Temozolomide
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| Systematic (IUPAC) name | |
|---|---|
| 4-methyl-5-oxo- 2,3,4,6,8-pentazabicyclo [4.3.0] nona-2,7,9-triene- 9-carboxamide | |
| Identifiers | |
| CAS number | 85622-93-1 |
| ATC code | L01AX03 |
| PubChem | 5394 |
| DrugBank | APRD00557 |
| Chemical data | |
| Formula | C6H6N6O2 |
| Mol. mass | 194.151 g/mol |
| Pharmacokinetic data | |
| Bioavailability | ? |
| 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. |
| Half life | 1.8 hours |
| Excretion | ? |
| Therapeutic considerations | |
| Pregnancy cat. |
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| Legal status | |
| Routes | Oral |
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Temozolomide (brand names Temodar and Temodal Schering-Plough Corporation) is an oral alkylating agent which can be used for the treatment of Grade IV astrocytoma -- an aggressive brain tumor, also known as glioblastoma multiforme. The agent was developed by Malcolm Stevens and his team at Aston University in Birmingham,[1] 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.
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 an enzyme called O-6-methylguanine-DNA methyltransferase (MGMT) or O-6-alkylguanine-DNA alkyltransferase (AGT or AGAT).[2] In some tumors, epigenetic silencing of the MGMT/AGT gene prevents the synthesis of this enzyme, and as a consequence such tumors are more sensitive to killing by temozolomide.[3] Conversely, the presence of MGMT protein in brain tumors predicts poor response to temozolomide and these patients receive little benefit from chemotherapy with temozolomide.[4]
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[edit] Indications
Nitrosourea- and procarbazine-refractory anaplastic astrocytoma
Newly-diagnosed glioblastoma multiforme
Temozolomide (sometimes referred to as TMZ) is an imidazotetrazine derivative of the alkylating agent dacarbazine. It undergoes rapid chemical conversion in the systemic circulation at physiological pH to the active compound, MTIC (monomethyl triazeno imidazole carboxamide). Temozolomide exhibits schedule-dependent antineoplastic activity by interfering with DNA replication. Temozolomide has demonstrated activity against recurrent glioma. In a recent randomized trial, concomitant and adjuvant temozolomide chemotherapy with radiation significantly improves progression free survival and overall survival in glioblastoma multiforme patients.
The most common non-hematological adverse effects associated with temozolomide were nausea and vomiting and were either self-limiting or readily controlled with standard antiemetic therapy. These effects were 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 are to be swallowed whole with a glass of water. Antiemetic therapy may be administered 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 breast milk. 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.
[edit] Formulations
Temozolomide is available in the United States in 5 mg, 20 mg, 100 mg, 140 mg, 180 mg & 250 mg capsules.
[edit] 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.[5] 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.[6]
Because tumor cells that synthesize the MGMT/AGT enzyme are more resistant to killing by temozolomide, it was investigated whether the inclusion of O-6-benzylguanine (O6-BG), an inhibitor of MGMT, would be able to overcome this resistance and improve the drug's therapeutic effectiveness. In the laboratory, this combination indeed showed increased activity in tumor cell culture in vitro and in animal models in vivo.[7] 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.[8]
[edit] References
- ^ Newlands ES, Stevens MF, Wedge SR, Wheelhouse RT, Brock C (January 1997). "Temozolomide: a review of its discovery, chemical properties, pre-clinical development and clinical trials". Cancer Treat. Rev. 23 (1): 35–61. PMID 9189180.
- ^ Jacinto, FV; Esteller, M (Aug 2007). "MGMT hypermethylation: a prognostic foe, a predictive friend.". DNA Repair 6 (8): 1155–1160. doi:. ISSN 1568-7864. PMID 17482895. http://www.ncbi.nlm.nih.gov/pubmed/17482895.
- ^ Hegi ME, Diserens AC, Gorlia T, et al. (Mar 2005). "MGMT gene silencing and benefit from temozolomide in glioblastoma". N. Engl. J. Med. 352 (10): 997–1003. doi:. ISSN 0028-4793. PMID 15758010.
- ^ Stupp et al. (May 2009). "Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial.". Lancet Oncology 10 (5): 459–466. doi:. ISSN 1470-2045. PMID 19269895.
- ^ Gilbert MR (March 2006). "New treatments for malignant gliomas: careful evaluation and cautious optimism required". Ann. Intern. Med. 144 (5): 371–3. ISSN 0003-4819. PMID 16520480.
- ^ Pyrko P, Schönthal AH, Hofman FM, Chen TC, Lee AS (October 2007). "The unfolded protein response regulator GRP78/BiP as a novel target for increasing chemosensitivity in malignant gliomas" (Free full text). Cancer Res. 67 (20): 9809–16. doi:. ISSN 0008-5472. PMID 17942911. http://cancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=17942911.
- ^ Ueno T, Ko SH, Grubbs E, et al. (Mar 2006). "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" (Free full text). Mol. Cancer Ther. 5 (3): 732–8. doi:. ISSN 1535-7163. PMID 16546988. http://mct.aacrjournals.org/cgi/pmidlookup?view=long&pmid=16546988.
- ^ Quinn et al. (Mar 2009). "Phase II trial of temozolomide plus o6-benzylguanine in adults with recurrent, temozolomide-resistant malignant glioma.". J. Clin. Oncol. 27 (8): 1262–1267. doi:. ISSN 0732-183X. PMID 19204199.
[edit] External links
- Chemotherapy Drug Shrinks Brain Tumors American Academy of Neurology, May 21, 2007
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