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At least 433 records · Page 24Linked to original sources
PubMed1993

Effect of chemoradiotherapy using ACNU, vincristine, and nicardipine with high-dose irradiation on malignant astrocytomas.

Fifty-two patients with malignant astrocytoma were treated with cellular synchronization radiation therapy at the University of Tokyo Hospital between 1977 and 1989. Twenty-five patients (Group 1) received 1-(4-amino-2-methyl-5-pyrimidinyl)methyl-3-(2-chloroethyl)-3- nitrosourea hydrochloride (ACNU), vincristine, and 60 Gy of irradiation, and 27 patients (Group 2) ACNU, vincristine, the Ca-channel blocker nicardipine, and 72 Gy of irradiation. Median survival times for Groups 1 and 2 were 15 and 30 months, respectively. Although there was no significant difference, Group 2 achieved longer survival with 1-, 2-, and 3-year survival rates of 85.2, 65.8, and 46.9% compared to rates of 66.7, 40.0, and 26.7%, respectively, for Group 1.

Adolescent↗
PubMed1993

Effects of ACNU and cranial irradiation on the mouse immune system.

The effects of ACNU and cranial irradiation on the immune system were studied in three groups of 90 mice: Group A, intraperitoneal injection of ACNU (30 mg/kg); Group B, single exposure of 10 Gy to the head; and Group C, intraperitoneal injection of ACNU (30 mg/kg) and single exposure of 10 Gy to the head. Peripheral white blood cell counts, spleen cell subsets, natural killer (NK) cell activity, lymphocyte blastogenesis, and production of interferon (IFN)-gamma were analyzed once a week for 6 weeks after treatment. In Group A, NK cell activity decreased between weeks 4-5, concanavalin A blastogenesis decreased during weeks 1-5, and the levels of L3T4 (CD4) and Lyt2 cells (CD8) and IFN-gamma production decreased during weeks 2-5. However, all tested parameters returned to the normal range at 6 weeks. In Group B, all parameters except for the L3T4 cell level and the IFN-gamma production decreased during week 1, and returned to the normal range thereafter. The concentration of L3T4 cells decreased during week 2 and between weeks 5-6. The IFN-gamma production increased during week 1, decreased during week 2, and returned to the normal range thereafter. In Group C, the suppressive effects were severe and continued for a longer period than in either Group A or B. Concanavalin A blastogenesis, L3T4 cell concentration, and IFN-gamma production were still suppressed after 6 weeks. Therefore, intensive radiochemotherapy for brain tumor may suppress the immunological function.

Animals↗
PubMed1994

Vasculopathy of the anterior choroidal artery following intra-arterial chemotherapy--case report.

A 40-year-old male, treated with radiotherapy and supraophthalmic intracarotid artery (ICA) ACNU infusion for glioblastoma in the right occipital lobe, developed cerebral infarction secondary to vasculopathy manifesting as hemiparesis 3 months after a second ICA injection. The initial diagnosis was focal neurotoxicity, but angiography revealed severe vasospasm of the anterior choroidal artery. The symptoms improved gradually with therapy for the vasospasm. Angiography is required to discriminate vasospasm and focal neurotoxicity as a complication of ICA injection of antineoplastic agents.

Adult↗
PubMed1995

Intra-arterial ACNU and cisplatin chemotherapy for the treatment of glioblastoma multiforme.

Intra-arterial (IA) chemotherapy has achieved no obvious clinical superiority as a treatment for glioblastoma multiforme despite the many theoretical advantages. The clinical courses of 38 patients who underwent surgery and radiotherapy with IA 1-(4-amino-2-methyl-5-pyrimidinyl)-methyl-3-(2-chloroethyl)-3-nitrosourea hydrochloride (ACNU) and cisplatin were reviewed. Tumor regrowth was evaluated by comparison of contrast-enhanced areas on computed tomographic scans. The initial response rate was 19 of 32 patients evaluated, and the median survival time (MST) for all 38 patients was 53 weeks. Local recurrence was observed in 20 patients, and distant recurrence (areas more than 3 cm from the original tumor margin) was observed in 15 patients. The MST was 59 weeks for patients without distant recurrence, and 42 weeks for patients with distant recurrence (statistically not significant). Adjuvant IA ACNU and cisplatin chemotherapy did not improve the survival time. An important clinical feature was the high incidence of distant recurrence, in contrast to experience with other conventional therapy regimens. Distant recurrence, without extended survival, may suggest insufficient control of tumor regrowth.

