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PubMed1997

Chemotherapy of human malignant glioma: prevention of efficacy by dexamethasone?

Steroids are commonly administered for the control of edema, mass effect, and side effects from therapy to patients with malignant glioma who are receiving radiotherapy and chemotherapy. Here, we report that therapeutic concentrations of dexamethasone (DEX) attenuate cytotoxicity and growth inhibition of human malignant glioma cells induced by exposure to several chemotherapeutics, including ACNU, VM-26, vincristine, cytarabine, methotrexate, and adriamycin. DEX-mediated cytoprotection is not linked to DEX effects on glioma cell proliferation. However, the cytoprotective effects of DEX appeared to be more prominent in cell lines with wild-type p53 status (n = 2) than in p53 mutant cell lines (n = 3). Further, DEX-mediated rescue from chemotherapy does not directly involve Bcl-2 family proteins since DEX failed to change the expression of Bcl-2 or Bax proteins and since bcl-2 gene transfer-mediated cytoprotection was not redundant with the effects of DEX. DEX thus appears to control a common, bcl-2-independent death pathway in glioma cells that is not limited to specific drug actions. Chemotherapy is usually given as an elective, adjuvant treatment to glioma patients in stable condition who can tolerate steroid withdrawal. To maximize therapeutic efficacy, steroids should be withdrawn from glioma patients prior to chemotherapy.

Antibiotics, Antineoplastic↗
PubMed1992

Enhancement of radiosensitivity by tamoxifen in C6 glioma cells.

The antiestrogen drug tamoxifen, which is used extensively in the treatment of breast cancer, has also been reported to inhibit the proliferation of some estrogen receptor-negative cell lines, including malignant glioma in vitro. To explore the possible role of tamoxifen in the treatment of malignant glioma, we have investigated its effects on cell growth and radiosensitivity in C6 glioma cells using a colony-forming assay and a tetrazolium-formazan growth rate assay. Pretreatment of C6 cells with tamoxifen resulted in dose-dependent inhibition of cell growth and enhancement of the antitumor effects of ACNU and irradiation. The radiosensitivity of the treated cells was enhanced by the administration of 5 mumol/L of tamoxifen either before and during irradiation or continuously before, during, and after irradiation [37% survival dose (Do) = 2.68 +/- 0.19 and 2.64 +/- 0.04 Gy, respectively, P < 0.01)], as compared with controls (Do = 3.79 +/- 0.25 Gy). In addition, protein kinase C activity was also inhibited by tamoxifen at the concentration in which the radiosensitivity was augmented in C6 cells. Taken together, our results demonstrate a synergistic effect of tamoxifen with radiation on intracellular damage in C6 glioma cells, which may in part be due to the inhibition of protein kinase C, suggesting that tamoxifen serves as a useful agent in combination therapy of glioma.

Brain Neoplasms↗
PubMed1993

Ventriculolumbar perfusion of 3-[(4-amino-2-methyl-5-pyrimidinyl)methyl]-1-(2-chloroethyl)-1-nitrosou rea hydrochloride.

We report on the toxicity, intrathecal pharmacokinetics, and therapeutic effect of the ventriculolumbar perfusion of 3-[(4-amino-2-methyl-5-pyrimidinyl)methyl]-1-(2-chloroethyl)-1-nitros our ea hydrochloride (ACNU) against the subarachnoid dissemination of primary central nervous system tumors. Fifteen patients received ventriculolumbar perfusion of ACNU. One was treated with ventriculolumbar perfusion of ACNU alone, and the others underwent concomitant systemic chemotherapy; three of these patients received irradiation as well. ACNU was administered at an initial dose of 0.5 and was increased to 1.5 to 10.0 mg in six patients. Because of a lack of Level 2 or greater toxicity, the subsequent seven patients received 8.7 to 10.0 mg of ACNU dissolved in artificial cerebrospinal fluid (CSF) at a concentration of 0.1 mg/ml, from the start of the treatment. During ACNU administration, the lumbar CSF was drained at approximately the same rate as that of the infusion. Twelve patients received from 3 to 42 courses (average, 14 courses). The cumulative dose of ACNU ranged from 5 to 330.4 mg (average, 82.9 mg). One patient had a convulsion; two patients experienced transient headache, nausea, and vomiting; two others reported transient headache, nausea, vomiting, and fecal incontinence; and one experienced transient nausea, vomiting, and fecal incontinence. No side effects were noted in the other nine patients. When 9.0 to 9.5 mg of ACNU, dissolved in 90 to 95 ml of artificial CSF, was administered for 37 to 52 min, the maximum concentration of ACNU in the lumbar CSF was 9.86 to 12.79 micrograms/ml and the area under the drug concentration-time curve was 260.8 to 502.5 micrograms.min/ml.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed2004

Correlation between promoter hypermethylation of the O6-methylguanine-deoxyribonucleic acid methyltransferase gene and prognosis in patients with high-grade astrocytic tumors treated with surgery, radiotherapy, and 1-(4-amino-2-methyl-5-pyrimidinyl)methyl-3-(2-chloroethyl)-3-nitrosourea-based chemotherapy.

