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Nucleic Acids as Therapeutic Targets and Agents
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Lomustine alkylates both DNA and RNA, and can produce cross-links. As with the other nitrosoureas, it can also inhibit several key enzymic processes by carbamoylation of amino acids in proteins. It is cell-cycle nonspecific and produces delayed bone marrow toxicity with a long time period post administration for the white blood cells to reach their lowest number (i.e., the “nadir”), and permanent bone marrow damage resulting from prolonged exposure. Thus, it is administered at four- to six-week intervals to avoid severe bone marrow toxicity. In addition, lomustine frequently causes moderately severe nausea, vomiting, and fatigue. It should be avoided in acute porphyria, is contraindicated in coeliac disease and renal impairment, and should not be given during conception (for men or women), pregnancy, or breast feeding.
PCV (procarbazine, lomustine [CCNU®], vincristine)
Published in Maxwell Summerhayes, Susanna Daniels, Practical Chemotherapy, 2018
Maxwell Summerhayes, Susanna Daniels
High emetogenic potential (see local protocol). This may be overstating the emetogenic potential of lomustine, but in view of the importance of preventing vomiting after the single oral dose of the latter, a cautious approach is suggested. Note that many patients with brain tumours will already be taking significant doses of oral steroids to reduce cerebral oedema. In such cases, additional steroids are not required for anti-emesis.
Can we rely on synthetic pharmacotherapy for the treatment of glioblastoma?
Published in Expert Opinion on Pharmacotherapy, 2021
Chibueze D. Nwagwu, David C. Adamson
Re-irradiation and stereotactic radiotherapy have also been considered as options, although irradiation could be toxic in previously irradiated patients [23]. Several other options have been considered for recurrent glioblastoma, including TMZ re-challenge, anti-angiogenic therapies, epidermal growth factor inhibitors, nitrosoureas, and continued temozolomide [11]. Although not considered standard of care for recurrent glioblastoma, lomustine is FDA approved and has particularly been used as control for phase III trials evaluating several agents in the treatment of recurrent glioblastoma patients. This stems from promising results from various trials utilizing lomustine as a combinatory option [24,25]. Most notably, Wick et al., in a randomized trial of 437 recurrent glioblastoma patients showed lomustine in combination with bevacizumab to have an overall survival of 9.1 months, although this was not significant compared to lomustine monotherapy, which showed an overall survival of 8.6 months [24]. Despite this, the poor outcomes persist.
Have treatment protocols for primary CNS lymphoma advanced in the past 10 years?
Published in Expert Review of Anticancer Therapy, 2019
With the exception of the above-mentioned CALGB 50202 trial [40], treatment results in elderly patients are invariably worse than for younger patients irrespective of treatment and for most elderly patients the disease is not curable. HDMTX in doses from 3 up to 8 g/m2 can be applied to a high fraction of elderly patients with manageable renal and hematological toxicity [41] and HDMTX as part of first-line treatment is associated with improved survival for elderly patients [42]. The only randomized trial comparing two HDMTX-based polychemotherapy protocols was performed on older patients (60 years and older): HDMTX (3.5 g/m2) plus temozolomide was compared to HDMTX in combination with procarbazine, vincristine, and cytarabine with median OS of 14 months and 31 months, respectively [43]. A combination of rituximab, HDMTX, procarbazine, and lomustine (R-MPL) for patients 65 years and older led to a median OS of 20.7 months in the PRIMAIN study [44]. Lomustine had to be omitted during the study due to infectious complications and 38/107 patients were treated with R-MP only. In the G-PCNSL-SG1-trial, the median OS for patients <70 years was 26.2 months vs. 12.5 months for patients aged 70 or older [25,45]. For selected ‘biologically young’ patients, MTX-based chemotherapy with HD-ASCT as consolidation is considered an option [46].
Potential effects of nicotine on glioblastoma and chemoradiotherapy: a review
Published in Expert Review of Neurotherapeutics, 2019
Diane D. McConnell, Steven B. Carr, N. Scott Litofsky
Very few studies address the combination of these three drugs as a single treatment in vitro or in vivo. Procarbazine may inhibit transmethylation of the methyl groups of methionine into t-RNA, causing cessation of protein synthesis, and consequently DNA and RNA synthesis. DNA may also be damaged directly by hydrogen peroxide, formed during auto-oxidation of procarbazine, which may attack sulfhydryl groups in residual protein tightly bound to DNA. These effects are specific for the S and G2 phases of the cell cycle [97]. Procarbazine drug resistance often involves methylating pathways. Potential resistance mechanisms involve O6-alkylguanine DNA alkyltransferase (AGT)-mediated repair of O6-methylguanine activity, as well as hMSH2 mismatch-repair deficiency (MRD) [97]. Lomustine [1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea] (CCNU) is an alkylating nitrosourea compound very similar to BCNU. Lomustine inhibits DNA synthesis by induction of alkylation and double cross-linking of DNA at the O6-position of guanine. Much like TMZ and procarbazine, the expression of MGMT leads to resistance of Lomustine [98]. Nicotine’s role in the induction of the DNA repair protein AGT (MGMT) is controversial, and nicotine may be a possible promoter for MGMT expression in tumor cells [99].