Adolescent↗
PubMed1996

Phase II study of DTIC, ACNU, and vincristine combination chemotherapy for supratentorial malignant astrocytomas.

This phase II clinical study evaluated the use of 5-(3-3'-dimethyl-1-triazeno)imidazole-4-carboxamide (DTIC) pretreatment to reduce cellular resistance and enhance the antitumor effects of chloroethyl nitrosoureas in 32 patients with supratentorial malignant gliomas, including 13 anaplastic astrocytoma and 19 glioblastoma multiforme. All patients received a total dose of 50-65 Gy radiation therapy after surgery. Chemotherapy consisted of DTIC (1 mg/kg) on days 1-5, 1-(4-amino-2-methyl-5-pyrimidinyl)methyl-3-(2-chloroethyl)-3-nitrosourea hydrochloride (2 mg/kg) on day 5, and vincristine (0.02 mg/kg) on days 1 and 15 every 5 weeks. One patient achieved complete response and 12 patients showed partial response. Median survival time was 18 months and median time-to-progression was 11 months. No significant toxicity was encountered. There was no significant benefit of this pretreatment to combination chemotherapy when compared with previous results. This study does not support a further role for DTIC as a depleter of O6-alkylguanine deoxyribonucleic acid alkyltransferase activity preceding chloroethyl nitrosourea-based chemotherapy.

Adolescent↗
PubMed2004

Randomized controlled trial on malignant brain tumors--activities of the Japan Clinical Oncology Group-Brain Tumor Study Group.

The Japan Clinical Oncology Group (JCOG)-Brain Tumor Study Group was organized with the support of the Health and Labour Sciences Research Grants of the Ministry of Health, Labour and Welfare. The group is now preparing a multi-institutional randomized controlled phase II/III study of chemoradiotherapy using ACNU versus procarbazine and ACNU for astrocytoma grades 3 and 4. The overall survival and response rates will be compared between the patients treated with ACNU and those treated with ACNU plus procarbazine. This study, under the surveillance of the JCOG, aims to set a standard protocol for treating patients with malignant glioma. Moreover, the study will establish a proper methodology for performing randomized studies in the field of neuro-oncology.

Antineoplastic Agents↗
PubMed1996

[Monoclonal rheumatoid factor in a patient with multiple myeloma after chemotherapy].

A patient with multiple myeloma was treated with several cycles of chemotherapy and developed monoclonal IgA rheumatoid factor. The monoclonal rheumatoid factor in this case reacted with 2 types of monoclonal antiidiotypic antibody derived from monoclonal rheumatoid factors in a patient with Sjögren's syndrome and a patient with macroglobulinemia. Two possible mechanisms accounting for the development of rheumatoid factor activity during a course of chemotherapy are discussed. The first possibility is that the rheumatoid factor or activity had been initially covered by an antiidiotypic antibody but was disclosed by the decreased production of this antibody following by the immunosuppressive therapy. The second possibility is that monoclonal IgA acquired rheumatoid factor activity by a point mutation resulting in a change in the molecular structure of the idiotype.

Aged↗
PubMed1992

Development of resistance to antitumor chloroethylnitrosoureas in vitro in brain tumor cells.

