This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.Cyclophosphamide (CY) is one of the most commonly used chemotherapeutic agents in the treatment of pediatric solid tumors. Escalation of CY dose is limited by bone marrow toxicity. Despite standardized CY dosing based upon body size, patients experience variabily severe side effects, including nausea, vomiting, and low blood counts, after receiving CY. Preliminary data in adults suggests that genetic variations of proteins responsible for CY metabolism may explain some of the variation in patient side effects. Two prospective CHRMC Oncology Group (COG) studies in children with pediatric solid tumors will determine whether patient genetic variations in CY metabolizing proteins are associated with toxicity (ANBL0532 for neuroblastoma and ARST0531 for intermediate-risk RMS, chaired by local CHRMC investigators, Julie Park and Doug Hawkins, respectively). ANBL0532 and ARST0531 will use two different CY doses and schedules. The current study will complement the COG studies by defining the mechanistic bassis for a pharmacokinetic (PK) relationship between genetic factors associated with CY toxicity.
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