Temozolomide and Irinotecan combination (TEMIRI)

The combination of temozolomide and irinotecan, frequently termed the TEMIRI regimen, is a therapeutic strategy leveraging a synergistic pharmacodynamic interaction between an alkylating agent and a topoisomerase I inhibitor [3, 6]. Temozolomide is an oral prodrug that undergoes spontaneous hydrolysis to MTIC, which methylates DNA at the O6 and N7 positions of guanine and the N3 position of adenine [2]. Irinotecan is a camptothecin derivative that is converted by carboxylesterases to its active metabolite, SN-38, which binds to and stabilizes the topoisomerase I-DNA complex [2, 3]. This stabilization prevents the religation of single-strand DNA breaks, which are then converted into lethal double-strand breaks during DNA replication [8]. The synergy between these agents is thought to occur because temozolomide-induced DNA lesions create a requirement for topoisomerase-mediated repair or replication bypass, which irinotecan subsequently blocks [1, 2]. Clinically, this combination is widely utilized in pediatric oncology for relapsed or refractory solid tumors, including neuroblastoma, Ewing sarcoma, and rhabdomyosarcoma [3, 8, 9]. It is also employed in adult patients for the treatment of recurrent high-grade gliomas and certain subsets of metastatic colorectal cancer [4, 6]. The efficacy of the regimen is often modulated by the expression of O6-methylguanine-DNA methyltransferase (MGMT), an enzyme that repairs temozolomide-induced damage [5, 6]. Common toxicities associated with this interaction include significant myelosuppression and gastrointestinal distress, such as severe diarrhea [3, 4, 8].

Other names

TMZ/CPT-11Temozolomide + Irinotecan pharmacodynamic interactionTemozolomide/Irinotecan regimenTMZ-IRITEMIRI

The interaction involves temozolomide-induced DNA methylation (primarily O6-methylguanine) and irinotecan-mediated inhibition of topoisomerase I, which prevents the repair of single-strand breaks and leads to lethal double-strand breaks during DNA replication [1, 2, 8].