{"id":4404742,"date":"2022-01-05T02:42:00","date_gmt":"2022-01-05T07:42:00","guid":{"rendered":"https:\/\/myendoconsult.com\/learn\/?p=4404742"},"modified":"2023-03-16T06:02:18","modified_gmt":"2023-03-16T11:02:18","slug":"mechanism-of-action-of-temozolamide","status":"publish","type":"post","link":"https:\/\/myendoconsult.com\/learn\/mechanism-of-action-of-temozolamide\/","title":{"rendered":"Mechanism of Action of Temozolamide"},"content":{"rendered":"

\u00a0<\/strong>The mechanism of action of temozolomide and its clinical application in the management of\u00a0prolactinomas<\/a> <\/strong>will be reviewed.<\/p>\n

Physiology<\/h2>\n

Cellular protective mechanisms from mutagens :\u00a0<\/strong>Endogenous and exogenous factors can promote DNA damage and inadvertently set off a cascade of events that leads to the formation of tumors. Cells in normal physiology maintain their integrity through a myriad of protective pathways such as mismatch repair<\/strong>, nucleotide excision repair,<\/strong> and methylguanine-DNA methyltransferase<\/strong> (MGMT) enzymatic processes(1).<\/p>\n

Mechanism of action<\/h2>\n

Temozolomide (TMZ) is an alkylating chemotherapeutic agent that promotes the methylation of specific guanine (position O-6) and purine (positions N3 and N7) residues in DNA. This introduces breaks in the DNA of rapidly growing cells, like lactotroph tumors, leading to their apoptosis (programmed cell death)(2).<\/p>\n

\"\"<\/p>\n

Fig. 1.0 Schematic representation of the mechanism of action of temozolomide. <\/strong><\/p>\n

TMZ promotes the methylation of guanine(G) at the number 6 carbon position, a step that leads to the formation of methylguanine residues in DNA. There is a “suicide enzyme” called methylguanine-DNA methyltransferase (MGMT), whose primary role is to remove these abnormal methyl groups, thus restoring the integrity of guanine residues in DNA (Step A).<\/em> This defective methylated guanine pairs with thymine (T) instead of cytosine (C) (by convention) during replication. Mismatch repair enzymes excise these mispaired guanine-thymine<\/strong> residues, although this ultimately is an exercise in futility. Continuous cycles of erroneous G and T pairing and T excisions lead to irreparable DNA breaks that promote cell death (step B)<\/em> (2). Redrawn and modified from Zhang J et al. (2012) Temozolomide: mechanisms of action, repair, and resistance. Curr Mol Pharmacol 5:102\u2013114<\/em><\/p>\n

Practice Guide<\/h2>\n
    \n
  • An assessment of MGMT promoter methylation status<\/em> is a useful predictive biomarker<\/em>(3) in patients with aggressive prolactinomas or carcinomas(4). There is an inverse relationship between tumor levels of MGMT and the degree of responsiveness to temozolomide(4). Although MGMT as a biomarker is a novel approach to predicting response to TMZ, therapeutic response after a minimum of 3 cycles of treatment fared better than tumor levels of MGMT in a large cohort of patients with pituitary tumors (including prolactinomas)(5).<\/li>\n
  • TMZ being a chemotherapeutic agent is associated with expected short-term toxicity concerns such as nausea, emesis, and fatigue(6). Cytopenias (hematologic toxicity), requiring dose reduction or cessation of therapy, are however infrequent(5,6). Safety data after 5 to 8 years of exposure to TMZ is very reassuring, making it a valuable long-term salvage therapeutic option(7).<\/li>\n<\/ul>\n

    Clinical Trial Evidence<\/h2>\n

    There are no published randomized trials evaluating the safety and efficacy of temozolomide compared to placebo. A recent systematic review of all published case reports and case series provided some meaningful insight into the response of dopaminergic agonist-resistant prolactinomas to temozolomide(6).<\/p>\n

    \n

    Key Message<\/strong>Temozolomide has a favorable side effect profile and is a reasonable rescue therapeutic option in patients who have exhibited a suboptimal response to DAs, radiation therapy, or surgery. Approximately 75% of patients with treatment resistant prolactinomas achieved a reduction in tumor volume and serum prolactin levels after a trial of temozolomide.<\/p>\n<\/blockquote>\n