OBJECTIVE: O(6)-Methylguanine-deoxyribonucleic acid methyltransferase (MGMT) is a deoxyribonucleic acid repair protein associated with the chemoresistance of chloroethylnitrosoureas. We investigated whether MGMT promoter hypermethylation is associated with prognosis in patients with high-grade astrocytic tumors treated uniformly with surgery, radiotherapy, and 1-(4-amino-2-methyl-5-pyrimidinyl)methyl-3-(2-chloroethyl)-3-nitrosourea (ACNU)-based chemotherapy. METHODS: Using the methylation-specific polymerase chain reaction, we assayed promoter hypermethylation of the MGMT gene in tumor deoxyribonucleic acid from 116 adult patients with supratentorial high-grade astrocytic tumors (42 anaplastic astrocytomas [AAs] and 74 glioblastomas multiforme [GBMs]). The Cox proportional hazards model was used in forward stepwise regression to assess the relative role of prognostic factors (i.e., age at surgery, sex, Karnofsky Performance Scale score, extent of surgical resection, methylation status of the MGMT promoter, and association between MGMT promoter methylation and survival). RESULTS: MGMT promoter hypermethylation was confirmed in 19 (45.2%) of 42 AA patients and 33 (44.6%) of 74 GBM patients. It was significantly associated with both longer overall and progression-free survival time in AA but not GBM patients. CONCLUSION: Our results demonstrate that MGMT promoter hypermethylation is associated with longer survival time in patients with AA who were treated with surgery, radiotherapy, and ACNU-based chemotherapy but not in patients with GBM.

Adolescent↗
PubMed1995

Potentiation of the cytotoxicity of chloroethylnitrosourea by O6-arylmethylguanines.

It was reported recently that monomeric O6-benzylguanine (1) acts as an alternative substrate for a DNA repair enzyme, O6-alkylguanine-DNA alkyltransferase (AGT), and that therefore pretreatment of cells with 1 induces depletion of AGT resulting in an enhanced cytotoxic response to alkylating antitumor agents. In order to study the interaction of O6-benzylguanine derivatives with AGT and to obtain greater AGT depletion, we synthesized the following O6-arylmethylguanine derivatives and related compounds: O6-(4-, 3- and 2-fluorobenzyl)guanines (2, 3, 4), O6-(4-, 3- and 2-trifluoromethylbenzyl)guanines (5, 6, 7), O6-(4-, 3- and 2-pyridylmethyl)guanines (8, 9, 10), O6-(2- and 1-naphthylmethyl)guanines (11, 12), O6-biphenylmethylguanine (13), S and Se analogues of O6-benzylguanine (14, 15) and O6-phenylguanine (16). Ten of these are new compounds. All these compounds were tested for their potentiation of N'-[(4-amino-2-methyl-5-pyrimidinyl)methyl]-N-(2-chloroethyl)-N-nitrosou rea (ACNU) cytotoxicity using HeLa S3 and C6-1 cells. Compounds 2, 3, 5, 8, 9, 11 and 13 were active, as was 1. Compounds 7 and 12, with a substituent at the alpha position of the benzyl group, and compound 10, the alpha-nitrogen analogue of 1, were almost completely devoid of potentiating activity. These results suggest that the alpha-position of the O6-benzyl group plays an important role in the interaction of O6-benzylguanines with AGT. Of the other compounds, 4 and 6 exhibited very weak activity and 14, 15 and 16 were inactive. Possible reasons for these differences in activity are discussed in relation to the biomimetic dealkylation rates of O6-benzylguanine derivatives and the chemical characteristics of their substituents.

Alkylation↗
PubMed1996

Cytotoxicity of fluoroethylating agents is potentiated by O6-benzylguanine.

