DNA REPAIR MEDIATED RESISTANCE IN CNS TUMORS

Duke University, Durham NC

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Abstract

Malignant central nervous system (CNS) tumors are perhaps the most difficult and frustrating neoplasms to treat, in large part due to the eloquent site in which these lesions arise and grow. Medulloblastoma, the most common malignant brain tumor in childhood, continues to represent a therapeutic challenge. The prognosis for most patients with primary malignant gliomas remains even worse. Demonstration of the activity of bifunctional alkylators such as cyclophosphamide in the treatment of medulloblastoma and glioma has provided the opportunity for significant advances in the treatment of these tumors. Resistance to cyclophosphamide is multifactorial, with a diverse spectrum of mechanisms observe in murine and human neoplasia, including increased aldehyde dehydrogenase activity, increased GST activity and elevated levels of GSH. More recent studies indicate preferential repair of DNA interstrand crosslinks (ICL) in a 4-HC resistant medulloblastoma line compared to a parental line, supporting further studies designed to define the scope and relevance of a DNA ICL repair as a mechanism underlying resistance of medulloblastoma and glioma to cyclophosphamide. However, several considerations need to be addressed in analyzing the role of crosslink repair in alkylator resistance (Chaney and Sancar 1996). Not only will it be necessary to demonstrate an increased removal of adducts of crosslinks but also to demonstrate which repair pathway(s) is (are) involved. Demonstration of repair enzymes at increased levels in resistant cell lines must be followed by studies demonstrating that these enzymes are rate limiting for the repair pathway. The ultimate proof of principle will be the demonstration that the repair pathway is more active in the resistant cells. These studies will require technological approaches/reagents not currently available until now. The hypothesis of this proposal is that: repair of DNA ICL is a major mechanism of resistance to cyclophosphamide in medulloblastoma and glioma. The specific aims of this proposal are 1) to define the molecular events mediating repair of phosphoramide mustard-induced DNA ICL by human cell extracts; 2) to define the role of repair of phosphoramide mustard-induced DNA ICL in mediating cyclophosphamide resistance in medulloblastoma and malignant glioma; and 3) to define the pathways operational in the repair of phosphoramide mustard-induced DNA ICL in cyclophosphamide resistant medulloblastoma and glioma.