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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
The most significant property of the nitrosoureas is their effect on cancer cells in the brain and cerebrospinal fluid, the so-called “sanctuary sites”. This is due to the relatively high lipophilicity of these agents compared to other cytotoxic agents (e.g., the nitrogen mustards). However, they are also active in lymphomas and carcinomas of the breast, bronchus, colon, and GI tract, the latter being notably intractable to drug treatment. Unfortunately, the nitrosoureas cause severe bone marrow toxicity, which is usually dose-limiting. Apart from these side effects, new cases of acute leukemia and bone marrow dysplasias have been observed in patients after long-term nitrosourea therapy. Collectively, these problems have led to a significant reduction in use of the nitrosourea agents as other less-toxic anticancer agents have become available. Lomustine and carmustine are the best-known examples of synthetic nitrosoureas, while streptozotocin is an example of a naturally occurring compound containing a nitrosourea moiety.
Central Nervous System
Published in Pat Price, Karol Sikora, Treatment of Cancer, 2020
Procarbazine is a prodrug activated in the liver to an alkylating agent. It has a low single-agent response rate in glioma therapy and is usually used in combination with nitrosourea. It causes nausea, vomiting, and myelosuppression and interacts adversely with alcohol and some smoked and preserved foods.
Drug Delivery
Published in David A. Walker, Giorgio Perilongo, Roger E. Taylor, Ian F. Pollack, Brain and Spinal Tumors of Childhood, 2020
Gudrun Fleischhack, Martin Garnett, Kévin Beccaria
Alkylating agents are highly effective in the treatment of a broad spectrum of malignancies in childhood, including CNS tumors. These agents exert their cytotoxic effect by covalent binding to DNA or proteins on nucleophilic macromolecules. By the formation of these reactive intermediates they disturb the DNA replication and transcription in form of single- or double-strand breaks and cross-linking the nucleic acids or nucleic acids with proteins. Hydrophilic alkylating agents (e.g., oxazaphosphorines) require active transport into the cells and are cell cycle-dependent whereas lipophilic alkylating agents (e.g., nitrosoureas) diffuse into the cells and are independent of cell proliferation. Besides these differences their antineoplastic activity and toxicity profile vary considerably due to their pharmacokinetic profiles (metabolism, CNS penetration, elimination, and detoxification). Based on their steep dose–response curve characteristics they are often used in high-dose chemotherapy regimens where the severe myelosuppression can be overcome by autologous or allogeneic stem cell transplantation. All these agents can produce relevant acute toxicity (e.g., renal, gastrointestinal, cutaneous, and neurological) and long-term side effects (e.g., infertility and permanent impaired renal function—all agents, pulmonary fibrosis linked to nitrosoureas). Additionally, they are highly carcinogenic, mutagenic, and teratogenic.15
Current therapeutic options for glioblastoma and future perspectives
Published in Expert Opinion on Pharmacotherapy, 2022
Elisa Aquilanti, Patrick Y. Wen
Nitrosoureas are alkylating agents that have adequate blood–brain barrier penetration. Examples of nitrosoureas are lomustine (CCNU), nimustine (ACNU), carmustine (BCNU), and fotemustine. Lomustine is the most used in the United States, and it is generally preferred over carmustine because of its oral administration. Lomustine is dosed at 90–130 mg/m2 every 6 weeks. Fotemustine is frequently used in some European countries. In randomized phase III trials that used lomustine as a control arm, the lomustine-only group showed response rates of ~10% or less, progression-free survival at 6 months of ~20% and overall survival of 6–9 months [28,40–42]. Lomustine was studied in combination regimens with procarbazine and vincristine (PCV) in older clinical trials, which showed response rates of ~3–11%, progression-free survival of ~3 months and overall survival of ~8 months [43,44].
Quercetin-loaded nanoparticles enhance cytotoxicity and antioxidant activity on C6 glioma cells
Published in Pharmaceutical Development and Technology, 2020
Melike Ersoz, Aysegul Erdemir, Serap Derman, Tulin Arasoglu, Banu Mansuroglu
Glioblastomas are one of the most common and aggressive type of brain tumors in human. Conventional therapy for glioblastoma usually includes surgery followed by radiotherapy and chemotherapy (Davis 2016). Nitrosoureas, platinum compounds, and temozolomide are considered as the most effective chemotherapeutic drugs in the treatment of glioblastoma (Alphandéry 2018). One of the most challenging drawbacks in glioblastoma treatment is insufficient uptake and penetration of chemotherapeutic drugs to tumor site due to physiological barriers such as the blood–brain barrier (BBB) and the blood–brain tumor barrier. As such, an estimated 99% of drugs in development fail to cross the BBB which severely limits the treatment. Additionally, most of the chemotherapeutic drugs exhibit significant toxic effects to non-cancerous cells which also is an important problem need to be resolved (Van Tellingen et al. 2015).
Effects of Black Raspberries and Their Constituents on Rat Prostate Carcinogenesis and Human Prostate Cancer Cell Growth In Vitro
Published in Nutrition and Cancer, 2020
Jillian N. Eskra, Alaina Dodge, Michael J. Schlicht, Maarten C. Bosland
Cy-3-Rut, cyanidin chloride, 3,3′-diethyloxacarbocyanin iodide, resazurin, sulforhodamine B (SRB), flutamide, and carboxymethylcellulose were purchased from Sigma-Aldrich (St. Louis, MO). EA was obtained from Indofine Chemical (Hillsborough, NJ). PCA was purchased from LKT Labs (St. Paul, MN). UroA was obtained from Santa Cruz (Dallas, TX). Crystalline testosterone, testosterone propionate, and 17β-estradiol were obtained from Steraloids (Newport, RI). Noble agar was purchased from Affymetrix (Cleveland, OH). DMSO, EtOH, formaldehyde, formic acid, and trichloroacetic acid were obtained from Thermo Fisher Scientific (Waltham, MA). Ketamine was obtained from Henry Schein Animal Health (Dublin, OH). Xylazine was purchased from Lloyd Laboratories (Shenandoah, IA). N-methyl-N-nitrosourea was obtained from the NCI Carcinogen Repository (MRIGlobal, Kansas City, MO).