O6-Benzylguanine (BG) is a potent depleter of a repair enzyme O6-alkylguanine-DNA alkyltransferase. Pretreatment of cells with BG potentiates the cytotoxicity of chloroethylating anti-cancer agents. In this study we used HeLa S3 cells to examine the cytotoxic potentiation of 39 compounds after BG pretreatment. Compounds tested included anti-cancer agents and carcinogens, and among them only the cytotoxicity of methylating, chloroethylating and fluoroethylating agents was potentiated. This is the first description of the cytotoxic potentiation of fluoroethylating agents. Potentiation ratios were found to vary even among compounds possessing the same alkylating group. By pretreatment with 10 microM of BG, the cytotoxicity of methylating agents such as N-methyl-N-nitrosourea and streptozotocine was potentiated 3.7 and 9.4 fold, respectively. For chloroethylating agents, the potentiation ratios were 3.5 for N-chloroethyl-N-nitrosourea, 8.6 for N-[(4-amino-2-methyl-5-pyrimidinyl)methyl]-N'-(2-chloroethyl)-N'-nitroso urea (ACNU), 2.2 for N,N'-bis(2-chloroethyl)-N-nitrosourea (BCNU), 3.0 for N-(2-chloroethyl)-N'-cyclohexyl-N-nitrosourea (CCNU) and 5.2 for chloroethyl methanesulfonate. With respect to fluoroethylating agents, the potentiation ratios were 7.2 for N-fluoroethyl-N-nitrosourea, 2.0 for N-cyclohexyl-N'-fluoroethyl-N'-nitrosourea and 5.5 for fluoroethyl methanesulfonate. No effect was observed with the bromoethylating agent, N-bromoethyl-N-nitrosourea. There was no potentiation of the cytotoxicity of anti-cancer agents such as mitomycin C (MMC), cisplatin (CDDP), 5-fluorouracil (5FU), bleomycin (BLM), prednisolone, camptothecin, etoposide, methotrexate or vinblastine. A possible mechanism for the cytotoxic potentiation of the test compounds by BG pretreatment is discussed.

Antineoplastic Agents↗
PubMed1989

Intracellular glutathione levels in human colon cancer cells naturally resistant to cross-linking agents.

Correlation between sensitivity to two cross-linking agents, 1-(4-amino-2-methylpyridine-5-yl)-methyl-3-(2-chloroethyl)-3-nitrosourea (ACNU) and cisplatin (DDP), and intracellular glutathione (GSH) level was investigated for two naturally drug-resistant human colon cancer cell lines in comparison with two drug-sensitive human leukemia cell lines. As a result, no appreciable correlation was observed between them. We also studied the possibility that DL-buthionine-S,R-sulfoximine (BSO), an inhibitor of GSH biosynthesis, can sensitize the cancer cells to these anticancer agents via depletion of intracellular GSH. It was found that BSO potentiated ACNU cytotoxicity against human leukemia K562 cells and DDP cytotoxicity against K562 and human colon cancer WiDr cells. It indicates that cancer cells with higher GSH level are more effectively sensitized by BSO regardless of degree of their intrinsic sensitivity to these anticancer agents. These results suggest that intracellular GSH level is not a common mechanism for natural resistance to cross-linking agents in human colon cancer cells but one of the determinants of sensitivity to these anticancer agents of GSH-rich cells.

Antimetabolites↗
PubMed1985

Identification of major urinary metabolites of ACNU, 3-[(4-amino-2-methyl-5-pyrimidinyl)methyl]-1-(2-chloroethyl)-1-nitroso urea hydrochloride in rats.

Metabolites of 3-[(4-amino-2-methyl-5-pyrimidinyl)methyl]-1-(2-chloroethyl)-1- nitrosourea hydrochloride (ACNU) in rat urine were investigated. After intravenous administration of 14C-ACNU into rats, four major radioactive metabolites and two minor ones were detected in the urine by two-dimensional thin-layer chromatographic analysis. The main metabolite was identified to be an imidazolidinone compound, 1-[(4-amino-2-methyl-5-pyrimidinyl)methyl]-5-hydroxy-2-imidazolidinone (M-D). One of the other major metabolites was identified to be a nitrosated compound of the main metabolite i.e., 1-[(4-amino-2-methyl-5-pyrimidinyl)methyl]- 5-hydroxy-3-nitroso-2-imidazolidinone (M-C). These were new types of metabolites which have not been reported in the metabolic study of other chloroethylnitrosourea derivatives. Compared with authentic compounds, two metabolites were identified to be a denitrosated derivative of ACNU i.e., 1-[(4-amino-2-methyl-5-pyrimidinyl)methyl]-3-(2-chloroethyl)urea (M-B), and a cyclized pyrimidopyrimidine compound which lacks the ethylene moiety of ACNU, i.e., 3,4-dihydro-7-methylpyrimido[4,5-d]pyrimidin-2-(1H)-one (M-A). The two minor metabolites were supposed to be compounds derived from M-A. Discussions were made on mechanism of formation of these metabolites in vivo.