    This was a meta-analysis of case series and reports evaluating tumoral response to temozolomide in 42 subjects with either a prolactin-secreting adenoma or carcinoma. Patients with resistance to dopaminergic agonist therapy received oral temozolomide dosed as 150-200mg\/m2<\/sup> in 1 to 24 therapeutic cycles. The primary outcome was defined as a change in tumor size and improvement in hyperprolactinemia. A significant reduction in tumor size and prolactin levels, compared to baseline, occurred in 76.5% and 75% of patients, respectively(6).<\/p>\n

    References<\/h2>\n
      \n
    1. Sharma S, Salehi F, Scheithauer BW, Rotondo F, Syro LV, Kovacs K. Role of MGMT in Tumor Development, Progression, Diagnosis, Treatment and Prognosis. Anticancer Res. 2009 Oct 1;29(10):3759\u201368.<\/li>\n
    2. Zhang J, Stevens MFG, Bradshaw TD. Temozolomide: mechanisms of action, repair and resistance. Curr Mol Pharmacol. 2012 Jan;5(1):102\u201314.<\/li>\n
    3. Cankovic M, Nikiforova MN, Snuderl M, Adesina AM, Lindeman N, Wen PY, et al. The Role of MGMT Testing in Clinical Practice: A Report of the Association for Molecular Pathology. J Mol Diagn. 2013 Sep 1;15(5):539\u201355.<\/li>\n
    4. Whitelaw BC, Dworakowska D, Thomas NW, Barazi S, Riordan\u2010Eva P, King AP, et al. Temozolomide in the management of dopamine agonist\u2013resistant prolactinomas. Clin Endocrinol (Oxf). 2012;76(6):877\u201386.<\/li>\n
    5. Raverot G, Sturm N, de Fraipont F, Muller M, Salenave S, Caron P, et al. Temozolomide Treatment in Aggressive Pituitary Tumors and Pituitary Carcinomas: A French Multicenter Experience. J Clin Endocrinol Metab. 2010 Oct 1;95(10):4592\u20139.<\/li>\n
    6. Almalki MH, Aljoaib NN, Alotaibi MJ, Aldabas BS, Wahedi TS, Ahmad MM, et al. Temozolomide therapy for resistant prolactin-secreting pituitary adenomas and carcinomas: a systematic review. Horm Athens Greece. 2017 Apr;16(2):139\u201349.<\/li>\n
    7. Khasraw M, Bell D, Wheeler H. Long-term use of temozolomide: Could you use temozolomide safely for life in gliomas? J Clin Neurosci. 2009 Jun 1;16(6):854\u20135.<\/li>\n<\/ol>\n","protected":false},"excerpt":{"rendered":"

      \u00a0The mechanism of action of temozolomide and its clinical application in the management of\u00a0prolactinomas will be reviewed. Physiology Cellular protective mechanisms from mutagens :\u00a0Endogenous and exogenous factors can promote DNA damage and inadvertently set off a cascade of events that leads to the formation of tumors. Cells in normal physiology maintain their integrity through a […]<\/p>\n","protected":false},"author":1,"featured_media":4404421,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[245],"tags":[],"class_list":["post-4404742","post","type-post","status-publish","format-standard","has-post-thumbnail","hentry","category-moa-prolactinoma","post-wrapper","thrv_wrapper"],"_links":{"self":[{"href":"https:\/\/myendoconsult.com\/learn\/wp-json\/wp\/v2\/posts\/4404742","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/myendoconsult.com\/learn\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/myendoconsult.com\/learn\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/myendoconsult.com\/learn\/wp-json\/wp\/v2\/users\/1"}],"replies":[{"embeddable":true,"href":"https:\/\/myendoconsult.com\/learn\/wp-json\/wp\/v2\/comments?post=4404742"}],"version-history":[{"count":18,"href":"https:\/\/myendoconsult.com\/learn\/wp-json\/wp\/v2\/posts\/4404742\/revisions"}],"predecessor-version":[{"id":4415993,"href":"https:\/\/myendoconsult.com\/learn\/wp-json\/wp\/v2\/posts\/4404742\/revisions\/4415993"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/myendoconsult.com\/learn\/wp-json\/wp\/v2\/media\/4404421"}],"wp:attachment":[{"href":"https:\/\/myendoconsult.com\/learn\/wp-json\/wp\/v2\/media?parent=4404742"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/myendoconsult.com\/learn\/wp-json\/wp\/v2\/categories?post=4404742"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/myendoconsult.com\/learn\/wp-json\/wp\/v2\/tags?post=4404742"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}