Wikipedia:WikiProject Chemicals/Chembox validation/VerifiedDataSandbox and Temozolomide: Difference between pages

{{Short description|Cancer medication}}

{{Use dmy dates|date=September 2023}}

{{cs1 config |name-list-style=vanc |display-authors=6}}

{{Infobox drug

| Verifiedfields = changed

| Watchedfields = changed

| verifiedrevid = 477861554

| type = <!-- empty -->

| image = Temozolomide structure.svg

| width = 160

| alt =

| width2 = 160

| alt2 =

| caption =

<!-- Clinical data -->

| pronounce =

| tradename = Temodar, Temodal, Temcad, others<ref>{{cite web | title=Temozolomide | website=Drugs.com | date=4 May 2020 | url=https://www.drugs.com/international/temozolomide.html | access-date=7 May 2020 | archive-date=29 August 2021 | archive-url=https://web.archive.org/web/20210829080310/https://www.drugs.com/pro/temozolomide.html | url-status=live }}</ref>

| licence_CA = <!-- Health Canada may use generic or brand name (generic name preferred) -->

| licence_EU = yes

| DailyMedID = Temozolomide

| pregnancy_AU = D

| pregnancy_AU_comment =

| pregnancy_category=

| routes_of_administration = [[Oral administration|By mouth]], [[intravenous]]

| class =

| ATCvet =

| ATC_prefix = L01

| ATC_suffix = AX03

| ATC_supplemental =

<!-- Legal status -->

| legal_AU = <!-- S2, S3, S4, S5, S6, S7, S8, S9 or Unscheduled -->

| legal_AU_comment =

| legal_BR = <!-- OTC, A1, A2, A3, B1, B2, C1, C2, C3, C4, C5, D1, D2, E, F -->

| legal_BR_comment =

| legal_CA = <!-- OTC, Rx-only, Schedule I, II, III, IV, V, VI, VII, VIII -->

| legal_CA_comment =

| legal_DE = <!-- Anlage I, II, III or Unscheduled -->

| legal_DE_comment =

| legal_NZ = <!-- Class A, B, C -->

| legal_NZ_comment =

| legal_UK = POM

| legal_UK_comment = <ref>{{cite web | title=Temodal Capsules - Summary of Product Characteristics (SmPC) | website=(emc) | date=24 October 2019 | url=https://www.medicines.org.uk/emc/product/1463/smpc | access-date=7 May 2020 | archive-date=20 September 2020 | archive-url=https://web.archive.org/web/20200920054701/https://www.medicines.org.uk/emc/product/1463/smpc | url-status=live }}</ref>

| legal_US_comment = <ref name="Temodar FDA label" />

| legal_EU = Rx-only

| legal_EU_comment = <ref name="Temodal EPAR" />

| legal_UN = <!-- N I, II, III, IV / P I, II, III, IV -->

| legal_UN_comment =

| legal_status = Rx-only

<!-- Pharmacokinetic data -->

| bioavailability = almost 100%

| protein_bound = 15% (10–20%)

| metabolism = [[hydrolysis]]

| metabolites = 3-methyl-(triazen-1-yl)imidazole-4-carboxamide (MTIC, the [[active moiety|active species]]); temozolomide acid

| onset =

| duration_of_action =

| excretion = mainly [[kidney]]

<!-- Identifiers -->

| CAS_supplemental =

| IUPHAR_ligand = 7301

| ChEBI_Ref = {{ebicite|changed|EBI}}

| ChEBI = 72564

| NIAID_ChemDB =

| PDB_ligand =

| synonyms = TMZ

<!-- Chemical and physical data -->

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

| C=6 | H=6 | N=6 | O=2

| SMILES = O=C(c1ncn2C(=O)N(\N=N/c12)C)N

| StdInChI_comment =

| density =

| density_notes =

| melting_point = 212

| melting_high =

| melting_notes = (decomp.)