Animals↗
PubMed1985

In vitro metabolism of ACNU, 3-[(4-amino-2-methyl-5-pyrimidinyl)methyl]-1-(2-chloroethyl)-1-nitroso urea hydrochloride, a water-soluble antitumor nitrosourea.

In vitro decomposition of ACNU, 3-[(4-amino-2-methyl-5-pyrimidinyl)methyl]-1-(2-chloroethyl)-1-nitros ourea hydrochloride, in various conditions was studied with the use of the 14C-labeled compound. Metabolite A, 3,4-dihydro-7-methylpyrimido[4,5-d]pyrimidin-2(1H)-one (an intramolecular cyclized product), was formed spontaneously in the phosphate buffer (pH 7.4) with simultaneous liberation of the alkylating moiety. With rat liver enzyme preparations, formation of three metabolites was observed. Those were metabolite B, 1-[(4-amino-2-methyl-5-pyrimidinyl)methyl]-3-(2-chloroethyl)urea (a denitrosated product), metabolite C, 1-[(4-amino-2-methyl-5-pyrimidinyl) methyl]-5-hydroxy-3-nitroso-2-imidazolidinone (a product via oxidative dechlorination), and metabolite D, 1-[(4-amino-2-methyl-5-pyrimidinyl)methyl]-5-hydroxy-2-imidazolidinone (a denitrosated product of metabolite C). Formation of metabolite B was catalyzed with both cytosolic and microsomal enzymes, not inhibited with SKF-525A, and partly dependent on nicotinamide adenine dinucleotide phosphate (NADPH). These results suggest that at least two enzymatic steps would be involved in the formation of this product. Metabolites C and D were produced by the microsomal preparation, being dependent on O2 and NADPH, inhibited by CO and SKF-525A, and enhanced by phenobarbital pretreatment. When metabolite C was incubated with cytosolic and microsomal preparations, more efficient formation of metabolite D with the former than the latter was observed. From these results, it was assumed that oxidative dechlorination of ACNU to metabolite C would be catalyzed with the microsomal mixed function oxidase, and metabolite D would be produced via denitrosation process of metabolite C.

Animals↗
PubMed1991

[Integrative assessment of the developmental pharmacology and developmental toxicology, with special reference to the brain].

Increasing numbers of neurotoxins or therapeutic agents that have specific target cells or receptors can be used to assess the developmental correlation between the structure and function of various organs including the brain. Patients with chronic diseases are now able to maintain their social activities but still must be medicated for a long period of their life. This might increase the potential hazard of prenatal drug exposure in the progeny. Functional teratology is quite a new concept in neuroscience. Recent observations of our laboratory and those of others suggest that the sensitive period for functional teratology might encompass the whole stage of fetal life in animals and humans. The shortage of precise information on the developmental integration of the structure and function of the neurons with different properties is a problem to be solved for the further progress of developmental pharmacology and toxicology. Single exposures to drugs at a different stage during the gestational period of rats or mice might provide more useful information on the relationship between the lesioned area and related functional disorders manifested postnatally. This paper reviews recent advances in developmental neuropharmacology and functional neuroteratology including beneficial points of the short-term exposures to drugs.

Animals↗
PubMed1980

Studies on the mechanism of action of ACNU, 1-(4-amino-2-methylpyrimidine-5-yl) methyl-3-(2-chloroethyl)-3-nitrosourea hydrochloride: effects on cultured HeLa S3 cells.

Treatment of cultured HeLa S3 cells with ACNU, 100 microgram/ml, for 30 min inhibited the cell growth intensely. The cell number was minimum on the 4th day after the treatment and recovered gradually, but it was still 24% of control of the 14th day. The colony formation, as an index of proliferation ability of cells, was remarkably inhibited and the number of colony formed on the 14th day after the treatment was 8% of control. DNA synthesis was inhibited by 59%, whereas little or no effect was observed on RNA or protein synthesis after 24 hr. Ethylene-14C-ACNU was bound to DNA and RNA to a similar degree, and that bound to the acid-insoluble fraction within 30 min was decreased by half after 24 hr and sustained thereafter. A significant decrease in sedimentation velocity of DNA on alkaline sucrose density gradient centrifugation was observed after 24 hr, and the decrease on neutral sucrose density gradient centrifugation was noticeable already by 2 hr. From the results of this study and other reports, the mechanism of action of ACNU seems to be alkalization of DNA followed by damage to DNA, which progresses quite slowly compared with other alkylating agents, causing cell damage and cell death.

