human
The task is to decide the Hallmarks of Cancer (HOC) taxonomy of the article based on its abstract. The input is an abstract text. There are 10 topics you will need to decide whether the article is related to. Topics: sustaining proliferative signaling, evading growth suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis, activating invasion and metastasis, genomic instability and mutation, tumor promoting inflammation, cellular energetics, avoiding immune destruction. The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics.
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    INPUT: BACKGROUND Although chemotherapy offers promise of increased survival for children with medulloblastoma and glioblastoma multiforme , drug resistance occurs frequently , resulting in tumor progression and death . Resistance to nitrosoureas and methylating agents , which damage DNA , can be mediated by a DNA repair protein , O6-alkylguanine-DNA alkyltransferase ( AGAT ) . Depletion of this protein with alkylguanines or methylating agents , however , restores tumor cell sensitivity to the cytotoxicity of chloroethylnitrosoureas ( e.g. , carmustine [ BCNU] ) . PURPOSE This study was designed to determine whether resistance to the activity of nitrosourea ( the drug BCNU ) in BCNU-resistant human medulloblastoma ( D341 Med ) and human glioblastoma multiforme ( D-456 MG ) can be reversed by the methylating agent streptozocin and the O6-substituted guanines O6-methylguanine and O6-benzylguanine . METHODS Xenografts were grown subcutaneously in athymic BALB/c mice . BCNU was administered as a single intraperitoneal injection at doses of 100 mg/m2 , 75 mg/m2 , or 38 mg/m2--i.e. , 1.0 , 0.75 , or 0.38 , respectively , of the dose lethal to 10% of treated animals ( LD10 ) . Mice were treated intraperitoneally with a single dose of O6-benzylguanine or O6-methylguanine ( 240 mg/m2 ) or with streptozocin ( 600 mg/m2 ) daily for 4 days . Response was assessed by tumor growth delay and tumor regression . AGAT activity in the xenografts was measured at 1 and 6 hours after pretreatment , at the time tumors were excised . RESULTS Pretreatment with O6-benzylguanine , O6-methylguanine , or streptozocin reduced AGAT activity to 4% , 25% , and 95% of control values , respectively , in D341 Med and 0% , 0% , and 25% of control values , respectively , in D-456 MG 1 hour after injection . After 6 hours , levels changed to 7% , 61% , and 116% of control values in D341 Med and 0% , 79% , and 21% of control values in D-456 MG , respectively . Both D341 Med and D-456 MG xenografts were completely resistant to BCNU at its LD10 . Pretreatment with O6-benzylguanine increased BCNU sensitivity in both types of xenograft . In contrast , treatment with BCNU plus O6-methylguanine or streptozocin did not produce growth delays substantially different from those produced by BCNU alone , reflecting the more efficient depletion of AGAT by O6-benzylguanine . Following therapy with BCNU plus O6-benzylguanine at 0.38 LD10 , tumor regressions were seen in eight of 10 D341 Med and in all 10 D-456 MG xenografts . CONCLUSION We recommend comprehensive clinical toxicologic evaluation of combination therapy with O6-benzylguanine plus BCNU , which would allow subsequent design of phase I clinical trials .
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agent
genomic instability and mutation
The task is to decide the Hallmarks of Cancer (HOC) taxonomy of the article based on its abstract. The input is an abstract text. There are 10 topics you will need to decide whether the article is related to. Topics: sustaining proliferative signaling, evading growth suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis, activating invasion and metastasis, genomic instability and mutation, tumor promoting inflammation, cellular energetics, avoiding immune destruction. The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics.
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    INPUT: BACKGROUND Although chemotherapy offers promise of increased survival for children with medulloblastoma and glioblastoma multiforme , drug resistance occurs frequently , resulting in tumor progression and death . Resistance to nitrosoureas and methylating agents , which damage DNA , can be mediated by a DNA repair protein , O6-alkylguanine-DNA alkyltransferase ( AGAT ) . Depletion of this protein with alkylguanines or methylating agents , however , restores tumor cell sensitivity to the cytotoxicity of chloroethylnitrosoureas ( e.g. , carmustine [ BCNU] ) . PURPOSE This study was designed to determine whether resistance to the activity of nitrosourea ( the drug BCNU ) in BCNU-resistant human medulloblastoma ( D341 Med ) and human glioblastoma multiforme ( D-456 MG ) can be reversed by the methylating agent streptozocin and the O6-substituted guanines O6-methylguanine and O6-benzylguanine . METHODS Xenografts were grown subcutaneously in athymic BALB/c mice . BCNU was administered as a single intraperitoneal injection at doses of 100 mg/m2 , 75 mg/m2 , or 38 mg/m2--i.e. , 1.0 , 0.75 , or 0.38 , respectively , of the dose lethal to 10% of treated animals ( LD10 ) . Mice were treated intraperitoneally with a single dose of O6-benzylguanine or O6-methylguanine ( 240 mg/m2 ) or with streptozocin ( 600 mg/m2 ) daily for 4 days . Response was assessed by tumor growth delay and tumor regression . AGAT activity in the xenografts was measured at 1 and 6 hours after pretreatment , at the time tumors were excised . RESULTS Pretreatment with O6-benzylguanine , O6-methylguanine , or streptozocin reduced AGAT activity to 4% , 25% , and 95% of control values , respectively , in D341 Med and 0% , 0% , and 25% of control values , respectively , in D-456 MG 1 hour after injection . After 6 hours , levels changed to 7% , 61% , and 116% of control values in D341 Med and 0% , 79% , and 21% of control values in D-456 MG , respectively . Both D341 Med and D-456 MG xenografts were completely resistant to BCNU at its LD10 . Pretreatment with O6-benzylguanine increased BCNU sensitivity in both types of xenograft . In contrast , treatment with BCNU plus O6-methylguanine or streptozocin did not produce growth delays substantially different from those produced by BCNU alone , reflecting the more efficient depletion of AGAT by O6-benzylguanine . Following therapy with BCNU plus O6-benzylguanine at 0.38 LD10 , tumor regressions were seen in eight of 10 D341 Med and in all 10 D-456 MG xenografts . CONCLUSION We recommend comprehensive clinical toxicologic evaluation of combination therapy with O6-benzylguanine plus BCNU , which would allow subsequent design of phase I clinical trials .
    OUTPUT:
