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Clinical data | |
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Trade names | Temodar, Temodal, Temcad, others [1] |
Other names | TMZ |
AHFS/Drugs.com | Monograph |
MedlinePlus | a601250 |
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Routes of administration | By mouth, intravenous |
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Pharmacokinetic data | |
Bioavailability | almost 100% |
Protein binding | 15% (10–20%) |
Metabolism | hydrolysis |
Metabolites | 3-methyl-(triazen-1-yl)imidazole-4-carboxamide (MTIC, the active species); temozolomide acid |
Elimination half-life | 1.8 hours |
Excretion | mainly kidney |
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ECHA InfoCard | 100.158.652 |
Chemical and physical data | |
Formula | C6H6N6O2 |
Molar mass | 194.154 g·mol−1 |
3D model (JSmol) | |
Melting point | 212 °C (414 °F) (decomp.) |
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Temozolomide, sold under the brand name Temodar among others, is an anticancer medication used to treat brain tumors such as glioblastoma and anaplastic astrocytoma. [4] [5] It is taken by mouth or via intravenous infusion. [4] [5]
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). [5] 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. [5]
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. [4] [6] [7] Olaparib in combination with temozolomide demonstrated substantial clinical activity in relapsed small cell lung cancer. [8] It is available as a generic medication.
In the United States, temozolomide is indicated for the treatment of adults with newly diagnosed glioblastoma concomitantly with radiotherapy and subsequently as monotherapy treatment; [4] [9] or adults with newly diagnosed or refractory anaplastic astrocytoma. [4] [9]
In the European Union, temozolomide is indicated for adults with newly diagnosed glioblastoma multiforme concomitantly with radiotherapy and subsequently as monotherapy treatment; [5] [6] 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. [5] [6]
Temozolomide is also used to treat aggressive pituitary tumors and pituitary cancer. [10]
Temozolomide is contraindicated in people with hypersensitivity to it or to the similar drug dacarbazine. [11]
The most common side effects 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). [5] 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. [5]
Combining temozolomide with other myelosuppressants may increase the risk of myelosuppression. [11]
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. [12] [ medical citation needed ] This methylation damages the DNA and triggers the death of tumor cells. [13] [ medical citation needed ] 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. [14] 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. [15] Conversely, the presence of AGT protein in brain tumors predicts poor response to temozolomide and these patients receive little benefit from chemotherapy with temozolomide. [16]
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.[ medical citation needed ] Intake with food decreases maximal plasma concentrations by 33% and the area under the curve by 9%.[ medical citation needed ] Only 15% (10–20%) of the substance are bound to blood plasma proteins.[ medical citation needed ] 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).[ medical citation needed ] Other metabolites include temozolomide acid and unidentified hydrophilic substances. [11]
Plasma half-life is 1.8 hours.[ medical citation needed ] The substance and its metabolites are mainly excreted via the urine. [11]
Temozolomide is an imidazotetrazine derivative. [17] It is slightly soluble in water and aqueous acids, [18] and decomposes at 212 °C (414 °F). [19] It was recently discovered that temozolomide is an explosive, tentatively assigned as UN Class 1. [20] [21]
Mirroring its medicinal use as an alkylating antineoplastic agent, temozolomide has been reported to be a comparatively safe and stable in situ source of diazomethane in organic synthesis.[ medical citation needed ] In particular, its use as a methylating and cyclopropanating reagent was demonstrated. [22]
The agent was discovered at Aston University in Birmingham, England. Its preclinical activity was reported in 1987. [17] [23] [24]
It was approved for medical use in the European Union in January 1999, [5] and in the United States in August 1999. [25] The intravenous formulation was approved in the United States in February 2009. [26]
Laboratory studies and clinical trials have started investigating the possibility of increasing the anticancer potency of temozolomide by combining it with other pharmacologic agents. For example, clinical trials have indicated that the addition of chloroquine might be beneficial for the treatment of glioma patients. [27] Laboratory studies found that temozolomide killed brain tumor cells more efficiently when epigallocatechin gallate (EGCG), a component of green tea, was added; however, the efficacy of this effect has not yet been confirmed in brain-tumor patients. [28] Preclinical studies reported in 2010 on investigations into the use of the novel oxygen diffusion-enhancing compound trans sodium crocetinate (TSC) when combined with temozolomide and radiation therapy [29] and a clinical trial was underway as of August 2015 [update] . [30]