| boiling_point =

| boiling_notes =

| solubility =

| sol_units =

| specific_rotation =

'''Temozolomide''', sold under the brand name '''Temodar''' among others, is an [[anticancer medication]] used to treat brain tumors such as [[glioblastoma]] and [[anaplastic astrocytoma]].<ref name="Temodar FDA label">{{cite web | title=Temodar- temozolomide capsule Temodar- temozolomide injection, powder, lyophilized, for solution | website=DailyMed | date=31 January 2020 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=046a9011-3911-4d3f-a15f-fbb56d5aad56 | access-date=7 May 2020 | archive-date=8 April 2021 | archive-url=https://web.archive.org/web/20210408174114/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=046a9011-3911-4d3f-a15f-fbb56d5aad56 | url-status=live }}</ref><ref name="Temodal EPAR">{{cite web | title=Temodal EPAR | website=[[European Medicines Agency]] (EMA) | date=17 September 2018 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/temodal | access-date=7 May 2020 | archive-date=22 October 2020 | archive-url=https://web.archive.org/web/20201022204633/https://www.ema.europa.eu/en/medicines/human/EPAR/temodal | url-status=live }} Text was copied from this source which is © European Medicines Agency. Reproduction is authorized provided the source is acknowledged.</ref> It is taken by mouth or via intravenous infusion.<ref name="Temodar FDA label" /><ref name="Temodal EPAR" />

The most common side effects with temozolomide are [[nausea]], [[vomiting]], [[constipation]], [[loss of appetite]], [[alopecia]] (hair loss), [[headache]], [[fatigue]], [[convulsion]]s (seizures), [[rash]], [[neutropenia]] or [[lymphopenia]] (low white-blood-cell counts), and [[thrombocytopenia]] (low blood platelet counts).<ref name="Temodal EPAR" /> People receiving the solution for infusion may also have injection-site reactions, such as pain, irritation, itching, warmth, swelling and redness, as well as bruising.<ref name="Temodal EPAR" />

Temozolomide is an [[alkylating antineoplastic agent|alkylating agent]] used to treat serious brain cancers; most commonly as second-line treatments for [[astrocytoma]] and as the first-line treatment for glioblastoma.<ref name="Temodar FDA label"/><ref name=NICE>{{cite web | url=https://www.nice.org.uk/guidance/ta23/resources/guidance-on-the-use-of-temozolomide-for-the-treatment-of-recurrent-malignant-glioma-brain-cancer-pdf-2294454507973 | format=PDF | title=Guidance on the use of temozolomide for the treatment of recurrent malignant glioma (brain cancer) | date=3 March 2016 | access-date=7 May 2020 | archive-date=11 July 2021 | archive-url=https://web.archive.org/web/20210711144230/https://www.nice.org.uk/guidance/ta23/resources/guidance-on-the-use-of-temozolomide-for-the-treatment-of-recurrent-malignant-glioma-brain-cancer-pdf-2294454507973 | url-status=live }}</ref><ref>{{cite journal | vauthors = Sasmita AO, Wong YP, Ling AP | title = Biomarkers and therapeutic advances in glioblastoma multiforme | journal = Asia-Pacific Journal of Clinical Oncology | volume = 14 | issue = 1 | pages = 40–51 | date = February 2018 | pmid = 28840962 | doi = 10.1111/ajco.12756 | doi-access = free }}</ref> [[Olaparib]] in combination with temozolomide demonstrated substantial clinical activity in relapsed [[small cell lung cancer]].<ref>{{cite journal | vauthors = Farago AF, Yeap BY, Stanzione M, Hung YP, Heist RS, Marcoux JP, Zhong J, Rangachari D, Barbie DA, Phat S, Myers DT, Morris R, Kem M, Dubash TD, Kennedy EA, Digumarthy SR, Sequist LV, Hata AN, Maheswaran S, Haber DA, Lawrence MS, Shaw AT, Mino-Kenudson M, Dyson NJ, Drapkin BJ | title = Combination Olaparib and Temozolomide in Relapsed Small-Cell Lung Cancer | journal = Cancer Discovery | volume = 9 | issue = 10 | pages = 1372–1387 | date = October 2019 | pmid = 31416802 | pmc = 7319046 | doi = 10.1158/2159-8290.CD-19-0582 | doi-access = free }}</ref> It is available as a [[generic medication]].

