Temozolomide

From WikiMD
Jump to navigation Jump to search


Temozolomide (brand names Temodar and Temodal and Temcad) is an oral chemotherapy drug. It is an alkylating agent used for the treatment of Grade IV astrocytoma — an aggressive brain tumor, also known as glioblastoma multiforme — as well as for treating melanoma, a form of skin cancer. Temozolomide is also indicated for relapsed Grade III anaplastic astrocytoma and not indicated for, but as of 2011 used to treat oligodendroglioma brain tumors in some countries, replacing the older (and less well tolerated) PCV (Procarbazine-Lomustine-Vincristine) regimen.

The agent was developed by Malcolm Stevens[1] and his team at Aston University in Birmingham,[2][3] Temozolomide is a prodrug and an imidazotetrazine derivative of the alkylating agent dacarbazine. 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 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]

Indications

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

Structure and mechanism

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, 3-methyl-(triazen-1-yl)imidazole-4-carboxamide (MTIC). 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, from 12.1 months to 14.6 months, progression free survival and overall survival in glioblastoma multiforme patients.

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.[7] 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.

Formulations

Temozolomide is available in the United States in 5 mg, 20 mg, 100 mg, 140 mg, 180 mg & 250 mg capsules. Now also available in an IV form for people who can not swallow capsules or who have insurance that does not cover oral cancer agents.

A generic version is available in the UK.

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.[8] 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.[9] 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 [10] and a clinical trial is currently underway.[11]

Because tumor cells that express the MGMT gene are more resistant to killing by temozolomide, it was investigatedTemplate:According to whom 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.[12] 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.[13]

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.[14]

High doses of temozolomide in high grade gliomas have low toxicity, but the results are comparable to the standard doses.[15]

Notes

A case report suggests that temozolomide may be of use in relapsed primary CNS lymphoma.[16] Confirmation of this possible use seems indicated.

References

  1. Malcolm Stevens - interview, Cancer Research UK impact & achievements page
  2. 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. doi:10.1016/S0305-7372(97)90019-0. PMID 9189180.CS1 maint: multiple names: authors list (link)
  3. Stevens MF; Hickman JA; Langdon SP; Chubb D; Vickers L; Stone R; Baig G; Goddard C; Gibson NW; Slack JA; et al. (November 1987). "Antitumor activity and pharmacokinetics in mice of 8-carbamoyl-3-methyl-imidazo[5,1-d]-1,2,3,5-tetrazin-4(3H)-one (CCRG 81045; M & B 39831), a novel drug with potential as an alternative to dacarbazine". Cancer Res. 47 (22): 5846–52. PMID 3664486. Unknown parameter |author-separator= ignored (help); Explicit use of et al. in: |author11= (help)
  4. 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.
  5. 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 (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.CS1 maint: multiple names: authors list (link)
  6. 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.
  7. Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 21030284, please use {{cite journal}} with |pmid=21030284 instead.
  8. 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.
  9. 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". Cancer Res. 67 (20): 9809–16. doi:10.1158/0008-5472.CAN-07-0625. PMID 17942911.CS1 maint: multiple names: authors list (link)
  10. Sheehan J, Cifarelli C, Dassoulas K, Olson C, Rainey J, Han S (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.CS1 maint: multiple names: authors list (link)
  11. "Safety and Efficacy Study of Trans Sodium Crocetinate (TSC) With Concomitant Radiation Therapy and Temozolomide in Newly Diagnosed Glioblastoma (GBM)". ClinicalTrials.gov. November 2011.
  12. 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. Unknown parameter |author-separator= ignored (help); Explicit use of et al. in: |author4= (help)
  13. 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.
  14. http://labs.fhcrc.org/kiem/Hans-Peter_Kiem.html
  15. Dall'oglio S, D'Amico A, Pioli F, Gabbani M, Pasini F, Passarin MG, Talacchi A, Turazzi S, Maluta S (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.CS1 maint: multiple names: authors list (link)
  16. Osmani AH, Masood N; Masood (2012). "Temozolomide for relapsed primary CNS lymphoma". J Coll Physicians Surg Pak. 22 (9): 594–595. PMID 22980617.
Wikipedia

External links

Template:Chemotherapeutic agents Comprehensive list of medications or pharmaceutical drugs used in the United States with their NDC or national drug code, brand name, dosage, forms of administration etc. sorted alphabetically.

See also

External links

The following is the collection of detailed information and links to the National Institute of Health (NIH) comprehensive drug information portal and other reliable sources of information. Select the drug name below to show drug description, drug classification, other common drug names, and information on the reasons why prescribed, how medication should be used, and what possible side effects could occur.

Drug names

A • B • C • D • E • F • G • H • I • J • K • L • M • N • O • P • Q • R • S • T • U • V • W • X • Y • Z

Search for other drug names not listed above Portions of content adapted from Wikipedias article on Temozolomide licensed under GNU FDL.


