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 |
|
| Legal status |
|
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 Registry Number |
85622-93-1 Y |
| ATC code |
L01AX03 |
| 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.) |
| N (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.[1][2]
Contents
- 1 Indications
- 2 Side-effects
- 3 Mechanism of action
- 4 Chemical properties
- 5 History
- 6 Research
- 7 References
- 8 External links
Indications
- Nitrosourea- and procarbazine-refractory anaplastic astrocytoma[1][2]
- Newly diagnosed glioblastoma multiforme[1]
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 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 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.[3] 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.[4] 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.[5] Conversely, the presence of AGT protein in brain tumors predicts poor response to temozolomide and these patients receive little benefit from chemotherapy with temozolomide.[6]
Chemical properties
Temozolomide is a prodrug and an imidazotetrazine derivative of the alkylating agent dacarbazine.[7]
History
The agent was developed by Malcolm Stevens and his team at Aston University in Birmingham.[7][8][9] It has been available in the US since August 1999, and in other countries since the early 2000s.[7]
Research
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.[10] 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.[11] More recently, use of the novel oxygen diffusion-enhancing compound trans sodium crocetinate (TSC) when combined with temozolomide and radiation therapy has been investigated in preclinical studies [12] and a clinical trial is currently underway.[13]
While the above-mentioned approaches have investigated whether the combination of temozolomide with other agents might improve therapeutic outcome, there are also efforts underway to study whether the temozolomide molecule itself can be altered in order to further increase its activity. In one such approach, perillyl alcohol, a natural compound with demonstrated therapeutic activity in brain cancer patients,[14] was permanently fused to the temozolomide molecule. This 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 NEO212 has not yet been tested in humans, it did show superior cancer therapeutic activity in animal models of glioma,[15] melanoma,[16] and brain metastasis of triple-negative breast cancer.[17]
Because tumor cells that express the MGMT Gene are more resistant to killing by temozolomide, it was investigated whether the inclusion of O6-benzylguanine (O6-BG), an AGT inhibitor, would be able to 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.[18] 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.[19]
There are also efforts to engineer 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.[20]
High doses of temozolomide in high grade gliomas have low toxicity, but the results are comparable to the standard doses.[21]
References
- ^ a b c Temodar label Last updated Feb 2011
- ^ a b NICE NICE technology appraisal guidance [TA23]: Guidance on the use of temozolomide for the treatment of recurrent malignant glioma (brain cancer) Published date: April 200
- ^ Sitbon Sitruk, L.; Sanson, M.; Prades, M.; Lefebvre, G.; Schubert, B.; Poirot, C. (2010). "Chimiothérapie à gonadotoxicité inconnue et préservation de la fertilité : Exemple du témozolomide☆". Gynécologie Obstétrique & Fertilité 38 (11): 660–662. doi:10.1016/j.gyobfe.2010.09.002. PMID 21030284.
- ^ Jacinto, FV; Esteller, M (August 2007). "MGMT hypermethylation: a prognostic foe, a predictive friend.". DNA Repair 6 (8): 1155–60. doi:10.1016/j.dnarep.2007.03.013. PMID 17482895.
- ^ Hegi ME, Diserens AC, Gorlia T, Hamou MF, de Tribolet N, Weller M, Kros JM, Hainfellner JA, Mason W, Mariani L, Bromberg JE, Hau P, Mirimanoff RO, Cairncross JG, Janzer RC, Stupp R; Diserens; Gorlia; Hamou; De Tribolet; Weller; Kros; Hainfellner; Mason; Mariani; Bromberg; Hau; Mirimanoff; Cairncross; Janzer; Stupp (March 2005). "MGMT gene silencing and benefit from temozolomide in glioblastoma". N. Engl. J. Med. 352 (10): 997–1003. doi:10.1056/NEJMoa043331. PMID 15758010.
- ^ National Cancer Institute Of Canada Clinical Trials, Group; Hegi, ME; Mason, WP; Van Den Bent, MJ; Taphoorn, MJ; Janzer, RC; Ludwin, SK; Allgeier, A 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:10.1016/S1470-2045(09)70025-7. PMID 19269895.
