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Synergistic Combinations of Hyperthermia and Inhibitors of Nucleic Acids and Protein Synthesis
Published in Leopold J. Anghileri, Jacques Robert, Hyperthermia In Cancer Treatment, 2019
The exact mechanisms whereby 6-MP becomes incorporated into cellular DNA are still unclear. Although 6-MP was found to inhibit the coordinated induction of various enzymes required for DNA synthesis and may cause other potentially lethal effects in model systems, the cytotoxicity cannot be solely ascribed to the incorporation of thiopurines into DNA. It seems more likely that the purine analogues exert their activity by multiple mechanisms including effects on purine nucleotide synthesis and metabolism and alterations in the synthesis and function of RNA and DNA.
Therapies
Published in Marc H. De Baets, Hans J.G.H. Oosterhuis, Myasthenia Gravis, 2019
Azathioprine acts as a purine analogue.27-29 The active metabolite is 6-mercaptopurine, which is phosphorylated intracellularly to thioinosine monophosphate (T-IMP) by the enzyme hypoxanthine-guanine phosphori-bosyltransferase (HGPRT). T-IMP inhibits several steps in the conversion of inosine monophosphate to adenine and guanine nucleotides. Accumulating T-IMP can cause feedback inhibition of the first step in purine biosynthesis. Additional effects probably contribute to the overall immunosuppressive action of azathioprine.
Pharmacology of Therapeutic Agents in Photomedicine
Published in Henry W. Lim, Nicholas A. Soter, Clinical Photomedicine, 2018
Ira C. Davis, Matthew J. Stiller, Jerome L. Shupack
Azathioprine (Fig. 4), a purine analogue, is well absorbed after oral intake, and is metabolized to 6-mercaptopurine, which is not cytotoxic, and to 6-thioinosinic acid and 6-thioguanylic acid which are cytotoxic (45). Conversion primarily by erythrocytes and the liver to inactive metabolites occurs within 10 hr. These metabolites are excreted in the urine. Azathioprine is metabolized by xanthine oxidase. Therefore concomitant allopurinol administration will increase azathioprine levels. Azathioprine inhibits DNA and RNA synthesis and mitoses by incorporating into nucleic acids. Both B- and T-lymphocyte immune responses are affected (43).
Selecting appropriate therapy for hairy cell leukemia: current state and future prospects based on molecularly defined characterization
Published in Expert Opinion on Pharmacotherapy, 2022
Constantin A. Dasanu, Juliana Alvarez-Argote, Catherine B Goff
Rituximab is a chimeric murine/human monoclonal antibody that kills CD20+ HCL cells via apoptosis and antibody-dependent cytotoxicity. This agent can be used either concurrently or 4 weeks after administration of a purine analog, with similar clinical results. A total of eight weekly rituximab cycles are utilized in this setting. Five-year disease-free survival and overall survival (OS) in HCL were 94.8% and 96.8%, respectively [1]. Preliminary data suggest that adding rituximab to cladribine improves the durability of responses in HCL due to probable MRD eradication [18–20] and represents the preferred first-line approach at our center. We prefer sequential use of rituximab as our experience shows that cytopenias tend to be more prolonged and severe with concurrent use. Rituximab in combination with the nucleoside analog bendamustine was also shown to be effective in both first- and second-line therapy, with absent MRD in a small HCL patent series and case reports [1]. The humanized type II anti-CD20 monoclonal antibody obinutuzumab has also shown efficacy in combination with nucleoside analogs [21]. Obtaining hepatitis B serology before starting an anti-CD20 antibody (and offering hepatitis B prophylaxis to the patients at risk for reactivation) is paramount. We recommend the 23-valent polysaccharide pneumococcal pneumonia vaccination 2 weeks prior to the first-line therapy and every 5 years thereafter. Ideally, COVID-19 vaccination series would also be completed prior to cladribine-rituximab, in an attempt to prevent a severe COVID-19 infection.
Safety of nelarabine in adults with relapsed or refractory T-cell acute lymphoblastic leukemia/lymphoma
Published in Expert Opinion on Drug Safety, 2021
Anna Candoni, Davide Lazzarotto, Giuseppe Petruzzellis
Central neurotoxicity can include amnesia, aphasia, dysarthria, hemiparesis, sensory loss, somnolence, confusion, loss of consciousness, convulsions, malaise, and fatigue, with onset of symptoms occurring frequently between six and 10 days following administration of the drug [6,7,21]. Severe neurological toxicity, even rare, can manifest as coma, status epilepticus, leukoencephalopathy or demyelination and ascending peripheral neuropathies similar to Guillain-Barré syndrome [7,22,23]. Previously or concurrently treatment with intrathecal chemotherapy or craniospinal or total body irradiation (as a part of conditioning regimen) could increase the risk and severity of neurological adverse events and, in these circumstances, some cases of severe and irreversible myelopathy (transverse acute myelitis, bilateral ascending peripheral neuropathy) have been reported [7,24]. The mechanism of this toxicity remains unclear, but a correlation between severe neurotoxicity and high levels of purine analog in the central nervous system has been described [25]. In fact, in non-human primate pharmacokinetic studies, Nelarabine and its metabolite (ara-G) have been shown to have excellent penetration into the cerebrospinal fluid and this could partially explain the additive neurotoxicity effect when this drug has been administered with concurrent intrathecal chemotherapy or brain radiotherapy [24–26].
Treatment of hairy cell leukemia
Published in Expert Review of Hematology, 2020
Dai Chihara, Robert J. Kreitman
Ibrutinib is a Bruton’s tyrosine kinase (BTK) inhibitor that has become standard treatment for several B-cell malignancies such as chronic lymphocytic leukemia, mantle cell lymphoma, and lymphoplasmacytic lymphoma [69,70]. In vitro, HCL including HCLv uniformly expressed BTK protein and ibrutinib significantly inhibited HCL proliferation [71]. A multicenter phase II study was conducted and preliminary results with 28 patients unfit for purine analog or relapsed after purine analog were presented at the 2016 ASH Annual Meeting [72]. The median age of patients was 65 years (range: 43–78) and the patients received a median of four lines of therapies (range: 1–11). The ORR was 46% and the CR rate was 14%. Interestingly, eight patients (29%) had stable disease not meeting criteria for PR but achieved clinical benefit, including resolution of symptoms and improvement in normal blood counts. Twenty patients (71%) remained on treatment at the median follow up of 22 months. This phase II study is still ongoing (NCT01841723), and full results of the study are awaited. One patient with HCLv and CLL was reported to have some clinical benefit to combination ibrutinib and venetoclax [73].