Temozolomide

Temozolomide

Systematic (IUPAC) name
4-methyl-5-oxo-2,3,4,6,8-pentazabicyclo[4.3.0]nona-2,7,9-triene-9-carboxamide
Clinical data
Trade names	Temodar, Temodal, Temcad
AHFS/Drugs.com	monograph
MedlinePlus	a601250
Licence data	EMA:Link, US FDA:link
Pregnancy category	US: D (Evidence of risk)
Legal status	US: ℞-only
Routes of administration	Oral, intravenous
Pharmacokinetic data
Protein binding	15%
Metabolism	spontaneously hydrolyzed at physiologic pH to the active species, 3-methyl-(triazen-1-yl)imidazole-4-carboxamide (MTIC) and to temozolomide acid metabolite.
Biological half-life	1.8 hours
Identifiers
CAS Number	85622-93-1 Y
ATC code	L01AX03 (WHO)
PubChem	CID: 5394
IUPHAR/BPS	7301
DrugBank	DB00853 Y
ChemSpider	5201 Y
UNII	YF1K15M17Y Y
KEGG	D06067 Y
ChEBI	CHEBI:72564 N
ChEMBL	CHEMBL810 Y
Chemical data
Formula	C6H6N6O2
Molecular mass	194.151 g/mol
SMILES O=C(c1ncn2C(=O)N(\N=N/c12)C)N
InChI InChI=1S/C6H6N6O2/c1-11-6(14)12-2-8-3(4(7)13)5(12)9-10-11/h2H,1H3,(H2,7,13) Y Key:BPEGJWRSRHCHSN-UHFFFAOYSA-N Y
Physical data
Melting point	212 °C (414 °F) (decomp.)
NY (what is this?)  (verify)

Temozolomide, (TMZ) (brand names Temodar and Temodal and Temcad) is an oral chemotherapy drug. It is an alkylating agent used as a treatment of some brain cancers; as a second-line treatment for astrocytoma and a first-line treatment for glioblastoma multiforme.

Indications

• Nitrosourea- and procarbazine-refractory anaplastic astrocytoma
• Newly diagnosed glioblastoma multiforme

Side-effects

The most common non-hematological adverse effects associated with temozolomide - nausea and vomiting - are either self-limiting or readily controlled with standard antiemetic therapy. These effects are usually mild to moderate (grade 1 to 2). The incidence of severe nausea and vomiting is around 4% each. Patients who have pre-existing or a history of severe vomiting may require antiemetic therapy before initiating temozolomide treatment. Temozolomide should be administered in the fasting state, at least one hour before a meal. (Capsules must not be opened or chewed, but swallowed whole with a glass of water.) Antiemetic therapy may be administered before, or following, administration of temozolomide. Temozolomide is contraindicated in patients with hypersensitivity to its components or to dacarbazine. The use of temozolomide is not recommended in patients with severe myelosuppression.

Temozolomide is genotoxic, teratogenic and fetotoxic and should not be used during pregnancy. Lactating women should discontinue nursing while receiving the drug because of the risk of secretion into breast milk. One study indicated that women that have taken temozolomide without concomitant fertility preservation measures achieve pregnancy to a lesser rate later in life, but the study was too small to show statistical significance in the hypothesis that temozolomide would confer a risk of female infertility. In male patients, temozolomide can have genotoxic effects. Men are advised not to father a child during or up to six months after treatment and to seek advice on cryoconservation of sperm prior to treatment, because of the possibility of irreversible infertility due to temozolomide therapy.

Very rarely Temozolomide can cause acute respiratory failure.

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.

Chemical properties

Temozolomide is a prodrug and an imidazotetrazine derivative of the alkylating agent dacarbazine.

History

The agent was developed by Malcolm Stevens and his team at Aston University in Birmingham. It has been available in the US since August 1999, and in other countries since the early 2000s.

Research

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. 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. 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 and a clinical trial was underway as of August  2015.

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, 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 NEO212 has not been tested in humans, it has shown superior cancer therapeutic activity in animal models of glioma, melanoma, and brain metastasis of triple-negative breast cancer.

Because tumor cells that express the MGMT gene are more resistant to killing by 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. However, a recently 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.

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.

High doses of temozolomide in high-grade gliomas have low toxicity, but the results are comparable to the standard doses.

External links

• Chemotherapy Drug Shrinks Brain Tumors American Academy of Neurology, May 21, 2007
• Information for people undergoing treatment with temozolomide Cancer Research UK (CancerHelp UK)