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.ABSTRACTHYPOTHESISTemozolomide has demonstrated activity in adults with anaplatic astrocytoma, yet no significant activity has been demonstrated TMZ alone in pediatric high-grade gliomas or brainstem tumors. Since many brain tumors express the repair protein, AGT, this may be a mechanism of drug resistance in this patient population. O6-BG irreversibly inactivates and depletes AGT. The combination of O6-BG with TMZ may therefore increase efficacy of TMZ in this patient population.
SPECIFIC AIMS Primary Objective:1.1 To estimate the sustained objective rates to the combination of intravenous O6-benzylguanine (O6-BG) and oral temozolomide (TMZ) in children with recurrent or pgoressive high-grade gliomas and recurrent or progressive brainstem tumors.Secondary Ojbective:1.2 To further describe the toxicity of the combination of O6-BG and TMZ in children.1.3 To evaluate changes in MR spectroscopic patterns, MR diffusion and MR perfussion in children with refractory or recurrent high-grade gliomas or brainstem tumors who are interested with the combination of O6-BG and TMZ.BACKGROUND AND SIGNIFICANCEHigh-grade astrocytic tumors are rapidly growing, poorly differentiated, infiltrative tumors. Although surgical excision may be possible, it rarely provides prolonged disease control. Even with radiation, these tumors tend to recur locally. 1. Long-term survival rates are 30-40% for grade 3 astrocytic tumors and 10% for grade 4 tumors. 2. Tumors arising in the brainstem are also notoriously difficult to treat. They account for 10-20% of pediatric central nervous system tumors. 3. The diffuse intrinsic tumors account for the majority (75-80%) of brainstem tumors in the pediatric age group. 4. Because of their tenuous location, surgery plays no role in the treatment of these patients, and the mainstay of treatment is radiation. Although the majority of patients will clinically improve with radiation therapy, the progression-free interval is short (median 6 months) and the median survival time is less than 1 year. 5. Fewer than 20% of patients survive 2 years, 6 and <10% survive 3 years. Although some chemotherapeutic agents have shown moderate activity against gliomas, none has been shown to significantly increase survival in children with brainstem gliomas. The reasons for this are unclear but are likely related to difficulty with drug delivery and drug resistance. Drug resistance, either intrinsic or acquired, is frequently seen in tumors of the CNS, and many different mechanisms have been described.O6-BG increases tumor cell sensitivity to agents that alkylate the O6-position of guanine, such as nitrosoureas and TMZ, by 2.5 to 10-fold 33, 46-48. The greatest enhancement of activity occurs in cells with higher levels of AGT 47,49. Pretreatment with O6-BG has been shown to increase the cytotoxicity of TMZ in vitro and in malignant glioma xenograft models 10,50 and against a variety of human tumor xenografts 51-53. At micromolar concentrations, O6-BG completely depletes (greater than or equal to 99%) AGT levels within the tumor 18 hours after O6-BG administration were below the level of detection (<10 fmol/mg protein) in 11/11 patients 54. No serious side effectswere observed wither with O6-BG alone or in combination with 13 mg/m2 of BCNU 54,55.
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