Temozolomide
[CAS# 85622-93-1]

Identification

• Classification: API >> Antineoplastic agents >> Antimetabolite antineoplastic
• Name: Temozolomide
• Synonyms: 4-Methyl-5-oxo-2,3,4,6,8-pentazabicyclo[4.3.0]nona-2,7,9-triene-9-carboxamide
• Molecular Formula: C₆H₆N₆O₂
• Molecular Weight: 194.15
• CAS Registry Number: 85622-93-1
• EC Number: 630-358-9
• SMILES: CN1C(=O)N2C=NC(=C2N=N1)C(=O)N

Properties

• Density: 2.0±0.1 g/cm³ Calc.^*
• Melting point: 212 °C (Decomposes) (Expl.)
• Boiling point: 526.6±42.0 °C 760 mmHg (Calc.)^*
• Flash point: 272.3±27.9 °C (Calc.)^*
• Solubility: 50 mM in DMSO (Expl.)
• Index of refraction: 1.895 (Calc.)^*

^* Calculated using Advanced Chemistry Development (ACD/Labs) Software.

Safety Data

• Hazard Symbols: GHS06;GHS07;GHS08 Danger
• Risk Statements: H204-H300-H302-H315-H319-H335-H340-H341-H350-H351-H360-H372
• Safety Statements: P203-P210-P230-P234-P236-P240-P250-P260-P261-P264-P264+P265-P270-P271-P280-P301+P316-P301+P317-P302+P352-P304+P340-P305+P351+P338-P318-P319-P321-P330-P332+P317-P337+P317-P362+P364-P370+P380+P375-P401-P403+P233-P405-P501-P503

Hazard Classification

Hazard	Class	Category Code	Hazard Statement
Reproductive toxicity	Repr.	1B	H360
Skin irritation	Skin Irrit.	2	H315
Eye irritation	Eye Irrit.	2	H319
Specific target organ toxicity - single exposure	STOT SE	3	H335
Carcinogenicity	Carc.	1B	H350
Germ cell mutagenicity	Muta.	1B	H340
Specific target organ toxicity - repeated exposure	STOT RE	1	H372
Germ cell mutagenicity	Muta.	2	H341
Acute toxicity	Acute Tox.	4	H302
Carcinogenicity	Carc.	2	H351
Acute toxicity	Acute Tox.	2	H300
Acute toxicity	Acute Tox.	1	H300
Explosives	Expl.	1.4	H204
Reproductive toxicity	Repr.	1A	H360
Acute toxicity	Acute Tox.	4	H332
Acute toxicity	Acute Tox.	4	H312
Carcinogenicity	Carc.	1A	H350
Specific target organ toxicity - repeated exposure	STOT RE	2	H373
Reproductive toxicity	Repr.	2	H361
Germ cell mutagenicity	Muta.	1A	H340
Germ cell mutagenicity	Muta.	2	H340
Carcinogenicity	Carc.	2	H350
Specific target organ toxicity - single exposure	STOT SE	3	H336
Eye irritation	Eye Irrit.	2A	H319
Reproductive toxicity	Repr.	2	H360
Specific target organ toxicity - single exposure	STOT SE	2	H371

Discovery and Applications

Temozolomide is an oral alkylating agent that has become a central component in the treatment of certain brain cancers, particularly glioblastoma multiforme and anaplastic astrocytoma. It is classified as an imidazotetrazine derivative and is chemically related to the older alkylating agent dacarbazine. Temozolomide was developed to improve therapeutic efficacy while offering better pharmacokinetic properties, including oral bioavailability and central nervous system (CNS) penetration, which are critical for treating brain tumors.

Temozolomide was first synthesized in the early 1980s at Aston University in Birmingham, United Kingdom. The development was led by a group of researchers who were exploring new compounds with antitumor activity that could be administered orally and cross the blood-brain barrier. Unlike many traditional chemotherapeutic agents that require intravenous administration and are limited by poor CNS access, temozolomide demonstrated the ability to reach therapeutic concentrations in the brain following oral administration, which significantly contributed to its clinical utility in neuro-oncology.

The drug acts primarily by methylating DNA at the O⁶ and N⁷ positions of guanine residues. This methylation results in DNA mismatches during replication, ultimately leading to cell cycle arrest and apoptosis in rapidly dividing tumor cells. The most critical cytotoxic lesion caused by temozolomide is the O⁶-methylguanine adduct. The ability of tumor cells to repair this lesion via the DNA repair enzyme O⁶-methylguanine-DNA methyltransferase (MGMT) plays a key role in determining sensitivity to the drug. Tumors with low MGMT expression or with epigenetic silencing of the MGMT gene are generally more responsive to temozolomide therapy.

Temozolomide received accelerated approval from regulatory agencies in the early 2000s based on its efficacy and tolerability in clinical trials. It has since been established as the standard of care for newly diagnosed glioblastoma when used in combination with radiotherapy and continued as maintenance therapy. This treatment regimen, known as the Stupp protocol, has been shown to improve both progression-free and overall survival compared to radiotherapy alone.

In addition to glioblastoma, temozolomide has also been used in the treatment of other malignant gliomas and metastatic melanoma. Its utility is currently being evaluated in a range of other CNS tumors and some systemic cancers. Research is ongoing to explore the potential benefits of combining temozolomide with other therapeutic modalities, including immunotherapy and targeted agents, to overcome resistance mechanisms and enhance treatment efficacy.

Temozolomide is typically well tolerated relative to other chemotherapeutic agents, with a manageable side effect profile. Common adverse effects include nausea, vomiting, fatigue, myelosuppression, and increased risk of infections. Prophylactic treatment may be recommended to prevent opportunistic infections in patients undergoing prolonged therapy.

The success of temozolomide has spurred interest in the design of other small-molecule chemotherapeutics with favorable oral bioavailability and CNS penetration. It serves as a model compound in drug development for brain tumors and remains an important subject of ongoing research focused on improving outcomes in patients with high-grade gliomas.

The pharmacological and therapeutic significance of temozolomide has been firmly established through decades of clinical research and practical application. Its development marked a major advance in neuro-oncology, particularly due to its unique ability to treat tumors within the CNS effectively through systemic administration.

References

1991. Comparison of the cytotoxicity in vitro of temozolomide and dacarbazine, prodrugs of 3-methyl-(triazen-1-yl)imidazole-4-carboxamide. Cancer Chemotherapy and Pharmacology, 28(4).
DOI: 10.1007/bf00688855

2005. Benefit of Temozolomide Compared to Procarbazine in Treatment of Glioblastoma Multiforme at First Relapse: Effect on Neurological Functioning, Performance Status, and Health Related Quality of Life. Cancer Investigation, 23(2).
DOI: 10.1081/cnv-200050453

2024. Cytarabine/methotrexate. Reactions Weekly.
DOI: 10.1007/s40278-024-55154-4