Cellular mechanisms of cyclophosphamide resistance: model studies in human medulloblastoma cell lines.

Abstract

Cyclophosphamide is extremely active in the treatment of medulloblastoma, the most common malignant tumor arising in the central nervous system of children’. Phase 2 trials in children with recurrent and newly diagnosed medulloblastoma have confirmed both clinical and radiographic responses to this alkylating agent2-5and a current Children’s Oncology Group international Phase 3 trial is comparing a cyclophosphamide-based regimen to a CCNU-based regimen for children with newly diagnosed high-risk medulloblastoma. Unfortunately, patients with medulloblastoma treated with cyclophosphamide frequently fail therapy, confirming the emergence of drug-resistant tumor cells. Although selection of alternative treatment for these patients who relapse is the only option currently available, definition of the mechanism(s) responsible for cyclophosphamide resistance might provide new therapeutic strategies to reverse or even prevent resistance to this alkylator