bovilla, SubbaRao V. Madhunapantula
Even though several naturally occurring and synthetic HDAC inhibitors have been developed, only very few agents have reached the clinical trials stage. Even among those which have reached clinical trials stage, many have failed to hit the market due to various toxicities and poor efficacy in inhibiting the disease symptoms at the dose tested. For example, SAHA (Vorinostat) is an FDA-approved drug for treating T-cell lymphoma. However, when administered at a dose of 300 mg/day, the patients have reported diarrhea, thrombocytopenia, nausea and pyrexia. Adverse events such as cardio-toxicity were reported when tested at a dose of 400 mg/day (Duvic and Vu, 2007). Similarly, systemic toxic effects have been reported for other FDA-approved HDAC inhibitors, which include Belinostat, Panobinostat, etc. (Allen and Lechowicz, 2018). Therefore, care must be executed when recommending HDAC inhibitors for treatment. Recent studies have focused on reducing the toxicity of HDAC inhibitors by: (a) combining with other pharmacological agents or other treatment methods such as radiation therapy, surgery etc.; (b) developing targeted nanodrug formulations; and (c) antibody conjugates. However, further studies are currently required to determine the safety and efficacy of these methods or formulations.
Clinical Trials
Published in Abhaya Indrayan, Research Methods for Medical Graduates, 2019
Sometimes a regimen is approved on the basis of a single-arm trial. Remember that such a trial does not establish superiority or equivalence. Belinostat was approved for relapsed peripheral T-cell lymphoma on the basis of such an uncontrolled trial [22]. Even in RCTs, the effect size may be statistically significant due to a large sample but actually too small to have clinical significance. Some trials look at surrogates such as progression-free survival where quality of life is possibly more relevant. Just beware of such fallacies and take steps to avoid them.
UGT1A1 Polymorphisms and Mutations Affect Anticancer Drug Therapy
Published in Sherry X. Yang, Janet E. Dancey, Handbook of Therapeutic Biomarkers in Cancer, 2021
Tristan M. Sissung, Roberto Barbier, Lisa M. Cordes, William D. Figg
Belinostat is a histone deacetylase inhibitor (HDI) approved for the treatment of relapsed or refractory peripheral T-cell lymphoma (PTCL) (1000 mg/m2 i.v. daily on days 1–5 of a 21-day cycle). Dose reductions of 25% (750 mg/m2) are recommended for hematologic and nonhematologic toxicities, including neutropenia and thrombocytopenia (nadir absolute neutrophil count<0.5 × 109/L or platelet count < 25 × 109/L). Since UGT1A1 catalyzes the primary metabolic pathway involved in belinostat elimination [91, 92], variability in UGT1A1 metabolic phenotypes are important considerations in belinostat therapy. Particularly, polymorphisms that limit belinostat metabolism through UGT1A1 result in significant pharmacokinetic variability [93–95]. The starting dose of belinostat in patients homozygous for the UGT1A1*28 allele should be reduced to 750 mg/m2. Co-therapy with strong UGT1A1 inducers and inhibitors is also of significant clinical concern. (https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/206256lbl.pdf) Albeit, formal drug-drug interaction (DDI) studies have not been conducted on belinostat at this time, but the irinotecan literature (summarized above) may be useful in selecting therapies that do not interact with belinostat. Irinotecan and belinostat coadministered to human liver microsomes resulted in inhibition of the metabolism of both drugs, and this combination has a very high potential for clinically significant DDIs due to pharmacokinetic variability [93] and overlap in the mechanism of action for these agents [96]. While the influence of pharmacogene variation on belinostat requires additional study, polymorphic variation in UGT1A1 (particularly that of UGT1A1*28/*28 and UGT1A1*6/*6, UGT1A1*60/*60), bilirubin processing disorder, and co-therapies with UGT1A1 substrates should be considered.
