Temozolomide

drugbox
IUPAC_name = 4-methyl-5-oxo- 2,3,4,6,8-pentazabicyclo [4.3.0] nona-2,7,9-triene- 9-carboxamide


width = 200
CAS_number = 85622-93-1
ATC_prefix = L01
ATC_suffix = AX03
ATC_supplemental =
PubChem = 5394
DrugBank = APRD00557
C=6 | H=6 | N=6 | O=2
molecular_weight = 194.151 g/mol
bioavailability =
protein_bound = 15%
metabolism = spontaneously hydrolized at physiologic pH to the active species, 3-methyl-(triazen-1-yl)imidazole-4-carboxamide (MTIC) and to temozolomide acid metabolite.
elimination_half-life = 1.8 hours
pregnancy_AU =
pregnancy_US =
pregnancy_category =
legal_AU =
legal_UK =
legal_US = Rx-only
legal_status =
routes_of_administration = Oral

Temozolomide (brand names "Temodar" and "Temodal" Schering-Plough Corporation) is an oral alkylating agent used for the treatment of refractory anaplastic astrocytoma -- a type of cancerous brain tumor. The agent was developed by Malcolm Stevens and his team at Aston University in Birmingham, UK. A derivative of imidazotetrazine, temozolomide is the prodrug of MTIC ("3-methyl-(triazen-1-yl)imidazole-4-carboxamide"). It has been available in the US since August 1999, and in other countries since the early 2000s.

A 2005 study has showed that its benefits depend on the methylation state of the "MGMT" gene; if the promotor of this gene was methylated (i.e. the DNA was being silenced by methyl groups being attached to it by the enzyme O-6-methylguanine-DNA methyltransferase), temozolomide was effective. [cite journal |author=Hegi ME, Diserens AC, Gorlia T, "et al" |title=MGMT gene silencing and benefit from temozolomide in glioblastoma |journal=N. Engl. J. Med. |volume=352 |issue=10 |pages=997–1003 |year=2005 |pmid=15758010 |doi=10.1056/NEJMoa043331]

Indications

Nitrosourea- and procarbazine-refractory anaplastic astrocytoma

Newly-diagnosed glioblastoma multiforme

Metastatic melanoma

Temozolomide is an imidazotetrazine derivative of the alkylating agent dacarbazine. Itundergoes rapid chemical conversion in the systemic circulation at physiological pH to theactive compound, MTIC (monomethyl triazeno imidazole carboxamide). Temozolomide exhibitsschedule-dependent antineoplastic activity by interfering with DNA replication. Temozolomidehas demonstrated activity against recurrent glioma. In a recent randomized trial, concomitantand adjuvant temozolomide chemotherapy with radiation significantly improves progression freesurvival and overall survival in glioblastoma multiforme patients.

The most common non-hematological adverse effects associated with temozolomide were nausea and vomitingand were either self-limiting or readily controlled with standard antiemetic therapy. These effects were usuallymild to moderate (grade 1 to 2). The incidence of severe nausea and vomiting is around 4% each. Patients whohave pre-existing or a history of severe vomiting may require antiemetic therapy before initiating temozolomidetreatment. Temozolomide should be administered in the fasting state, at least one hour before a meal. Capsules must notbe opened or chewed, but are to be swallowed whole with a glass of water. Antiemetic therapy may beadministered prior to, 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 in pregnancy.Nursing should be discontinued while receiving the drug because of the risk of secretion into breastmilk.In male patients, temozolomide can have genotoxic effects. Men are advised not to father a childduring or up to six months after treatment and to seek advice on cryoconservation of sperm prior totreatment, because of the possibility of irreversible infertility due to temozolomide therapy.

Formulations

Temozolomide is available in the United States in 5mg, 20mg, 100mg, 140mg, 180mg & 250mg capsules.

Further improvement of anticancer potency

Laboratory studies and clinical trials are investigating whether it might be possible to further increase 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. [cite journal |author=Gilbert MR |title=New treatments for malignant gliomas: careful evaluation and cautious optimism required |journal=Ann. Intern. Med. |volume=144 |issue=5 |pages=371–3 |year=2006 |month=Mar |pmid=16520480 |doi= |url=] In laboratory studies, it was 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. [cite journal |author=Pyrko P, Schönthal AH, Hofman FM, Chen TC, Lee AS |title=The unfolded protein response regulator GRP78/BiP as a novel target for increasing chemosensitivity in malignant gliomas |journal=Cancer Res. |volume=67 |issue=20 |pages=9809–16 |year=2007 |month=Oct |pmid=17942911 |doi=10.1158/0008-5472.CAN-07-0625 |url=]

The effectiveness of temozolomide depends on its ability to methylate DNA, which most often occurs at the N-7 or O-6 portions of guanine residues. Some cancer cells (such as melanoma and glioma cell lines) may be able to repair the damage done by temozolomide (or dacarbazine) via the enzyme O-6-alkylguanine-DNA-alkyltransferase, which can be inhibited by a recently discovered compound, O-6-benzylguanine, which has been shown to improve tumor response to temozolomide. [cite journal |author=Ueno T, Ko SH, Grubbs E, "et al" |title=Modulation of chemotherapy resistance in regional therapy: a novel therapeutic approach to advanced extremity melanoma using intra-arterial temozolomide in combination with systemic O6-benzylguanine |journal=Mol. Cancer Ther. |volume=5 |issue=3 |pages=732–8 |year=2006 |month=Mar |pmid=16546988 |doi=10.1158/1535-7163.MCT-05-0098 |url=]

References

External links

* [http://www.aan.com/press/index.cfm?fuseaction=release.view&release=509 Chemotherapy Drug Shrinks Brain Tumors] American Academy of Neurology, May 21, 2007