Cyclophosphamide therapy of medulloblastoma: from the laboratory to the clinic and back again (and again and again).

Medulloblastoma, the most common malignancy of childhood, was originally shown to be sensitive to cyclophosphamide in 1981. We have used combined laboratory and clinical investigations to demonstrate the synergy of cyclophosphamide and vincristine in the treatment of this tumor, the therapeutic gain associated with escalation of the dosage of cyclophosphamide, the consequence of and mechanisms underlying resistance of medulloblastoma to cyclophosphamide, the emerging importance of the neuraxis as a site of relapse of medulloblastoma, and newer approaches, including intrathecal 4-hydroperoxycyclophosphamide and busulfan, to treat neuraxis disease. These studies serve as a paradigm for laboratory-clinical translational research.