Cell Division↗
PubMed1992

Treatment results by uneven fractionated irradiation, low-dose rate telecobalt therapy as a boost, and intraoperative irradiation for malignant glioma.

The prognosis of malignant glioma is extremely poor. We applied conventionally fractionated irradiation combined with 1-(4-amino-2-methyl-5-pyrimidinyl)methyl-3-(2-chloroethyl)-3-nitrosourea (ACNU), uneven fractionated irradiation with ACNU, low dose rate telecobalt therapy as a boost, and intraoperative irradiation against 110 malignant gliomas to investigate the efficacy of these methods as alternative treatments for malignant glioma. Although local tumor control by uneven fractionated irradiation was better than that by the other methods, no significant improvement was obtained in survival rates. As a result of multiple regression analysis, age and histology were major factors for survival rates, and the difference of treatment methods was not important. Both low-dose rate telecobalt therapy as a boost and intraoperative irradiation showed little advantage because of the high risk of brain necrosis associated with them.

Adolescent↗
PubMed1992

DNA repair pathways in mammalian cells analyzed by isolation of ACNU-sensitive Chinese hamster ovary cells.

1-[(4-amino-2-methyl-5-pyrimidinyl)methyl]-3-(2-chloroethyl)-3- nitrosourea hydrochloride (ACNU) causes chloroethylation of DNA strand followed by cross linking through an ethylene bridge. We recently isolated two ACNU sensitive mutants from mutagenized Chinese hamster ovary cells, and found them to be new drug sensitive recessive mutants (Hata et al. 1991). The O6-methyl guanine DNA methyl transferase (MT) activities of these cells were undetectable as the parental cell line, indicating that the sensitivity of the mutant cell lines to ACNU was not due to the decreased cellular level of this enzyme. By complementation analysis with the 7 established UV-sensitive CHO cell lines, one of the mutants, UVS1, turned out to complement their UV-sensitivity and, therefore, build a new complementation group among all the CHO cell lines ever reported. The other mutant, CNU1 showed hypersensitivity only to chlorethylating agents (ACNU, CCNU) and exhibited a slightly reduced unscheduled DNA synthesis (UDS) induced by UV. It is, therefore, suggestive that this mutant is defective in a specific step of DNA repair systems, which is important for the processing of DNA damages produced by ACNU. Only cell lines from the complementation group 1 and 4 out of 7 established complementation groups of UV-sensitive CHO mutants were more sensitive to ACNU than UVS1 and CNU1, indicating some steps of excision repair pathways as well as specific repair system play important roles in repairing ACNU-induced DNA damages.

Animals↗
PubMed1988

Combination chemotherapy for multiple myeloma with melphalan, ifosfamide, prednisolone, nitrosourea and vincristine.

Melphalan, ifosfamide, prednisolone, nitrosourea [1-(4-amino-2-methyl-5-pyrimidyl)-3-(2-chloroethyl)-3-nitrosourea hydrochloride, ACNU or 1, 3-bis (2-chloroethyl)-1-nitrosourea, BCNU] and vincristine (MIP-NV) were given in combination to 48 patients with multiple myeloma. The response rate was 57% in previously untreated patients, and 39% in previously treated patients. The median survival time of previously untreated patients in stage IA + IIA was 49 months, and that of patients in stage IIIA + B was 27 months. The median survival time of stage III patients depended significantly on the duration of remission. The duration of remission and survival time of patients with relief of pain and improvement in daily activity were significantly longer than those of patients without such effects. Age, sex, blood hemoglobin concentration and bone lesion were important prognostic factors. As for the side effects, leukopenia (less than 1,000/microliter) and thrombocytopenia (less than 5 X 10(4)/microliter) occurred in 10.4% and 2.1% of the patients, respectively. It was concluded that multiple drug combination therapy with MIP-NV (MIP-NV therapy) was effective for patients with multiple myeloma at all clinical stages, because it resulted in long survival with low toxicity.

Adult↗