==Medical uses==

In the United States, temozolomide is [[indicated]] for the treatment of adults with newly diagnosed glioblastoma concomitantly with radiotherapy and subsequently as monotherapy treatment;<ref name="Temodar FDA label" /><ref name="FDA temozolomide 20230914" /> or adults with newly diagnosed or refractory anaplastic astrocytoma.<ref name="Temodar FDA label" /><ref name="FDA temozolomide 20230914">{{cite web | title=FDA approves new and updated indications for temozolomide under Projec | website=U.S. Food and Drug Administration | date=14 September 2023 | url=https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-new-and-updated-indications-temozolomide-under-project-renewal | access-date=14 September 2023 | archive-date=15 September 2023 | archive-url=https://web.archive.org/web/20230915015751/https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-new-and-updated-indications-temozolomide-under-project-renewal | url-status=live }}</ref>

In the European Union, temozolomide is indicated for adults with newly diagnosed glioblastoma multiforme concomitantly with radiotherapy and subsequently as monotherapy treatment;<ref name="Temodal EPAR" /><ref name=NICE/> or children from the age of three years, adolescents and adults with malignant glioma, such as glioblastoma multiforme or anaplastic astrocytoma, showing recurrence or progression after standard therapy.<ref name="Temodal EPAR" /><ref name=NICE/>

Temozolomide is also used to treat aggressive pituitary tumors and pituitary cancer.<ref>{{cite journal | vauthors = Raverot G, Burman P, McCormack A, Heaney A, Petersenn S, Popovic V, Trouillas J, Dekkers OM | title = European Society of Endocrinology Clinical Practice Guidelines for the management of aggressive pituitary tumours and carcinomas | journal = European Journal of Endocrinology | volume = 178 | issue = 1 | pages = G1–G24 | date = January 2018 | pmid = 29046323 | doi = 10.1530/EJE-17-0796 | doi-access = free | title-link = doi }}</ref>

==Contraindications==

Temozolomide is contraindicated in people with hypersensitivity to it or to the similar drug [[dacarbazine]].<ref name="AC" />

==Adverse effects==

The most common side effects include nausea (feeling sick), vomiting, constipation, loss of appetite, alopecia (hair loss), headache, fatigue (tiredness), convulsions (fits), rash, neutropenia or lymphopenia (low white-blood-cell counts), and thrombocytopenia (low blood platelet counts).<ref name="Temodal EPAR" /> People receiving the solution for infusion may also have injection-site reactions, such as pain, irritation, itching, warmth, swelling and redness, as well as bruising.<ref name="Temodal EPAR" />

== Interactions ==

Combining temozolomide with other myelosuppressants may increase the risk of myelosuppression.<ref name="AC" />

==Pharmacology==

===Mechanism of action===

The therapeutic benefit of temozolomide depends on its ability to [[Alkylation|alkylate]]/[[methylate]] DNA, which most often occurs at the N-7 or O-6 positions of [[guanine]] residues.<ref>{{cite journal | vauthors = Fu D, Calvo JA, Samson LD | title = Balancing repair and tolerance of DNA damage caused by alkylating agents | journal = Nature Reviews. Cancer | volume = 12 | issue = 2 | pages = 104–120 | date = January 2012 | pmid = 22237395 | doi = 10.1038/nrc3185 | pmc = 3586545 }}</ref>{{medcn|date=August 2023}} This methylation damages the DNA and triggers the death of tumor cells.<ref>{{cite journal | vauthors = Li Z, Pearlman AH, Hsieh P | title = DNA mismatch repair and the DNA damage response | journal = DNA Repair | volume = 38 | pages = 94–101 | date = February 2016 | pmid = 26704428 | pmc = 4740233 | doi = 10.1016/j.dnarep.2015.11.019 }}</ref>{{medcn|date=August 2023}} 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 ''O''⁶-alkylguanine DNA alkyltransferase (AGT) encoded in humans by the [[O-6-methylguanine-DNA methyltransferase|''O''-6-methylguanine-DNA methyltransferase]] (''MGMT'') gene.<ref>{{cite journal | vauthors = Jacinto FV, Esteller M | title = MGMT hypermethylation: a prognostic foe, a predictive friend | journal = DNA Repair | volume = 6 | issue = 8 | pages = 1155–1160 | date = August 2007 | pmid = 17482895 | doi = 10.1016/j.dnarep.2007.03.013 }}</ref> 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.<ref>{{cite journal | vauthors = 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 | title = MGMT gene silencing and benefit from temozolomide in glioblastoma | journal = The New England Journal of Medicine | volume = 352 | issue = 10 | pages = 997–1003 | date = March 2005 | pmid = 15758010 | doi = 10.1056/NEJMoa043331 | url = https://serval.unil.ch/notice/serval:BIB_59DF1F31757A | access-date = 9 April 2022 | url-status = live | doi-access = free | archive-url = https://web.archive.org/web/20190426152646/https://serval.unil.ch/notice/serval:BIB_59DF1F31757A | archive-date = 26 April 2019 }}</ref> Conversely, the presence of AGT protein in brain tumors predicts poor response to temozolomide and these patients receive little benefit from chemotherapy with temozolomide.<ref>{{cite journal | vauthors = Stupp R, Hegi ME, Mason WP, van den Bent MJ, Taphoorn MJ, Janzer RC, Ludwin SK, Allgeier A, Fisher B, Belanger K, Hau P, Brandes AA, Gijtenbeek J, Marosi C, Vecht CJ, Mokhtari K, Wesseling P, Villa S, Eisenhauer E, Gorlia T, Weller M, Lacombe D, Cairncross JG, Mirimanoff RO | title = 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 | journal = The Lancet. Oncology | volume = 10 | issue = 5 | pages = 459–466 | date = May 2009 | pmid = 19269895 | doi = 10.1016/S1470-2045(09)70025-7 | s2cid = 25150249 }}</ref>