While the above-mentioned approaches have investigated whether the combination of temozolomide with other agents might improve therapeutic outcome, efforts have also started to study whether altering the temozolomide molecule itself can increase its activity. One such approach permanently fused perillyl alcohol, a natural compound with demonstrated therapeutic activity in brain cancer patients, [31] to the temozolomide molecule. The resultant novel compound, called NEO212 or TMZ-POH, revealed anticancer activity that was significantly greater than that of either of its two parent molecules, temozolomide and perillyl alcohol. Although as of 2016 [update] , NEO212 has not been tested in humans, it has shown superior cancer therapeutic activity in animal models of glioma, [32] melanoma, [33] and brain metastasis of triple-negative breast cancer. [34]
Because tumor cells that express the O-6-methylguanine-DNA methyltransferase (MGMT) gene are more resistant to the effects of temozolomide, researchers investigated whether the inclusion of O6-benzylguanine (O6-BG), an AGT inhibitor, could overcome this resistance and improve the drug's therapeutic effectiveness. In the laboratory, this combination indeed showed increased temozolomide activity in tumor-cell culture in vitro and in animal models in vivo. [35] However, a recently[ timeframe? ] completed phase-II clinical trial with brain-tumor patients yielded mixed outcomes; while there was some improved therapeutic activity when O6-BG and temozolomide were given to patients with temozolomide-resistant anaplastic glioma, there seemed to be no significant restoration of temozolomide sensitivity in patients with temozolomide-resistant glioblastoma multiforme. [36]
Some efforts focus on engineering hematopoietic stem cells expressing the MGMT gene prior to transplanting them into brain-tumor patients. This would allow for the patients to receive stronger doses of temozolomide, since the patient's hematopoietic cells would be resistant to the drug. [37]
High doses of temozolomide in high-grade gliomas have low toxicity, but the results are comparable to the standard doses. [38]
Two mechanisms of resistance to temozolomide effects have now been described: 1) intrinsic resistance conferred by MGMT deficiency (MGMTd) and 2) intrinsic or acquired resistance through MMR deficiency (MMRd). The MGMT enzyme is the first line of repair of mismatched bases created by temozolomide. Cells are normally MGMT proficient (MGMTp) as they have an unmethylated MGMT promoter allowing the gene to be expressed normally. In this state, temozolomide induced DNA damage is able to be efficiently repaired in tumor cells (and normal cells) by the active MGMT enzyme. Cells may grow and pass through the cell cycle normally without arrest or death. However, some tumors cells are MGMT deficient (MGMTd). This is most commonly due to abnormal methylation of the MGMT gene promoter and suppression of gene expression. MGMTd has also been described to occur by promoter rearrangement. In cells with MGMTd, DNA damage by temozolomide activates the next stage of repair in cells with a proficient Mismatch Repair enzyme complex (MMRp). In MMRp the MMR protein complex identifies the damage and causes cells to arrest and undergo death which inhibits tumor growth. However, if cells have combined MGMTd and MMR deficiency (MGMTd + MMRd) then cells retain the induced mutations and continue to cycle and are resistant to effects of temozolomide.[ medical citation needed ]
In gliomas and other cancers MMRd has now been reported to occur as primary MMRd (intrinsic or germline Lynch bMMRd) or as secondary MMRd (acquired - not present in the original untreated tumor). The latter occurs after effective treatment and cytoreduction of tumors with temozolomide and then selection or induction of mutant MSH6, MSH2, MLH1, or PMS2 proteins and cells which are MMRd and temozolomide resistant. The latter is described as an acquired resistance pathway with hotspot mutations in glioma patients (MSH6 p.T1219I). [39]
A brain tumor occurs when abnormal cells form within the brain. There are two main types of tumors: malignant tumors and benign (non-cancerous) tumors. These can be further classified as primary tumors, which start within the brain, and secondary tumors, which most commonly have spread from tumors located outside the brain, known as brain metastasis tumors. All types of brain tumors may produce symptoms that vary depending on the size of the tumor and the part of the brain that is involved. Where symptoms exist, they may include headaches, seizures, problems with vision, vomiting and mental changes. Other symptoms may include difficulty walking, speaking, with sensations, or unconsciousness.