Rat brain tumor cell lines (9L, C6-1, C6-2), human brain tumor cells (T98G), and HeLa S3 cells were studied to assess their acquired resistance to the chloroethylnitrosoureas (CENUs), 1-(4-amino-2-methyl-5-pyrimidinyl)methyl-3-(2-chloroethyl)-3-nitrosourea hydrochloride (ACNU) and methyl-6-[3-(2-chloroethyl)-3-nitrosoureido]-6-deoxy-alpha-D-glucopyr anosid e (MCNU), after 10 repeated exposures of a panel of different drug concentrations. Assay end-point was colony-forming ability after 24-h drug exposure. Intrinsic resistance was tested at the 10% survival dose (SD10) and C6-1, T98G, and HeLa S3 cell lines were 3 to 16 times more resistant to ACNU than 9L and C6-2 cell lines. After repeated exposures to ACNU, 9L and C6-2 cells acquired 2- and 5-fold resistance to ACNU respectively, whereas C6-1 and T98G cells retained a resistance almost equivalent to the respective parent cells. HeLa S3 cells also acquired resistance to ACNU, as evidenced by a 3.5-fold increase. The SD10 of the cells to MCNU ranged from 4.3 microM (C6-2 cells) to 151.7 microM (T98G cells). After long-term exposure to MCNU, all five cell lines became significantly resistant compared to their respective parent cells. The easily obtained acquired resistance to CENUs suggests a clinical disadvantage of continual and repeated adjuvant monochemotherapy with these agents.

Animals↗
PubMed1981

Alteration of blood-CSF barrier by tumor invasion into the meninges.

Cyclophosphamide and 1-(4-amino-2-methyl-5-pyrimidinyl)methyl-3-(2-chloroethyl)-3-nitrosourea hydrochloride (ACNU) were found to have an equivalent cytostatic effect in rats with subcutaneous transplants of Walker 256 carcinosarcoma. Rats with meningeal carcinomatosis received a single intravenous dose of cyclophosphamide (30 mg/kg) or ACNU (15 mg/kg) at various times after intracisternal inoculation of 1 X 10(4) Walker 256 carcinosarcoma cells. Cyclophosphamide, administered 1 day after tumor inoculation, failed to prevent tumor growth in the subarachnoid space. The survival time of these rats was prolonged only 10% to 14% compared to the controls, while ACNU produced a maximum increased survival time of 180%. If administered 2, 3, 4, and 5 days after tumor inoculation, both drugs were effective; cyclophosphamide yielded a maximum increase in median survival time of 109%, 94%, 90%, and 52%, and ACNU 127%, 139%, 240%, and 100%, respectively. These results indicate that the blood-cerebrospinal fluid (CSF) barrier was circumvented in the early stage of subarachnoid tumor growth, although some areas remained where the infiltrating tumor cells were protected from systemically administered drugs by the intact barrier.

Animals↗
PubMed1983

Intra-arterial ACNU therapy for malignant brain tumors. Experimental studies and preliminary clinical results.

The authors examined the growth rate of mouse 203 glioma cells in vitro and found it to be markedly inhibited after exposure to ACNU for 5 minutes at a drug concentration of 100 micrograms/ml. Rats that had undergone intracranial implantation of T1 neurogenic tumor were treated by 5 mg/kg of ACNU administered either intravenously or intra-arterially. The median survival times for the control animals and the animals undergoing intravenous or intracarotid administration of ACNU were 23, 29, and 46 days, respectively. The difference in survival time between the intravenous and intracarotid administration groups was statistically significant (p less than 0.01) when examined by the Cox-Mantel test. In a clinical trial, 17 patients with glioblastoma were treated by ACNU, eight intravenously and nine by the intra-arterial route. The drug was given in doses of 2 to 3 mg/kg at least twice before and twice after a course of postoperative radiotherapy. Intra-arterial administration was performed over a period of 5 minutes under local anesthesia. The median postoperative survival time for the patients in the intra-arterial group was 12.5 months, compared with 9.0 months for those in the intravenous group. The survival rate for the intra-arterial group was slightly higher, although statistically not significant, probably because the number of cases was small. The degree of thrombocytopenia due to ACNU tended to be less marked in the intra-arterially treated patients. The theoretical advantages of the intra-arterial administration of ACNU are discussed.

