Temozolomide, sold under the brand name Temodar among others, is an anticancer medication used to treat brain tumors such as glioblastoma and anaplastic astrocytoma. It is taken by mouth or via intravenous infusion.
The most common side effects with temozolomide are nausea, vomiting, constipation, loss of appetite, alopecia (hair loss), headache, fatigue, convulsions (seizures), rash, neutropenia or lymphopenia (low white-blood-cell counts), and thrombocytopenia (low blood platelet counts). People receiving the solution for infusion may also have injection-site reactions, such as pain, irritation, itching, warmth, swelling and redness, as well as bruising.
Temozolomide is an alkylating agent used to treat serious brain cancers; most commonly as second-line treatments for astrocytoma and as the first-line treatment for glioblastoma. Olaparib in combination with temozolomide demonstrated substantial clinical activity in relapsed small cell lung cancer. It is available as a generic medication.
Medical uses
In the United States, temozolomide is indicated for the treatment of adults with newly diagnosed glioblastoma concomitantly with radiotherapy and subsequently as monotherapy treatment; or adults with newly diagnosed or refractory anaplastic astrocytoma.
In the European Union, temozolomide is indicated for adults with newly diagnosed glioblastoma multiforme concomitantly with radiotherapy and subsequently as monotherapy treatment; or children from the age of three years, adolescents and adults with malignant glioma, such as glioblastoma multiforme or anaplastic astrocytoma, showing recurrence or progression after standard therapy.
Temozolomide is also used to treat aggressive pituitary tumors and pituitary cancer.
Contraindications
Temozolomide is contraindicated in people with hypersensitivity to it or to the similar drug dacarbazine.
Adverse effects
The most common side effects with include nausea (feeling sick), vomiting, constipation, loss of appetite, alopecia (hair loss), headache, fatigue (tiredness), convulsions (fits), rash, neutropenia or lymphopenia (low white-blood-cell counts), and thrombocytopenia (low blood platelet counts). People receiving the solution for infusion may also have injection-site reactions, such as pain, irritation, itching, warmth, swelling and redness, as well as bruising.
Interactions
Combining temozolomide with other myelosuppressants may increase the risk of myelosuppression.
Pharmacology
Mechanism of action
The therapeutic benefit of temozolomide depends on its ability to alkylate/methylate DNA, which most often occurs at the N-7 or O-6 positions of guanine residues. This methylation damages the DNA and triggers the death of tumor cells. However, some tumor cells are able to repair this type of DNA damage, and therefore diminish the therapeutic efficacy of temozolomide, by expressing a protein O6-alkylguanine DNA alkyltransferase (AGT) encoded in humans by the O-6-methylguanine-DNA methyltransferase (MGMT) gene. In some tumors, epigenetic silencing of the MGMT gene prevents the synthesis of this enzyme, and as a consequence such tumors are more sensitive to killing by temozolomide. Conversely, the presence of AGT protein in brain tumors predicts poor response to temozolomide and these patients receive little benefit from chemotherapy with temozolomide.
Pharmacokinetics
Temozolomide is quickly and almost completely absorbed from the gut, and readily penetrates the blood–brain barrier; the concentration in the cerebrospinal fluid is 30% of the concentration in the blood plasma. Intake with food decreases maximal plasma concentrations by 33% and the area under the curve by 9%. Only 15% (10–20%) of the substance are bound to blood plasma proteins. Temozolomide is a prodrug; it is spontaneously hydrolyzed at physiological pH to 3-methyl-(triazen-1-yl)imidazole-4-carboxamide (MTIC), which further splits into monomethylhydrazine, likely the active methylating agent, and 5-aminoimidazole-4-carboxamide (AIC). Other metabolites include temozolomide acid and unidentified hydrophilic substances.
Plasma half-life is 1.8 hours. The substance and its metabolites are mainly excreted via the urine.
Chemical properties
Temozolomide is an imidazotetrazine derivative. It is slightly soluble in water and aqueous acids, and decomposes at . It was recently discovered that temozolomide is an explosive, tentatively assigned as UN Class 1.