mercaptopurine and Glioma

The authors review and discuss the basic concepts of cell kinetics as applied to brain tumors. Uncontrolled growth of a neoplasm represents an expanding tumor cell population. Four growth parameters characterize the behavior of a neoplastic population: cell cycle time, growth fraction, tumor doubling time, and cell loss. The concept of provisionally nondividing cells explains the disparity between cell cycle time and tumor doubling time. Human gliomas, like many non-neural solid tumors, contain variable proportions of actively proliferating and nonproliferating tumor cells; this ratio is expressed by the growth fraction. The major kinetic difference between glioblastomas and differentiated astrocytomas resides in their respective growth fractions, in all likelihood an inherent biological characteristic of each tumor. Glioblastoma proliferates at a rapid rate, and only a high rate of cell loss prevents this tumor from doubling its volume in less than 1 week. The selection of drugs and design of drug schedules for treatment of glioblastomas should be made with the knowledge that 60% to 70% of the cells in this tumor are resting (nonproliferating). If experience with other solid tumors is any guide, judicious selection and combined use of drugs according to kinetically sound schedules will produce more effective chemotherapy of brain tumors.

Topics: Alkylating Agents; Anti-Bacterial Agents; Antimetabolites; Astrocytoma; Brain; Brain Neoplasms; Cell Survival; DNA, Neoplasm; Glioma; Humans; Kinetics; Mercaptopurine; Mitosis; Neoplasm Metastasis; Prednisolone; Remission, Spontaneous; RNA, Neoplasm; Time Factors; Vincristine

On the basis of response rates of up to 50%, BCNU [1,3-bis(2-chloroethyl)-1-nitrosourea] is the primary drug used in the chemotherapy of anaplastic gliomas. Preclinical data obtained in several experimental systems show that the cytotoxicity of chloroethylnitrosoureas can be increased by the concomitant use of thiopurines. In this phase I trial, patients with anaplastic gliomas received standard-dose BCNU (200 mg/m2 x 1) in combination with escalating doses of intravenous 6-mercaptopurine (200, 350, 500, and 750 mg/m2 daily x 3), with BCNU being given on day 3 to maximize the effect of the drugs on cellular DNA. No increase in hematologic toxicity was demonstrated as the dose of 6-mercaptopurine was increased. Responses and stabilization of disease were observed in several patients. Due to the safety of and the evidence of activity found for this regimen in the present trial, 750 mg/m2 6-mercaptopurine has been incorporated into subsequent studies.

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Brain Stem; Carmustine; Child; Dose-Response Relationship, Drug; Drug Evaluation; Drug Synergism; Female; Glioma; Humans; Injections, Intravenous; Male; Mercaptopurine; Middle Aged

We used human anaplastic glioma xenografts to evaluate the therapeutic efficacy of combinations of alkylating drugs, either 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), 1-(2-chloroethyl)-3-(2,5-dioxo-3-piperidyl)-1-nitrosourea (PCNU), or procarbazine, and thiopurines, either 6-mercaptopurine (6MP) or 6-thioguanine (6TG). Using growth delay as the endpoint in subcutaneous (s.c.) tumors and increased life span as the endpoint in intracranial (i.c.) tumors, we found that combinations of chloroethylnitrosoureas (CENUs) and thiopurines were significantly more active than either type of agent alone. In contrast, combinations of procarbazine and thiopurines were not significantly more active than procarbazine alone. The therapeutic potentiation of the CENU was greater when the latter was given on the 4th day of the thiopurine treatment cycle than when it was given on the 1st day. Characterization of the interaction between CENUs and thiopurines also revealed a supraadditive therapeutic response at higher BCNU doses in combination with 6TG. Interaction between the nitrosoureas and the thiopurines probably occurs in the guanine base of tumor DNA and has important therapeutic implications.

Topics: Alkylating Agents; Animals; Antineoplastic Combined Chemotherapy Protocols; Carmustine; DNA; Glioma; Humans; Mercaptopurine; Mice; Mice, Inbred BALB C; Neoplasm Transplantation; Nitrosourea Compounds; Procarbazine; Survival Rate; Thioguanine; Transplantation, Heterologous

Twenty-one patients with recurrent malignant central nervous system gliomas were treated with a combination of 5-fluorouracil, CCNU, hydroxyurea, and 6-mercaptopurine. Thirteen patients had brain stem gliomas, 3 patients had spinal cord gliomas, 3 patients had thalamic gliomas, and 2 patients had cerebellar astrocytomas. All patients had received radiation therapy, and 4 brain stem patients had also been treated with chemotherapy. Sixteen patients (76%) responded to treatment with either stabilization of disease or improvement. Nine of the 13 patients with brain stem gliomas (71%) had response or stabilization of disease. The median time to tumor progression (TTP) for the brain stem patients who responded or had stabilization of disease was 25 weeks. The median survival from recurrence for the brain stem glioma patients was 27 weeks. Patients with cerebellar, thalamic, and spinal cord tumors did very well, with an 87% response or stabilization of disease and a median TTP of 122 weeks.

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Brain Stem; Child; Child, Preschool; Ependymoma; Female; Fluorouracil; Glioma; Humans; Hydroxyurea; Lomustine; Male; Mercaptopurine; Neoplasm Recurrence, Local; Spinal Cord Neoplasms

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: Cell Line; Cells, Cultured; Drug Resistance; Floxuridine; Glioma; Humans; Mercaptopurine; Morphine Dependence; Neoplasms, Experimental; Nervous System Diseases; Neuroblastoma; Neurophysiology; Thioguanine; Vasoactive Intestinal Peptide

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