methotrexate + ifosfamide

Methotrexate + ifosfamide is a combination of two cytotoxic small-molecule chemotherapeutics used as part of multi-drug regimens for various solid tumors and hematologic malignancies, most notably osteosarcoma and other sarcomas. Methotrexate is a folate analog antimetabolite that competitively inhibits dihydrofolate reductase, depleting reduced folates and thereby blocking thymidylate and purine synthesis, which impairs DNA replication and cell division in rapidly proliferating cells. Ifosfamide is an oxazaphosphorine alkylating agent that undergoes hepatic activation to form DNA-alkylating metabolites that induce inter- and intra-strand DNA cross-links, leading to inhibition of DNA replication and transcription and ultimately apoptosis. In clinical practice, high-dose methotrexate and high-dose ifosfamide are frequently co-administered within intensive combination chemotherapy protocols (often with cisplatin and doxorubicin or other agents) to improve tumor response, at the cost of significant hematologic, renal, and urothelial toxicity that requires careful supportive care, including mesna uroprotection and methotrexate rescue with leucovorin.[1][2][3]