===Pharmacokinetics===

Temozolomide is quickly and almost completely absorbed from the gut, and readily penetrates the [[blood–brain barrier]]; the concentration in the [[cerebrospinal fluid]] is 30% of the concentration in the [[blood plasma]].{{medcn|date=August 2023}} Intake with food decreases maximal plasma concentrations by 33% and the [[area under the curve (pharmacokinetics)|area under the curve]] by 9%.{{medcn|date=August 2023}} Only 15% (10–20%) of the substance are bound to blood plasma proteins.{{medcn|date=August 2023}} Temozolomide is a [[prodrug]]; it is spontaneously [[hydrolyze]]d at physiological [[pH]] to 3-methyl-(triazen-1-yl)imidazole-4-carboxamide (MTIC), which further splits into [[monomethylhydrazine]], likely the active methylating agent, and 5-aminoimidazole-4-carboxamide (AIC).{{medcn|date=August 2023}} Other metabolites include temozolomide acid and unidentified [[hydrophilic]] substances.<ref name="AC">{{cite book|title=Austria-Codex|at=Temodal 5 mg-Hartkapseln|publisher=Österreichischer Apothekerverlag|location=Vienna|year=2018|language=de}}</ref>

[[Plasma half-life]] is 1.8 hours.{{medcn|date=August 2023}} The substance and its metabolites are mainly excreted via the urine.<ref name="AC" />

<gallery>

File:MTIC skeletal.svg|MTIC, the [[active metabolite]]

File:5-aminoimidazole-4-carboxamide.svg|AIC (part of the naturally occurring [[AICA ribonucleotide]])

File:Dacarbazine.svg|The related drug [[dacarbazine]]<ref name=Sansom/> for comparison

</gallery>

==Chemical properties==

Temozolomide is an imidazotetrazine derivative.<ref name=Sansom/> It is slightly soluble in water and aqueous acids,<ref>{{cite web|url=https://www.ema.europa.eu/documents/scientific-discussion/temodal-epar-scientific-discussion_en.pdf|publisher=[[European Medicines Agency]]|title=Temodal: EPAR – Scientific Discussion|date=13 December 2005|access-date=25 April 2019|archive-date=29 August 2021|archive-url=https://web.archive.org/web/20210829080310/https://www.ema.europa.eu/en/documents/scientific-discussion/temodal-epar-scientific-discussion_en.pdf|url-status=live}}</ref> and decomposes at {{convert|212|°C|°F}}.<ref>{{cite book|title=Arzneistoff-Profile|editor=Dinnendahl, V |editor2=Fricke, U|publisher=Govi Pharmazeutischer Verlag|location=Eschborn, Germany|year=2016|edition=29|volume=9|isbn=978-3-7741-9846-3|language=de}}</ref> It was recently discovered that temozolomide is an explosive, tentatively assigned as [[HAZMAT Class 1 Explosives|UN Class 1]].<ref>{{cite journal | doi = 10.1021/acs.oprd.1c00206 | title = Importance of Thermal Stability Data to Avoid Dangerous Reagents: Temozolomide Case Study | year = 2021 | vauthors =Sperry JB, Stone S, Azuma M, Barrett C | journal = Organic Process Research & Development | volume = 25 | issue = 7 | pages = 1690–1700 | s2cid = 237644612 }}</ref><ref>{{cite journal | title = Temozolomide Is Explosive | vauthors = Lowe D | author-link1 = Derek Lowe (chemist) | type = Blog | journal = Science | date = 12 July 2021 | url = https://www.science.org/content/blog-post/temozolomide-explosive | access-date = 30 June 2022 | archive-date = 4 June 2022 | archive-url = https://web.archive.org/web/20220604072737/https://www.science.org/content/blog-post/temozolomide-explosive | url-status = live }}</ref>