A glioma is a type of tumor that starts in the glial cells of the brain or the spine. Gliomas comprise about 30 percent of all brain tumors and central nervous system tumours, and 80 percent of all malignant brain tumours.
Oligodendrogliomas are a type of glioma that are believed to originate from the oligodendrocytes of the brain or from a glial precursor cell. They occur primarily in adults but are also found in children.
Glioblastoma, previously known as glioblastoma multiforme (GBM), is the most aggressive and most common type of cancer that originates in the brain, and has very poor prognosis for survival. Initial signs and symptoms of glioblastoma are nonspecific. They may include headaches, personality changes, nausea, and symptoms similar to those of a stroke. Symptoms often worsen rapidly and may progress to unconsciousness.
Targeted therapy or molecularly targeted therapy is one of the major modalities of medical treatment (pharmacotherapy) for cancer, others being hormonal therapy and cytotoxic chemotherapy. As a form of molecular medicine, targeted therapy blocks the growth of cancer cells by interfering with specific targeted molecules needed for carcinogenesis and tumor growth, rather than by simply interfering with all rapidly dividing cells. Because most agents for targeted therapy are biopharmaceuticals, the term biologic therapy is sometimes synonymous with targeted therapy when used in the context of cancer therapy. However, the modalities can be combined; antibody-drug conjugates combine biologic and cytotoxic mechanisms into one targeted therapy.
Lomustine is an alkylating nitrosourea compound used in chemotherapy. It is closely related to semustine and is in the same family as streptozotocin. It is a highly lipid-soluble drug, thus it crosses the blood–brain barrier. This property makes it ideal for treating brain tumors, which is its primary use, although it is also used to treat Hodgkin lymphoma as a second-line option. It has also been used in veterinary practice as a treatment for cancers in cats and dogs.
PAC-1 is a synthesized chemical compound that selectively induces apoptosis, in cancerous cells. It was granted orphan drug status by the FDA in 2016.
Cilengitide is a molecule designed and synthesized at the Technical University Munich in collaboration with Merck KGaA in Darmstadt. It is based on the cyclic peptide cyclo(-RGDfV-), which is selective for αv integrins, which are important in angiogenesis, and other aspects of tumor biology. Hence, it is under investigation for the treatment of glioblastoma, where it may act by inhibiting angiogenesis, and influencing tumor invasion and proliferation.
O6-alkylguanine DNA alkyltransferase (also known as AGT, MGMT or AGAT) is a protein that in humans is encoded by the O6-methylguanine DNA methyltransferase (MGMT) gene. O6-methylguanine DNA methyltransferase is crucial for genome stability. It repairs the naturally occurring mutagenic DNA lesion O6-methylguanine back to guanine and prevents mismatch and errors during DNA replication and transcription. Accordingly, loss of MGMT increases the carcinogenic risk in mice after exposure to alkylating agents. The two bacterial isozymes are Ada and Ogt.
Paclitaxel trevatide is an experimental chemotherapy drug that is under development by Angiochem Inc, a Canadian biotech company. Phase II clinical trials have completed for several indications, and the company is preparing for phase III trials.
A radiosensitizer is an agent that makes tumor cells more sensitive to radiation therapy. It is sometimes also known as a radiation sensitizer or radio-enhancer.
Veliparib (ABT-888) is a potential anti-cancer drug acting as a PARP inhibitor. It kills cancer cells by blocking a protein called PARP, thereby preventing the repair of DNA or genetic damage in cancer cells and possibly making them more susceptible to anticancer treatments. Veliparib may make whole brain radiation treatment work more effectively against brain metastases from NSCLC. It has been shown to potentiate the effects of many chemotherapeutics, and as such has been part of many combination clinical trials.
