methotrexate + dexamethasone + ifosfamide + L-asparaginase + etoposide + mesna

The combination of methotrexate, dexamethasone, ifosfamide, L-asparaginase, and etoposide, co-administered with the uroprotective agent mesna, is a multi-agent chemotherapy protocol known as the SMILE regimen. This regimen was specifically developed for the treatment of extranodal natural killer (NK)/T-cell lymphoma, nasal type (ENKTL), an aggressive malignancy that often exhibits multidrug resistance due to the high expression of P-glycoprotein. The SMILE regimen overcomes this resistance by incorporating L-asparaginase, an enzyme that depletes asparagine and is not a substrate for the P-glycoprotein efflux pump. The other components provide synergistic cytotoxic effects by inhibiting dihydrofolate reductase (methotrexate), inducing apoptosis through glucocorticoid signaling (dexamethasone), alkylating DNA (ifosfamide), and inhibiting topoisomerase II (etoposide). Clinical research led by Mingzhi Zhang has evaluated this regimen in randomized trials, comparing its efficacy and safety against other protocols like DDGP in advanced-stage disease.

Other names

SMILE regimenModified SMILE regimen