Description
Temozolomide (CAS: 85622-93-1) was launched for the first time in the UK for the
treatment of patients with glioblastoma multiforme showing recurrence or
progression after standard therapy. It can be considered as a cyclic variant of
highly reactive triazenes producing a cascade of ionic or radical antitumoral
species. Temozolamide is a 3-methyl analog of mitozolomide and was shown to
be converted to cytotoxic triazene MCTIC. It can be prepared in 2 steps from 5-
aminoimidazole-4-carboxamide by diazotization then cyclization with
methylisocyanate. Mechanistically, the depletion of O6-alkylguanine-DNA
alkyltransferase (OGAT) in cells or tumors was shown to be correlated with the
cytotoxicity of temozolomide which is a potent inhibitor of this enzyme involved
in DNA repair activity.
Further approval applications for the treatment of other malignant gliomas such
as relapsed anaplastic astrocytoma, advanced metastatic melanoma were
submitted.
Chemical Properties
Off-white to light-pink crystalline solid, crystallized from dichloromethane, melting point 212℃ (decomposition). Maximum UV absorption (in 95% ethanol): 327nm.
Originator
CRC Technology (UK)
Uses
Temozolomide is an antineoplastic drug and an Imidazotetrazine alkylating agent. It induces apoptosis and causes cell cycle arrest at the G2/M checkpoint. It rapidly degrades in the body, producing the active metabolite MTIC, which exerts an anti-tumor effect. Moreover, temozolomide has shown effectiveness against paclitaxel-resistant tumors and has been utilized in the study of drug resistance mechanisms in glioblastoma cell lines.
Definition
ChEBI: An imidazotetrazine that is 3,4-dihydroimidazo[5,1-d][1,2,3,5]tetrazine which is substituted at positions 3, 4, and 8 by methyl, oxo, and carboxamide groups, respectively. A prodrug for MTIC (5-(3-methyltriaz-1-en-1-yl)-1H-i
idazole-4-carboxamide, formed by spontaneous hydrolysis of temozolomide in the body), it is used as an oral alkylating agent for the treatment of newly diagnosed malignant glioblastoma multiforme (concomitantly with radiotherapy) and malignant melanoma.
Preparation
The synthesis of temozolomide involves several steps. First, 5-Amino-4-imidazolecarboxamide is diazotized using nitrite. Then, the diazotized compound is reacted with methyl isocyanate in dichloromethane. This reaction leads to the cyclization of the compound, ultimately resulting in the formation of temozolomide.
Manufacturing Process
Reaction of 1H-imidazole-4-carboxilic acid amide with nitrous acid leads to the
diazonium salt (5-diazenyl-1-H-imidazole-4-carboxilic acid amide).
Condensation of the diazonium salt with methylisocyanate leads to initial
formation of unstable urea which cyclizes under the reaction condition to give
3,4-dihydro-3-methyl-4-oxoimidazo(5,1-d)-1,2,3,5-tetrazine-8-carboxamide
(temozolomide).
Brand name
Temodar (Schering);Temodal.
Therapeutic Function
Antineoplastic
General Description
Temozolomide can be called as an oral alkylating agent and antitumour drug, which may show potent activity in the treatment of recurrent gliomas or glioblastoma, a kind of tumour that affects the brain or spine.
Biological Activity
DNA methylating, chemotherapeutic agent. Displays antitumor activity against a board spectrum of tumors, including leukemias, lymphomas and solid tumors (IC 50 = 5.0 μ M for cytotoxicity against mouse TLX5 lymphoma cells).
Biochem/physiol Actions
Temozolomide is a DNA methylating agent and drug resistance-modifying agent; anti-tumor and anti-angiogenic. Temozolomide induces G2/M arrest and apoptosis through adduction of a methyl group to O6 position of guanine in genomic DNA and functional inactivation of DNA repair protein O(6)-alkylguanine DNA alkyltransferase (AGT) in base excision repair (BER) pathway.
Clinical Use
This imidazolotetrazine derivative is administered orally in capsule form for the treatment of glioblastoma multiforme or in patients with anaplastic astrocytoma who have not responded to procarbazine or the nitrosoureas.
Drug interactions
Potentially hazardous interactions with other drugs
Antipsychotics: avoid with clozapine, increased risk
of agranulocytosis.
Metabolism
Oral absorption is rapid and complete. The CYP450 enzymes are not extensively involved in temozolomide metabolism, and less than 6% of the drug is excreted unchanged in the urine. Women clear the drug less effectively than men and have a higher incidence of severe neutropenia and thrombocytopenia in the initial therapy cycle. Food decreases temozolomide absorption, and myelosuppression is the most significant adverse effect.
storage
Store at -20°C, protect from light, stored under nitrogen
References
1) Kurzen et al. (2003), Inhibition of angiogenesis by non-toxic doses of temozolomide; Anticancer Drugs, 14 515
2) Gunther et al. (2003), Temozolomide induces apoptosis and senescence in glioma cells cultured as multicellular spheroids; Br. J. Cancer, 88 463
3) Danson et al. (2001), Temozolomide: a novel oral alkylating agent; Curr. Opin. Expert Rev. Anticancer Ther., 10 13
4) Natsumeda et al. (2011), Induction of autophagy in temozolomide treated malignant gliomas; Neuropathology, 31 486