Temozolomide has also been reported to be a comparatively safe and stable ''in situ'' source of [[diazomethane]] in organic synthesis.{{cn|date=August 2023}} In particular, use as a [[methylation|methylating]] and [[cyclopropanation|cyclopropanating]] reagent has been demonstrated.<ref>{{cite journal | vauthors = Svec RL, Hergenrother PJ | title = Imidazotetrazines as Weighable Diazomethane Surrogates for Esterifications and Cyclopropanations | journal = Angewandte Chemie | volume = 59 | issue = 5 | pages = 1857–1862 | date = January 2020 | pmid = 31793158 | pmc = 6982548 | doi = 10.1002/anie.201911896 }}</ref>

==History==

The agent was discovered at [[Aston University]] in [[Birmingham|Birmingham, England]]. Its preclinical activity was reported in 1987.<ref name=Sansom>{{cite journal | vauthors = Sansom C | journal = Chemistry World | date = July 2009 | pages = 48–51 | url = http://www.rsc.org/images/TEMOZOLOMIDE_ChemistryWorldJul09_tcm18-155909.pdf | title = Temozolomide – birth of a blockbuster | access-date = 28 June 2015 | archive-date = 22 October 2020 | archive-url = https://web.archive.org/web/20201022123445/https://www.rsc.org/images/TEMOZOLOMIDE_ChemistryWorldJul09_tcm18-155909.pdf | url-status = live }}</ref><ref>{{cite web | archive-url = https://web.archive.org/web/20120314043035/http://info.cancerresearchuk.org/cancerandresearch/progress/cancer_drugs/drug_discovery/temozolomide/ | archive-date = 14 March 2012 | url-status = dead | url = http://info.cancerresearchuk.org/cancerandresearch/progress/cancer_drugs/drug_discovery/temozolomide/ | title = Malcolm Steven – interview | work = Cancer Research UK impact & achievements page| date = 22 August 2013 }}</ref><ref name="pmid9189180">{{cite journal | vauthors = Newlands ES, Stevens MF, Wedge SR, Wheelhouse RT, Brock C | title = Temozolomide: a review of its discovery, chemical properties, pre-clinical development and clinical trials | journal = Cancer Treatment Reviews | volume = 23 | issue = 1 | pages = 35–61 | date = January 1997 | pmid = 9189180 | doi = 10.1016/S0305-7372(97)90019-0 }}</ref>

It was approved for medical use in the European Union in January 1999,<ref name="Temodal EPAR" /> and in the United States in August 1999.<ref>{{cite web | title=Drug Approval Package: Temodar (Temozolomide) NDA# 021029 | website=U.S. [[Food and Drug Administration]] (FDA) | date=30 March 2001 | url=https://www.accessdata.fda.gov/drugsatfda_docs/nda/99/21029_Temodar.cfm | access-date=7 May 2020 | archive-date=31 March 2021 | archive-url=https://web.archive.org/web/20210331053748/https://www.accessdata.fda.gov/drugsatfda_docs/nda/99/21029_Temodar.cfm | url-status=live }}</ref> The intravenous formulation was approved in the United States in February 2009.<ref>{{cite web | title=Drug Approval Package: Temodar NDA #022277 | website=U.S. [[Food and Drug Administration]] (FDA) | date=24 November 2009 | url=https://www.accessdata.fda.gov/drugsatfda_docs/nda/2009/022277_temodar_toc.cfm | access-date=7 May 2020 | archive-date=28 March 2021 | archive-url=https://web.archive.org/web/20210328234511/https://www.accessdata.fda.gov/drugsatfda_docs/nda/2009/022277_temodar_toc.cfm | url-status=live }}</ref>