Organoboronic acids/esters as effective drug and prodrug candidates in cancer treatments: challenge and hope
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2023
Mothana K. Al-Omari, Mai Elaarag, Raed M. Al-Zoubi, Ahmad R. Al-Qudimat, Ayman A. Zarour, Enas A. Al-Hurani, Zainab E. Fares, Leena M. Alkharraz, Mohanad Shkoor, Abdulilah D. Bani-Yaseen, Omar M. Aboumarzouk, Aksam Yassin, Abdulla A. Al-Ansari
Boronate belinostat 24 and boronate 5-fluorouracil 25 derivatives have been both shown to inhibit growth in mice breast cancer cell lines86,109. Boronate belinostat 24 prodrug in vivo was found to be more potent than belinostat alone, it inhibits and reduces the tumour volume in the MCF-7 xenograft tumour model. This prodrug targets MDA-MB-231 and MCF-7 breast cancer cell lines as well as A549 lung cancer cell line, and HeLa for cervical cancer cell line109. Some potential side effects of belinostat may include fatigue, nausea, vomiting, diarrhoea, loss of appetite, and hematological toxicities such as anaemia, thrombocytopenia, or neutropenia. In rare cases, severe hypersensitivity reactions or pulmonary toxicity may occur109.
Epigenetic modulations in cancer: predictive biomarkers and potential targets for overcoming the resistance to topoisomerase I inhibitors
Published in Annals of Medicine, 2023
Moustafa M. Madkour, Wafaa S. Ramadan, Ekram Saleh, Raafat El-Awady
One of the main concerns of using Top I inhibitors in anticancer combination therapy is the risk of drug-drug interactions, which may lead to reduced efficiency or severe toxicity to normal cells. Drug metabolism through glucuronidation was reported as an important source of drug-drug interaction when Top I inhibitors were combined with HDAC inhibitors. Glucuronidation via UDP-glucuronosyltransferase enzymes (UGTs) has been shown to deactivate Top I inhibitors (such as SN-38) and HDAC inhibitors such as belinostat, vorinostat and panobinostat. Thus, they all compete for the deactivation by UGTs. It was reported that belinostat only, but not vorinostat or panobinostat, inhibited SN-38 glucuronidation via inhibiting the activity of UGT1A1. As the concentration of belinostat increased, the rate of SN-38 glucuronide (SN-38G) formation decreased dose-dependently, indicating a non-competitive increase in the inhibition of SN-38 glucuronidation. This emphasizes the potential clinical significance of drug-drug interaction between irinotecan and belinostat, since many individuals could be at risk of experiencing severe toxicity if the two drugs are administrated together [87].
Safety considerations with the current treatments for peripheral T-cell lymphoma
Published in Expert Opinion on Drug Safety, 2022
Tarsheen Sethi, Francesca Montanari, Francine Foss
Belinostat is a hydroxamic acid derivative and acts a a pan – HDAC inhibitor which inhibits Class I, II and IV histones [26]. Belinostat received accelerated FDA approval for the treatment of R/R PTCL based on an open-label, single-arm clinical trial which enrolled 129 patients with R/R PTCL [27]. Patients received belinostat at a dose of 1000 mg/m2 IV on Days 1–5 of a 21-day cycle. The ORR was 25.8%, median DOR of 8.4 months, and the median time to response of 5.6 weeks. The ORR for the two most common subtypes of PTCL (PTCL-NOS and AITL) were 23.4% and 45.5%, respectively. Overall, 87% of patients remained at full dose, and the median treatment duration was 7.0 weeks (range, 3.0 to 135.0 weeks). Only about 10% patients received treatment for a year or longer. The common reported toxicities were constitutional symptoms, including nausea (41.9%), fatigue (37.2%), and pyrexia (34.9). Thrombocytopenia was seen in 16.3% of patients (grade 4 in 7.0%). Two patients had a dose reduction because of prolonged QTc or increased transaminases. Two patients were found to have grade 3 QTc prolongation per central review but overall, it was concluded that belinostat had no significant effect on cardiac repolarization. Additional pharmacokinetic and pharmacodynamic analyses showed no correlation between belinostat concentration and QTc changes from baseline and no other clinically relevant EKG changes were noted.