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Lonafarnib + temozolomide is a combination therapy consisting of two small molecule drugs used primarily in the treatment of recurrent glioblastoma and other malignant brain tumors. Lonafarnib is an oral selective farnesyltransferase inhibitor that blocks the post-translational modification of proteins involved in cell signaling and proliferation, thereby inhibiting tumor growth. Temozolomide is an alkylating agent that induces cytotoxicity by methylating DNA at the O6 and N7 positions of guanine residues, leading to apoptosis in rapidly dividing tumor cells. The combination aims to leverage both cytostatic (lonafarnib) and cytotoxic (temozolomide) mechanisms for enhanced antitumor activity. Clinical studies have shown this regimen can be safely administered with manageable toxicity profiles; hematologic toxicities such as lymphopenia are most common. The maximum tolerated dose for lonafarnib in this combination was established at 200 mg twice daily alongside dose-dense temozolomide schedules[1][5][7].
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