==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.<ref>{{cite journal | vauthors = Gilbert MR | title = New treatments for malignant gliomas: careful evaluation and cautious optimism required | journal = Annals of Internal Medicine | volume = 144 | issue = 5 | pages = 371–373 | date = March 2006 | pmid = 16520480 | doi = 10.7326/0003-4819-144-5-200603070-00015 | s2cid = 21181702 }}</ref> Laboratory studies found that temozolomide killed brain tumor cells more efficiently when [[epigallocatechin gallate]] ([[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.<ref>{{cite journal | vauthors = 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 Research | volume = 67 | issue = 20 | pages = 9809–9816 | date = October 2007 | pmid = 17942911 | doi = 10.1158/0008-5472.CAN-07-0625 }}</ref> 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<ref>{{cite journal | vauthors = Sheehan J, Cifarelli CP, Dassoulas K, Olson C, Rainey J, Han S | title = Trans-sodium crocetinate enhancing survival and glioma response on magnetic resonance imaging to radiation and temozolomide | journal = Journal of Neurosurgery | volume = 113 | issue = 2 | pages = 234–239 | date = August 2010 | pmid = 20001586 | doi = 10.3171/2009.11.JNS091314 | doi-access = free }}</ref> and a clinical trial was underway {{as of | 2015 | August | lc = on}}.<ref>{{cite web | url = http://clinicaltrials.gov/ct2/show/NCT01465347?term=tsc&rank=4 | publisher = [[ClinicalTrials.gov]] | date = November 2011 | title = Safety and Efficacy Study of Trans Sodium Crocetinate (TSC) With Concomitant Radiation Therapy and Temozolomide in Newly Diagnosed Glioblastoma (GBM) | access-date = 1 February 2016 | archive-date = 21 October 2014 | archive-url = https://web.archive.org/web/20141021075402/http://clinicaltrials.gov/ct2/show/NCT01465347?term=tsc&rank=4 | url-status = live }}</ref>

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,<ref>{{cite journal | vauthors = Da Fonseca CO, Teixeira RM, Silva JC, Fischer JD, Meirelles OC, Landeiro JA, Quirico-Santos T | title = Long-term outcome in patients with recurrent malignant glioma treated with Perillyl alcohol inhalation | journal = Anticancer Research | volume = 33 | issue = 12 | pages = 5625–5631 | date = December 2013 | pmid = 24324108 }}</ref> 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 | lc = on}}, NEO212 has not been tested in humans, it has shown superior cancer therapeutic activity in animal models of [[glioma]],<ref>{{cite journal | vauthors = Cho HY, Wang W, Jhaveri N, Lee DJ, Sharma N, Dubeau L, Schönthal AH, Hofman FM, Chen TC | title = NEO212, temozolomide conjugated to perillyl alcohol, is a novel drug for effective treatment of a broad range of temozolomide-resistant gliomas | journal = Molecular Cancer Therapeutics | volume = 13 | issue = 8 | pages = 2004–2017 | date = August 2014 | pmid = 24994771 | doi = 10.1158/1535-7163.mct-13-0964 | doi-access = free }}</ref> [[melanoma]],<ref>{{cite journal | vauthors = Chen TC, Cho HY, Wang W, Nguyen J, Jhaveri N, Rosenstein-Sisson R, Hofman FM, Schönthal AH | title = A novel temozolomide analog, NEO212, with enhanced activity against MGMT-positive melanoma in vitro and in vivo | journal = Cancer Letters | volume = 358 | issue = 2 | pages = 144–151 | date = March 2015 | pmid = 25524552 | doi = 10.1016/j.canlet.2014.12.021 }}</ref> and [[brain metastasis]] of [[triple-negative breast cancer]].<ref>{{cite journal | vauthors = Chen TC, Cho HY, Wang W, Barath M, Sharma N, Hofman FM, Schönthal AH | title = A novel temozolomide-perillyl alcohol conjugate exhibits superior activity against breast cancer cells in vitro and intracranial triple-negative tumor growth in vivo | journal = Molecular Cancer Therapeutics | volume = 13 | issue = 5 | pages = 1181–1193 | date = May 2014 | pmid = 24623736 | doi = 10.1158/1535-7163.mct-13-0882 | doi-access = free }}</ref>

