mercaptopurine and Glioblastoma

This study was designed to evaluate strategies to overcome the resistance of anaplastic gliomas of the brain to external beam radiotherapy (ERT) plus carmustine (BCNU). Patients were > or = 15 years of age, had a histologic diagnosis of malignant glioma, and a Karnofsky performance status (KPS) > or = 60%.. In Randomization 1, patients were assigned to receive either ERT alone (61.2 Gy) or ERT plus mitomycin C (Mito, IV 12.5 mg/m(2)) during the first and fourth week of ERT. After this treatment, patients went on to Randomization 2, where they were assigned to receive either BCNU (i.v. 200 mg/m(2)) given at 6-week intervals or 6-mercaptopurine (6- MP, 750 mg/m(2) IV daily for 3 days every six weeks), with BCNU given on the third day of the 6-MP treatment. Three hundred twenty-seven patients underwent Randomization 1. One hundred sixty-four received ERT alone, and 163 received ERT + Mito [average 52.7 years; 63% male; 69% glioblastoma multiforme (GBM); 66% had a resection; 56% KPS > or = 90%]. Step-wise analysis of survival from Randomization 1 or 2 indicates that survival was significantly diminished by: (a) age > or = 45 years (b) KPS < 90%; (c) GBM/gliosarcoma histology; (d) stereotactic biopsy as opposed to open biopsy or resection. Median survival from Randomization 1 in both arms (ERT + Mito) was 10.8 months. Median survival from Randomization 2 was 9.3 months for BCNU/6MP vs. 11.4 months for the BCNU group (p = 0.35). Carmustine/6-MP showed a possible survival benefit for histologies other than GBM/GS. Two hundred and thirty-three patients underwent Randomization 2. The proportion of patients in the ERT group who terminated study prior to Randomization 2 was significantly less in the ERT group than in the ERT + Mito group (20 vs. 37%, p < 0.001).. (a) The addition of Mito to ERT had no impact on survival; (b) patients treated with ERT + Mito were at greater risk of terminating therapy prior to Randomization 2; (c) there was not a significant survival benefit to the addition of 6-MP to BCNU.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Carmustine; Combined Modality Therapy; Female; Glioblastoma; Humans; Karnofsky Performance Status; Male; Mercaptopurine; Middle Aged; Mitomycin; Prospective Studies; Quality Assurance, Health Care; Survival Rate

Temozolomide (TMZ) is a standard treatment for glioblastoma (GBM) patients. However, TMZ has moderate therapeutic effects due to chemoresistance of GBM cells through less clarified mechanisms. Here, we demonstrate that TMZ-derived 5-aminoimidazole-4-carboxamide (AICA) is converted to AICA ribosyl-5-phosphate (AICAR) in GBM cells. This conversion is catalyzed by hypoxanthine phosphoribosyl transferase 1 (HPRT1), which is highly expressed in human GBMs. As the bona fide activator of AMP-activated protein kinase (AMPK), TMZ-derived AICAR activates AMPK to phosphorylate threonine 52 (T52) of RRM1, the catalytic subunit of ribonucleotide reductase (RNR), leading to RNR activation and increased production of dNTPs to fuel the repairment of TMZ-induced-DNA damage. RRM1 T52A expression, genetic interruption of HPRT1-mediated AICAR production, or administration of 6-mercaptopurine (6-MP), a clinically approved inhibitor of HPRT1, blocks TMZ-induced AMPK activation and sensitizes brain tumor cells to TMZ treatment in mice. In addition, HPRT1 expression levels are positively correlated with poor prognosis in GBM patients who received TMZ treatment. These results uncover a critical bifunctional role of TMZ in GBM treatment that leads to chemoresistance. Our findings underscore the potential of combined administration of clinically available 6-MP to overcome TMZ chemoresistance and improve GBM treatment.

Topics: AMP-Activated Protein Kinases; Animals; Drug Resistance, Neoplasm; Glioblastoma; Humans; Hypoxanthine Phosphoribosyltransferase; Hypoxanthines; Mercaptopurine; Mice; Ribonucleotide Reductases; Temozolomide

The Neuro-oncology Service of the University of California Brain Tumor Research Center conducted a nonrandomized phase II study to evaluate, in patients with recurrent malignant glioma, the benefit of a four-drug combination (BFHM) consisting of carmustine (1,3-bis (2-chloroethyl)-1-nitrosourea), 5-fluorouracil, hydroxyurea, and 6-mercaptopurine. There were 29 evaluable glioblastoma multiforme patients and 45 nonglioblastoma anaplastic glioma patients available for analysis. Tumor progression was analyzed as the primary study endpoint. Of the glioblastoma patients, 16 of 29 (55%) responded or stabilized on therapy; of the other anaplastic gliomas, 32 of 45 (71%) responded or stabilized. For patients who stabilized or responded to treatment, BFHM achieved a median time to tumor progression of 46 weeks with a 25th percentile time to tumor progression of 68 weeks for anaplastic gliomas and a median time to tumor progression of 23 weeks with a 25th percentile time to tumor progression of 36 weeks for glioblastoma multiforme patients. A Cox multivariate analysis demonstrated that age and Karnofsky score were important prognostic variables for these patients.

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Carmustine; Drug Evaluation; Fluorouracil; Glioblastoma; Glioma; Humans; Hydroxyurea; Mercaptopurine; Middle Aged; Neurologic Examination; Statistics as Topic; Tomography, X-Ray Computed

Topics: Adolescent; Adult; Aged; Antineoplastic Agents; Astrocytoma; Blood-Brain Barrier; Brain Neoplasms; Child; Child, Preschool; Cyclophosphamide; Drug Therapy, Combination; Female; Fluorouracil; Glioblastoma; Glioma; Humans; Male; Mercaptopurine; Methotrexate; Middle Aged; Monomethylhydrazine; Neoplasm Metastasis; Vinblastine