Antitumor drug
Temozolomide is the first orally effective imidazole and tetraazine antitumor drug, belonging to the second generation of alkylating agents with anti-tumor activity, which does not require intrahepatic metabolic activation after oral administration, is characterized by easy penetration of the blood-brain barrier, good tolerance and no additive toxicity with other drugs, and has synergistic effect with radiotherapy, which is suitable for malignant gliomas that relapse after conventional treatment. Such as glioblastoma multiforme or degenerative astrocytoma, are also first-line drugs for the treatment of metastatic melanoma.
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 effect of Temozolomide on the treatment of recurrent glioblastoma multiforme has been confirmed by clinical trials to be safe and effective. Results of a Phase II randomized controlled trial showed that 225 patients with first-time recurrent glioblastoma multiforme were treated with temozolomide or procarbazide (125-150 mg/m2 orally every 56 days for 28 days) for 6 months, respectively, and there was no progression in the temozolomide group. Survival and overall survival were 21% and 60%, respectively, significantly higher than 8% and 44% in the procarbazide group. Mean progression-free survival and overall survival were 2.9 and 7.3 months in Temozolomide patients, respectively, which were also significantly higher than 1.9 and 5.8 months in the procarbazide group. The trial also assessed health-related quality of life at 3 and 6 months after the start of treatment and confirmed that more patients in the temozolomide group had improved or remained stable. The main adverse event of temozolomide was predictable and easily managed transient and noncumulative myelosuppression, which occurred in 24% of trials. Temozolomide is also prone to mild to moderate nausea and vomiting, which can be prevented with conventional antiemetic therapy. The efficacy and adverse drug reaction of temozolomide in the treatment of recurrent glioblastoma multiforme were significantly better than the existing standard drug procarbazide.
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.
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