Because tumor cells that express the [[O-6-methylguanine-DNA methyltransferase]] (MGMT) gene are more resistant to the effects of temozolomide, researchers investigated whether the inclusion of [[O6-benzylguanine|''O''⁶-benzylguanine]] (''O''⁶-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]].<ref>{{cite journal | vauthors = Ueno T, Ko SH, Grubbs E, Yoshimoto Y, Augustine C, Abdel-Wahab Z, Cheng TY, Abdel-Wahab OI, Pruitt SK, Friedman HS, Tyler DS | 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 = Molecular Cancer Therapeutics | volume = 5 | issue = 3 | pages = 732–738 | date = March 2006 | pmid = 16546988 | doi = 10.1158/1535-7163.MCT-05-0098 | s2cid = 14455128 }}</ref> However, a recently{{Clarify timeframe|date=November 2018}} completed phase-II clinical trial with brain-tumor patients yielded mixed outcomes; while there was some improved therapeutic activity when ''O''⁶-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]].<ref>{{cite journal | vauthors = Quinn JA, Jiang SX, Reardon DA, Desjardins A, Vredenburgh JJ, Rich JN, Gururangan S, Friedman AH, Bigner DD, Sampson JH, McLendon RE, Herndon JE, Walker A, Friedman HS | title = Phase II trial of temozolomide plus o6-benzylguanine in adults with recurrent, temozolomide-resistant malignant glioma | journal = Journal of Clinical Oncology | volume = 27 | issue = 8 | pages = 1262–1267 | date = March 2009 | pmid = 19204199 | pmc = 2667825 | doi = 10.1200/JCO.2008.18.8417 }}</ref>

Some efforts focus on engineering [[hematopoietic stem cell]]s 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 [[Haematopoiesis|hematopoietic]] cells would be resistant to the drug.<ref>{{cite web | url = https://www.fredhutch.org/en/news/center-news/2011/05/marrow-cells-chemotherapy.html | title = Investigative Engineered Bone Marrow Cell Therapy | publisher = Fred Hutchinson Cancer Research Center | date = 23 May 2011 | access-date = 27 June 2018 | archive-date = 29 November 2020 | archive-url = https://web.archive.org/web/20201129173222/https://www.fredhutch.org/en/news/center-news/2011/05/marrow-cells-chemotherapy.html | url-status = live }}</ref>

High doses of temozolomide in high-grade gliomas have low toxicity, but the results are comparable to the standard doses.<ref>{{cite journal | vauthors = Dall'oglio S, D'Amico A, Pioli F, Gabbani M, Pasini F, Passarin MG, Talacchi A, Turazzi S, Maluta S | title = Dose-intensity temozolomide after concurrent chemoradiotherapy in operated high-grade gliomas | journal = Journal of Neuro-Oncology | volume = 90 | issue = 3 | pages = 315–319 | date = December 2008 | pmid = 18688571 | doi = 10.1007/s11060-008-9663-9 | s2cid = 21517366 }}</ref>

Two mechanisms of resistance to temozolomide effects have now been described: 1) intrinsic resistance conferred by MGMT deficiency (MGMTd) and 2) intrinsic or acquired resistance through MMR deficiency (MMRd). The MGMT enzyme is the first line of repair of mismatched bases created by temozolomide. Cells are normally MGMT proficient (MGMTp) as they have an unmethylated MGMT promoter allowing the gene to be expressed normally. In this state, temozolomide induced DNA damage is able to be efficiently repaired in tumor cells (and normal cells) by the active MGMT enzyme. Cells may grow and pass through the cell cycle normally without arrest or death. However, some tumors cells are MGMT deficient (MGMTd). This is most commonly due to abnormal methylation of the MGMT gene promoter and suppression of gene expression. MGMTd has also been described to occur by promoter rearrangement. In cells with MGMTd, DNA damage by temozolomide activates the next stage of repair in cells with a proficient Mismatch Repair enzyme complex (MMRp). In MMRp the MMR protein complex identifies the damage and causes cells to arrest and undergo death which inhibits tumor growth. However, if cells have combined MGMTd and MMR deficiency (MGMTd + MMRd) then cells retain the induced mutations and continue to cycle and are resistant to effects of temozolomide.{{medcn|date=August 2023}}

