User Tools

Site Tools


temozolomide

Temozolomide

The last major advance in glioblastoma multiforme treatment was the introduction of temozolomide in 1999.


Methylation of the gene's promoter may play a significant role in carcinogenesis. In patients with glioblastoma multiforme, the methylation state of the MGMT gene determined whether tumor cells would be responsive to temozolomide; if the promoter was methylated, temozolomide was more effective.


Treatment with temozolomide following surgical debulking extends survival rate compared to radiotherapy and debulking alone. However, virtually all glioblastoma patients experience disease progression within 7 to 10 months. Although many salvage treatments, including bevacizumab, rechallenge with temozolomide, and other alkylating agents, have been evaluated, none of these clearly improves survival 1).

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.

Indications

Glioblastoma

Concurrent treatment with temozolomide and radiotherapy followed by maintenance temozolomide is the standard of care for patients with newly diagnosed glioblastoma.

O6 methylguanine DNA methyltransferase (MGMT), which is frequently expressed in cancer stem cells of glioblastoma, has been implicated in their resistance to temozolomide, the first-line chemotherapeutic agent against newly diagnosed glioblastoma.

JNK contributes to temozolomide resistance of stem-like glioblastoma cells via regulation of MGMT expression 2).

Temozolomide induced autophagic, but not apoptotic processes, in U251 cells and thus reduced their viability and migration 3).

It has been suggested that neoadjuvant temozolomide may provide sufficient tumor shrinkage to facilitate aggressive surgical debulking.

Steroids are very commonly administered concurrently with temozolomide and radiotherapy after the initial surgical resection of glioblastoma (GBM) to control neurological morbidity. Although the potent anti-inflammatory effect of steroids is well documented to ameliorate vasogenic edema in these tumors, the deleterious effects of steroids on the efficacy of alkylating agents or radiotherapy have been a matter of debate 4) 5) 6) 7).

Low grade glioma

Resistance

TMZ is currently the only mono-chemotherapeutic agent for newly-diagnosed high grade glioma patients and acquired resistance inevitably occurs in the majority of such patients, further limiting treatment options. Therefore, there is an urgent need to better understand the underlying mechanisms involved in TMZ resistance, a critical step to developing effective, targeted treatments. An emerging body of evidence suggests the intimate involvement of a novel class of nucleic acid, microRNA (miRNA), in tumorigenesis and disease progression for a number of human malignancies, including primary brain tumours. miRNA are short, single-stranded, non-coding RNA (∼22 nucleotides) that function as post-transcriptional regulators of gene expression 8).

Temozolomide rechallenge

Temozolomide rechallenge is a treatment option for MGMT promoter-methylated recurrent glioblastoma. Alternative strategies need to be considered for patients with progressive glioblastoma without MGMT promoter methylation 9).

Temozolomide dosage

Temozolomide (TMZ) for malignant gliomas is traditionally dosed in 5 out of a 28-day cycle, however alternative regimens exist, including dose-dense. Continuous daily dosing is available, but the acceptable dose and duration of therapy is unknown.

Zhou et al. document a 40-year-old male with recurrent anaplastic astrocytoma, IDH mutant and MGMT promotor methylation negative, who has well-tolerated continuous daily TMZ for 20 months at 100 mg per day for nearly the length of this period. A trial at 80 mg per day demonstrated disease progression with response upon return to 100 mg per day. Prior to the daily TMZ, the patient underwent three surgical resections, radiation therapy with concurrent TMZ according to the EORTC NCIC protocol, and subsequently bevacizumab in combination with use of the Optune device. Long-term survival of patients with recurrent malignant gliomas is uncommon, and currently no standard treatment strategies exist for these patients. We present this case to demonstrate the tolerability and dose dependency of prolonged daily TMZ dosing as a therapeutic option for recurrent anaplastic astrocytomas 10).

1)
Sharpe MA, Livingston AD, Gist TL, Ghosh P, Han J, Baskin DS. Successful Treatment of Intracranial Glioblastoma Xenografts With a Monoamine Oxidase B-Activated Pro-Drug. EBioMedicine. 2015 Aug 8;2(9):1122-32. doi: 10.1016/j.ebiom.2015.08.013. PubMed PMID: 26501110; PubMed Central PMCID: PMC4588367.
2)
Okada M, Sato A, Shibuya K, Watanabe E, Seino S, Suzuki S, Seino M, Narita Y, Shibui S, Kayama T, Kitanaka C. JNK contributes to temozolomide resistance of stem-like glioblastoma cells via regulation of MGMT expression. Int J Oncol. 2014 Feb;44(2):591-9. doi: 10.3892/ijo.2013.2209. Epub 2013 Dec 5. PubMed PMID: 24316756.
3)
Shen W, Hu JA, Zheng JS. Mechanism of temozolomide-induced antitumour effects on glioma cells. J Int Med Res. 2014 Feb;42(1):164-72. doi: 10.1177/0300060513501753. Epub 2013 Dec 10. PubMed PMID: 24326954.
4)
Piette C, Munaut C, Foidart JM, Deprez M. Treating gliomas with glucocorticoids: from bedside to bench. Acta Neuropathol. 2006;112(6):651–664.
5)
Wang H, Li M, Rinehart JJ, Zhang R. Pretreatment with dexamethasone increases antitumor activity of carboplatin and gemcitabine in mice bearing human cancer xenografts: in vivo activity, pharmacokinetics, and clinical implications for cancer chemotherapy. Clin Cancer Res. 2004;10(5):1633–1644.
6)
Weller M, Schmidt C, Roth W, Dichgans J. Chemotherapy of human malignant glioma: prevention of efficacy by dexamethasone? Neurology. 1997;48(6):1704–1709.
7)
Shields LB, Shelton BJ, Shearer AJ, et al. Dexamethasone administration during definitive radiation and temozolomide renders a poor prognosis in a retrospective analysis of newly diagnosed glioblastoma patients. Radiat Oncol. 2015;10:222.
8)
Low SY, Ho YK, Too HP, Yap CT, Ng WH. MicroRNA as potential modulators in chemoresistant high-grade gliomas. J Clin Neurosci. 2013 Oct 6. pii: S0967-5868(13)00518-3. doi: 10.1016/j.jocn.2013.07.033. [Epub ahead of print] PubMed PMID: 24411131.
9)
Weller M, Tabatabai G, Kästner B, Felsberg J, Steinbach JP, Wick A, Schnell O, Hau P, Herrlinger U, Sabel MC, Wirsching HG, Ketter R, Bähr O, Platten M, Tonn JC, Schlegel U, Marosi C, Goldbrunner R, Stupp R, Homicsko K, Pichler J, Nikkhah G, Meixensberger J, Vajkoczy P, Kollias S, Hüsing J, Reifenberger G, Wick W; DIRECTOR Study Group. MGMT Promoter Methylation Is a Strong Prognostic Biomarker for Benefit from Dose-Intensified Temozolomide Rechallenge in Progressive Glioblastoma: The DIRECTOR Trial. Clin Cancer Res. 2015 May 1;21(9):2057-64. doi: 10.1158/1078-0432.CCR-14-2737. Epub 2015 Feb 5. PubMed PMID: 25655102.
10)
Zhou Z, Howard TA, Villano JL. Long-term daily temozolomide with dose-dependent efficacy in MGMT promotor methylation negative recurrent high-grade astrocytoma. Cancer Chemother Pharmacol. 2017 Aug 8. doi: 10.1007/s00280-017-3415-5. [Epub ahead of print] PubMed PMID: 28791452.
temozolomide.txt · Last modified: 2017/08/10 19:18 by administrador