Adult↗
PubMed1985

Primary central nervous system lymphoma.

A retrospective analysis of 21 cases of primary central nervous system (CNS) lymphoma is reported. All patients presented with a solitary mass in the supratentorial region. None had previously received immunosuppressive therapy. Neuroradiological studies included technetium-99m-pertechnetate brain scanning in eight cases, cerebral arteriography in all 21 cases, and computerized tomography (CT) in 14 cases. The characteristic features were increased uptake in brain scans, mass effect in arteriograms, and marked contrast enhancement on CT scans. Abnormal tumor vessels were occasionally seen on arteriography, and subtraction films were usually required to appreciate tumor stain. All patients underwent craniotomy, and histological studies of the tumors showed a diffuse type of lymphoma in all cases. Immunoglobulin testing was performed in 19 cases and a monoclonal spike was verified in 10, suggesting a B cell origin. All patients were followed until their death except one who was still alive 12 months from onset of symptoms. Therapy included subtotal resection in all 21 cases, whole-brain irradiation in six cases, chemotherapy in two cases, and a combination of whole-brain irradiation and chemotherapy in nine cases. Three different forms of chemotherapy were used. The results suggest that chemotherapy is an important addition to subtotal resection and whole-brain irradiation in the treatment of primary CNS lymphoma.

Adult↗
PubMed1985

ACNU-resistant mutants of 9L rat glioma cell line. Isolation and preliminary characterization of these subclones.

Three ACNU-resistant subclones were isolated and characterized from a wild-typed 9L rat glioma cell line in culture. At an early stage after cloning, these ACNU-resistant subclones showed a high frequency of chromosomal aberrations compared with nonresistant 9L cells. These ACNU-resistant subclones revealed a cross resistance to BCNU, CCNU, methyl CCNU, nitrogen mustard, cyclophosphamide, and cis-platinum, which are alkylating agents. Further studies are necessary to clarify the mechanisms of ACNU-resistance from the aspect of repair of DNA alkylation damage.

Animals↗
PubMed1986

Effects of ACNU and radiotherapy on malignant glioma.

A randomized clinical study of irradiation and irradiation combined with ACNU in the treatment of malignant gliomas was performed in order to determine if there was an enhancing therapeutic effect of ACNU given in addition to radiotherapy. An effect was defined as a reduction in tumor size, changes in neurological signs and performance status within 1 month after the completion of radiotherapy, or statistically improved survival times. Seventy-seven patients from 14 neurosurgical clinics were included in this validated study group. Radiotherapy with a total dose of 5000 to 6000 rads, given in 25 to 30 subdoses, was applied to the whole brain and to a generous field surrounding the tumor. Patients who were assigned to receive chemotherapy were given ACNU intravenously once or twice during radiotherapy at a dose of 100 mg/sq m of body surface area. The response rate (more than 50% reduction of the tumor size) was 13.5% in the group treated by radiotherapy alone and 47.5% in the group with radiotherapy and ACNU. The hematological toxicity was more severe in the group treated with radiotherapy and ACNU. Other toxicity was mild and acceptable. The survival rates of patients with astrocytoma grade III and glioblastoma multiforme at 36 months after the surgery were 48.9% and 0% for radiotherapy alone and 59.0% and 16.3% for radiotherapy plus ACNU, respectively. The differences between the survival curves were not significant at the p = 0.05 level. This study has demonstrated that, although the use of ACNU during radiotherapy suppressed malignant gliomas more than radiotherapy alone, the survival time was not extended significantly. It is necessary to continue to search for an effective chemotherapeutic regimen to prolong survival of patients with malignant gliomas.

Adolescent↗
PubMed1987

Modulation in vitro and in vivo of ACNU resistance in a subline of C6 glioma with reserpine.