Antineoplastic Agents

Alkylating Agents - Altretamine, Bendamustine, Busulfan, Carmustine, Chlorambucil, Cyclophosphamide, Dacarbazine, Ifosfamide, Lomustine, Mechlorethamine, Melphalan, Procarbazine, Streptozocin, Temozolomide, Thiotepa, Trabectedin

Platinum Coordination Complexes - Carboplatin, Cisplatin, Oxaliplatin

Antibiotics Cytotoxic - Bleomycin, Dactinomycin, Daunorubicin, Doxorubicin, Epirubicin, Idarubicin, Mitomycin, Mitoxantrone, Plicamycin, Mithramycin, Valrubicin

Antimetabolites Antifolates - Methotrexate, Pemetrexed, Pralatrexate, Trimetrexate

Purine Analogues - Azathioprine, Cladribine, Clofarabine, Fludarabine, Mercaptopurine, Nelarabine, Pentostatin, Thioguanine

Pyrimidine Analogues - Azacitidine, Capecitabine, Cytarabine, Decitabine, Floxuridine, Fluorouracil, Gemcitabine, Trifluridine/Tipracil

Biologic Response Modifiers - Aldesleukin (IL-2), Denileukin Diftitox, Interferon gamma

Histone Deacetylase Inhibitors - Belinostat, Panobinostat, Romidepsin, Vorinostat

Hormonal Agents Antiandrogens - Abiraterone, Bicalutamide, Cyproterone, Enzalutamide, Flutamide, Nilutamide

Antiestrogens (including Aromatase Inhibitors) - Anastrozole, Exemestane, Fulvestrant, Letrozole

Selective Estrogen Receptor Modulators - Raloxifene, Tamoxifen, Toremifene

Gonadotropin Releasing Hormone Analogues - Degarelix, Goserelin, Histrelin, Leuprolide, Triptorelin

Peptide Hormones - Lanreotide, Octreotide, Pasireotide

Monoclonal Antibodies - Alemtuzumab, Atezolizumab, Avelumab, Bevacizumab, Blinatumomab, Brentuximab, Cetuximab, Daratumumab, Dinutuximab, Durvalumab, Elotuzumab, Gemtuzumab, Inotuzumab Ozogamicin, Ipilimumab, Necitumumab, Nivolumab, Ofatumumab, Olaratumab, Panitumumab, Pembrolizumab, Pertuzumab, Ramucirumab, Rituximab, Tositumomab, Trastuzumab

Protein Kinase Inhibitors - Abemaciclib, Acalabrutinib, Afatinib, Alectinib, Axitinib, Bortezomib, Bosutinib, Brigatinib, Cabozantinib, Carfilzomib, Ceritinib, Cobimetinib, Copanlisib, Crizotinib, Dabrafenib, Dasatinib, Enasidenib, Erlotinib, Gefitinib, Ibrutinib, Idelalisib, Imatinib, Ivosidenib, Ixazomib, Lapatinib, Lenvatinib, Neratinib, Nilotinib, Niraparib, Olaparib, Osimertinib, Palbociclib, Pazopanib, Ponatinib, Regorafenib, Ribociclib, Rucaparib, Ruxolitinib, Sonidegib, Sorafenib, Sunitinib, Trametinib, Vandetanib, Vemurafenib, Vismodegib

Taxanes - Cabazitaxel, Docetaxel, Paclitaxel

Topoisomerase Inhibitors - Etoposide, Irinotecan, Teniposide, Topotecan

Tyrosine Kinase Receptor Inhibitors See Protein Kinase Inhibitors

Vinca Alkaloids - Vinblastine, Vincristine, Vinorelbine

Miscellaneous - Asparaginase (Pegaspargase), Bexarotene, Eribulin, Everolimus, Hydroxyurea, Ixabepilone, Lenalidomide, Mitotane, Omacetaxine, Pomalidomide, Temsirolimus, Thalidomide, Venetoclax

This article is a stub. YOU can help Wikimd by expanding it!

Articles on Temozolomide

Wikipedia

Learn more about Temozolomide

Help WikiMD

Find something you can improve? Join WikiMD as an an editor and help improve this page or others.

Apple bitten.svg

WikiMD is a free medical encyclopedia and wellnesspedia moderated by medical professionals.

W8MD weight loss logo

Ad. Tired of being overweight?. W8MD's insurance Weight loss program can HELP*

Weight loss tips | Lose weight King of Prussia, PA | W8MD's medical weight loss | Lose weight New York City | Lose weight Philadelphia | Lose weight NYC | Weight loss Brooklyn NY | Advertise

Quick links: Medicine Portal | Encyclopedia‏‎‏‎ | Gray's Anatomy‏‎ | Topics‏‎ |‏‎ Diseases‏‎ | Drugs | Wellness | Obesity‏‎ | Metabolic syndrome | Weight loss*
Disclaimer: The entire contents of WIKIMD.ORG are for informational purposes only and do not render medical advice or professional services. If you have a medical emergency, you should CALL 911 immediately! Given the nature of the wiki, the information provided may not be accurate, misleading and or incorrect. Use the information on this wiki at your own risk! See full Disclaimer.
Link to this page: <a href="http://www.wikimd.org/wiki/Temozolomide">Temozolomide</a>

  • Individual results may vary for weight loss from our sponsors.