In gliomas and other cancers MMRd has now been reported to occur as primary MMRd (intrinsic or germline Lynch bMMRd) or as secondary MMRd (acquired - not present in the original untreated tumor). The latter occurs after effective treatment and cytoreduction of tumors with temozolomide and then selection or induction of mutant MSH6, MSH2, MLH1, or PMS2 proteins and cells which are MMRd and temozolomide resistant. The latter is described as an acquired resistance pathway with hotspot mutations in glioma patients (MSH6 p.T1219I).<ref>{{cite journal | vauthors = Touat M, Li YY, Boynton AN, Spurr LF, Iorgulescu JB, Bohrson CL, Cortes-Ciriano I, Birzu C, Geduldig JE, Pelton K, Lim-Fat MJ, Pal S, Ferrer-Luna R, Ramkissoon SH, Dubois F, Bellamy C, Currimjee N, Bonardi J, Qian K, Ho P, Malinowski S, Taquet L, Jones RE, Shetty A, Chow KH, Sharaf R, Pavlick D, Albacker LA, Younan N, Baldini C, Verreault M, Giry M, Guillerm E, Ammari S, Beuvon F, Mokhtari K, Alentorn A, Dehais C, Houillier C, Laigle-Donadey F, Psimaras D, Lee EQ, Nayak L, McFaline-Figueroa JR, Carpentier A, Cornu P, Capelle L, Mathon B, Barnholtz-Sloan JS, Chakravarti A, Bi WL, Chiocca EA, Fehnel KP, Alexandrescu S, Chi SN, Haas-Kogan D, Batchelor TT, Frampton GM, Alexander BM, Huang RY, Ligon AH, Coulet F, Delattre JY, Hoang-Xuan K, Meredith DM, Santagata S, Duval A, Sanson M, Cherniack AD, Wen PY, Reardon DA, Marabelle A, Park PJ, Idbaih A, Beroukhim R, Bandopadhayay P, Bielle F, Ligon KL | title = Mechanisms and therapeutic implications of hypermutation in gliomas | journal = Nature | volume = 580 | issue = 7804 | pages = 517–523 | date = April 2020 | pmid = 32322066 | pmc = 8235024 | doi = 10.1038/s41586-020-2209-9 | bibcode = 2020Natur.580..517T }}</ref>

== References ==

{{Reflist}}

== Further reading ==

{{refbegin}}

* {{cite journal | vauthors = Kaloshi G, Benouaich-Amiel A, Diakite F, Taillibert S, Lejeune J, Laigle-Donadey F, Renard MA, Iraqi W, Idbaih A, Paris S, Capelle L, Duffau H, Cornu P, Simon JM, Mokhtari K, Polivka M, Omuro A, Carpentier A, Sanson M, Delattre JY, Hoang-Xuan K | title = Temozolomide for low-grade gliomas: predictive impact of 1p/19q loss on response and outcome | journal = Neurology | volume = 68 | issue = 21 | pages = 1831–1836 | date = May 2007 | pmid = 17515545 | doi = 10.1212/01.wnl.0000262034.26310.a2 | doi-access = free }}

{{refend}}

== External links ==

* {{cite web | title=Temozolomide (Temodal) | website=Cancer Research UK | url=https://about-cancer.cancerresearchuk.org/about-cancer/cancer-in-general/treatment/cancer-drugs/drugs/temozolomide }}

* {{cite web | title=Temozolomide | work=NCI Dictionary of Cancer Terms | publisher=National Cancer Institute | url=https://www.cancer.gov/publications/dictionaries/cancer-terms/def/temozolomide }}

* {{cite web | title=Temozolomide | website=National Cancer Institute | date=5 October 2006 | url=https://www.cancer.gov/about-cancer/treatment/drugs/temozolomide }}

{{Schering-Plough|state=autocollapse}}

{{Chemotherapeutic agents}}

{{Portal bar | Medicine}}

[[Category:Cancer treatments]]

[[Category:Carboxamides]]

[[Category:DNA replication inhibitors]]

[[Category:Fetotoxicants]]

[[Category:Imidazotetrazines]]

[[Category:Lactams]]

[[Category:Drugs developed by Merck & Co.]]

[[Category:Prodrugs]]

[[Category:Drugs developed by Schering-Plough]]

[[Category:Teratogens]]

[[Category:Explosive chemicals]]

[[Category:Alkylating antineoplastic agents]]

[[Category:Methylating agents]]