- ^ a b c Clare Sansom for Chemistry World. July 2009 Temozolomide – birth of a blockbuster
- ^ Malcolm Stevens - interview, Cancer Research UK impact & achievements page
- ^ Newlands ES, Stevens MF, Wedge SR, Wheelhouse RT, Brock C; Stevens; Wedge; Wheelhouse; Brock (January 1997). "Temozolomide: a review of its discovery, chemical properties, pre-clinical development and clinical trials". Cancer Treat. Rev. 23 (1): 35–61. doi:10.1016/S0305-7372(97)90019-0. PMID 9189180.
- ^ Gilbert MR (March 2006). "New treatments for malignant gliomas: careful evaluation and cautious optimism required". Ann. Intern. Med. 144 (5): 371–3. doi:10.7326/0003-4819-144-5-200603070-00015. PMID 16520480.
- ^ Pyrko P, Schönthal AH, Hofman FM, Chen TC, Lee AS; Schönthal; Hofman; Chen; Lee (October 2007). "The unfolded protein response regulator GRP78/BiP as a novel target for increasing chemosensitivity in malignant gliomas". Cancer Res. 67 (20): 9809–16. doi:10.1158/0008-5472.CAN-07-0625. PMID 17942911.
- ^ Sheehan J, Cifarelli C, Dassoulas K, Olson C, Rainey J, Han S; Cifarelli; Dassoulas; Olson; Rainey; Han (2010). "Trans-sodium crocetinate enhancing survival and glioma response on magnetic resonance imaging to radiation and temozolomide". Journal of Neurosurgery 113 (2): 234–239. doi:10.3171/2009.11.JNS091314. PMID 20001586.
- ^ "Safety and Efficacy Study of Trans Sodium Crocetinate (TSC) With Concomitant Radiation Therapy and Temozolomide in Newly Diagnosed Glioblastoma (GBM)". ClinicalTrials.gov. November 2011.
- ^ Da Fonseca CO, Teixeira RM, Silva JC, DE Saldanha da Gama Fischer, Meirelles OC, Landeiro JA and Quirico-Santos T (2013). "Long-term outcome in patients with recurrent malignant glioma treated with perillyl alcohol inhalation.". Anticancer Res. 33 (12): 5625–5631. PMID 24324108.
- ^ Cho HY, Wang W, Jhaveri N, Lee DJ, Sharma N, Dubeau L, Schönthal AH, Hofman FM, Chen TC (2014). "NEO212, temozolomide conjugated to perillyl alcohol, is a novel drug for effective treatment of a broad range of temozolomide-resistant gliomas.". Mol. Cancer Ther. 13 (8): 2004–2017. PMID 24994771.
- ^ Chen TC, Cho HY, Wang W, Nguyen J, Jhaveri N, Rosenstein-Sisson R, Hofman FM, Schönthal AH (2015). "A novel temozolomide analog, NEO212, with enhanced activity against MGMT-positive melanoma in vitro and in vivo.". Cancer Lett. 358 (2): 144–151. PMID 25524552.
- ^ Chen TC, Cho HY, Wang W, Barath M, Sharma N, Hofman FM, Schönthal AH (2014). "A novel temozolomide-perillyl alcohol conjugate exhibits superior activity against breast cancer cells in vitro and intracranial triple-negative tumor growth in vivo.". Mol. Cancer Ther. 13 (5): 1181–1193. PMID 24623736.
- ^ Ueno T, Ko SH, Grubbs E et al. (March 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". Mol. Cancer Ther. 5 (3): 732–8. doi:10.1158/1535-7163.MCT-05-0098. PMID 16546988.
- ^ Friedman, HS; Jiang, SX; Reardon, DA; Desjardins, A; Vredenburgh, JJ; Rich, JN; Gururangan, S; Friedman, AH et al. (March 2009). "Phase II trial of temozolomide plus o6-benzylguanine in adults with recurrent, temozolomide-resistant malignant glioma". J. Clin. Oncol. 27 (8): 1262–7. doi:10.1200/JCO.2008.18.8417. PMC 2667825. PMID 19204199.
- ^ http://labs.fhcrc.org/kiem/Hans-Peter_Kiem.html
- ^ Dall'oglio S, D'Amico A, Pioli F, Gabbani M, Pasini F, Passarin MG, Talacchi A, Turazzi S, Maluta S; d'Amico; Pioli; Gabbani; Pasini; Passarin; Talacchi; Turazzi; Maluta (December 2008). "Dose-intensity temozolomide after concurrent chemoradiotherapy in operated high-grade gliomas". J Neurooncol 90 (3): 315–9. doi:10.1007/s11060-008-9663-9. PMID 18688571.
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)
