Temozolomide is the first orally effective imidazole and tetrazine antitumor drug, belonging to the second generation of alkylating agents with anti-tumor activity, which does not require intrahepatic metabolic activation after oral administration, and is characterized by easy penetration of the blood-brain barrier, good tolerance, no additive toxicity with other drugs, and synergistic effect with radiotherapy. It is suitable for malignant gliomas that relapse after conventional treatment, such as glioblastoma multiforme or degenerative astrocytoma, and is also a first-line drug for the treatment of metastatic melanoma.
Temozolomide was synthesized by Cancer Research UK and sold to Schering-Plough USA for development. This drug is different from existing antitumor drugs in that it has a novel chemical structure and is a derivative of imidazole and tetrazine. Temozolomide does not play a direct role and is rapidly converted to the active compound MTIC [5-(3-methyltriazene-1 -) imidazole-4-amide] by non-enzymatic pathway at physiological pH. It is believed that the cytotoxicity of MTIC is mainly due to its DNA alkylation (methylation), which occurs mainly at the O6 and N7 positions of guanine. Temozolomide has been proved effective in basic and clinical studies on some of the most common glioblastomas, and has been approved for marketing in the European Union and the United States in 1999, among which the approved indication in the United States is the second-line treatment of glioblastoma multiforme and degenerative astrocytoma. The approved indication for glioblastoma multiforme in countries within the European Union is for glioblastoma multiforme that continues to develop or relapse after conventional treatment. The effect of temozolomide on glioblastoma multiforme is gaining more recognition in Europe.
Pharmacokinetics
The drug is fully absorbed orally and has a bioavailability of nearly 100%. It shows broad-spectrum activity in mouse tumor models and can penetrate the human blood-brain barrier. The cytotoxic effects of temozolomide are due to its strong methylation of DNA bases. Under alkaline conditions, temozolomide rapidly breaks to form active methyldiazonium ions. Since brain tumors are more alkaline than the surrounding tissues, the activation energy of this drug is relatively concentrated in the tumor site, the anti-tumor effect is strong and certain selectivity, the side effect spectrum is also improved, the myelotoxicity is less, and the tolerance of patients is improved.
The bulk drug of Temozolomide is white or light brown/light pink powder with a relative molecular mass of 194.15. pH7 is easy to decompose, melting point 212ºC(decomposition). Maximum UV absorption (95% ethanol) : 327nm. It is slightly soluble in dimethyl sulfoxide, slightly soluble in water, almost insoluble in ethanol and slightly soluble in glacial acetic acid. Clinically, it can spontaneously and quickly degrade the active metabolite MTIC in vivo, and produce anti-tumor effects.
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