Neutron capture therapy (NCT) is a type of radiotherapy for treating locally invasive malignant tumors such as primary brain tumors, recurrent cancers of the head and neck region, and cutaneous and extracutaneous melanomas. It is a two-step process: first, the patient is injected with a tumor-localizing drug containing the stable isotope boron-10 (10B), which has a high propensity to capture low energy "thermal" neutrons. The neutron cross section of 10B is 1,000 times more than that of other elements, such as nitrogen, hydrogen, or oxygen, that occur in tissue. In the second step, the patient is radiated with epithermal neutrons, the sources of which in the past have been nuclear reactors and now are accelerators that produce higher energy epithermal neutrons. After losing energy as they penetrate tissue, the resultant low energy "thermal" neutrons are captured by the 10B atoms. The resulting decay reaction yields high-energy alpha particles that kill the cancer cells that have taken up enough 10B.
Alternating electric field therapy, sometimes called tumor treating fields (TTFields), is a type of electromagnetic field therapy using low-intensity, intermediate frequency electrical fields to treat cancer. TTFields disrupt cell division by disrupting dipole alignment and inducing dielectrophoresis of critical molecules and organelles during mitosis. These anti-mitotic effects lead to cell death, slowing cancer growth. A TTField-treatment device manufactured by the Israeli company Novocure is approved in the United States and Europe for the treatment of newly diagnosed and recurrent glioblastoma multiforme (GBM), malignant pleural mesothelioma (MPM), and is undergoing clinical trials for several other tumor types. Despite earning regulatory approval, the efficacy of this technology remains controversial among medical experts.
O6-Benzylguanine (O6-BG) is a synthetic derivative of guanine. It is an antineoplastic agent. It exerts its effect by acting as a suicide inhibitor of the enzyme O6-alkylguanine-DNA alkyltransferase which leads to interruption of DNA repair. O6-BG was used clinically in combination with the alkylating agent temozolomide for glioblastoma, however the combination was found to be overly toxic without adding significant benefit.
Antineoplastic resistance, often used interchangeably with chemotherapy resistance, is the resistance of neoplastic (cancerous) cells, or the ability of cancer cells to survive and grow despite anti-cancer therapies. In some cases, cancers can evolve resistance to multiple drugs, called multiple drug resistance.
Isabelle M. Germano is a neurosurgeon and professor of neurosurgery, neurology, and oncology at the Icahn School of Medicine at Mount Sinai Hospital. She is a Fellow of the American College of Surgeons and the American Association of Neurological Surgeons. Germano works with image-guided brain and spine surgery.
Matthias Preusser is an Austrian oncologist and Professor of Medical Oncology as well as Head of the Clinical Division of Oncology at the Medical University of Vienna. He is known for his work on neurooncology, Molecular Therapy targets and biomarkers and immunotherapy of cancer.
Zotiraciclib (TG02) is a potent oral spectrum selective kinase inhibitor for the treatment of cancer. It was discovered in Singapore by S*BIO Pte Ltd and falls under the category of small molecule macrocycles. It crosses the blood brain barrier and acts by depleting Myc through the inhibition of cyclin-dependent kinase 9 (CDK9). It is one of a number of CDK inhibitors under investigation; others targeting CDK9 for the treatment of acute myeloid leukemia include alvocidib and atuveciclib. Myc overexpression is a known factor in many cancers, with 80 percent of glioblastomas characterized by this property. Zotiraciclib has been granted orphan drug designation by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for the treatment of gliomas.
Anaplastic oligodendroglioma is a neuroepithelial tumor which is believed to originate from oligodendrocytes, a cell type of the glia. In the World Health Organization (WHO) classification of brain tumors, anaplastic oligodendrogliomas are classified as grade III. In the course of the disease, it can degenerate into highly malignant oligodendroglioma, grade IV. The vast majority of oligodendrogliomas occur sporadically, without a confirmed cause and without inheritance within a family.
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