Reserpine enhanced in vitro the cytotoxicity of 1-(4-amino-2-methyl-5-pyrimidinyl) methyl-3-(2-chloroethyl)-3-nitrosourea hydrochloride (ACNU) in both the C6 glioma and its ACNU-resistant subline, C6/ACNU. Reserpine also enhanced the chemotherapeutic effect of ACNU in C6/ACNU-bearing (C6/ACNU-meningeal gliomatosis) rats, in which ACNU resistance could be modulated by combined ACNU and reserpine therapy. When 10 microM reserpine was added to ACNU in culture, the concentration of drug required for 50% inhibition of cell growth (IC50) of ACNU for C6/ACNU cells decreased to the level of that for C6 cells. When 20 microM reserpine was added to the culture, intracellular uptake of ACNU in C6/ACNU cells increased further and the efflux of the drug from the cells decreased. In in vivo experiments in rats, combined chemotherapy with ACNU (1 mg/kg) and reserpine (250 micrograms/kg) by intrathecal injection significantly increased the life span of the rats as compared to results with ACNU chemotherapy alone. The enhanced cytotoxicity of ACNU in ACNU-resistant glioma cells in vitro and in vivo may be explained by the increase of intracellular concentration of ACNU resulting from the inhibition of ACNU efflux from the resistant cells by reserpine. It was concluded that ACNU resistance could be modulated in vitro and in vivo by combined therapy with ACNU and reserpine.

Animals↗
PubMed1987

Influence of modes of ACNU administration on tissue and blood drug concentration in malignant brain tumors.

The water-soluble nitrosourea compound ACNU is also lipid-soluble at normal physiological pH levels. It lacks toxic effects on vision that nitrosoureas occasionally produce following intra-arterial administration. In 28 cases of both primary and secondary malignant brain tumors, ACNU was administered at surgery or angiography by three different modes: intravenous injection in Group I (10 cases), intra-arterial injection via the carotid artery in Group II (11 cases), and intra-arterial injection via the carotid artery after opening the blood-brain barrier (BBB) by means of mannitol in Group III (seven cases). Tumor tissue and blood samples were taken serially at various time intervals after ACNU injection, and ACNU was measured by high-performance liquid chromatography. The time-concentration curve for ACNU was calculated in each case by the two- and one-compartment open models for determination of ACNU levels in blood and tissue, respectively. Pharmacokinetic parameters including biological half-life, blood and tissue levels (0-t minutes and 0-infinity minutes), total plasma clearance, and distribution volume of the beta phase were compared. Statistical analysis of tissue ACNU levels at 0-t minutes revealed higher concentrations in Group III patients than in Groups II and I: levels in Group II were significantly higher than in Group I. Mean biological half-life was 30.3, 23.0, and 38.5 minutes in Groups I, II, and III, respectively. Levels of ACNU were significantly increased in tumor tissue as well as in peritumoral tissue in one Group III patient with multiple metastatic anaplastic adenocarcinoma. In this series, treatment of malignant brain tumor by intra-arterial administration of ACNU produced significantly higher tissue levels of ACNU than did the systemic intravenous route.

Adenocarcinoma↗
PubMed1987

Specific induction of ACNU-resistance in V79 Chinese hamster cells and C6 rat glioma cells.

The antitumor compound ACNU (1-(4-amino-2-methyl-5-pyrimidinyl)methyl-3-(2-chloroethyl)-3-nitroso ure a hydrochloride) is widely used for treatment of malignant brain tumors. The authors have investigated the mechanism of acquisition of ACNU resistance at the cellular level by isolating ACNU-resistant mutants from V79 Chinese hamster cells and C6 rat glioma cells after treatment of the cells with ACNU or other alkylating agents. In V79 Chinese hamster cells, ACNU at 1 to 4 micrograms/ml caused dose-dependent induction of drug-resistant mutants to ACNU (10 micrograms/ml) and 8-azaguanine (20 micrograms/ml), but not to ouabain (1 mM). Values for the mean lethal dose of ACNU-resistant mutants were 2.4 to 17.2 times those of the parent V79 cells. The ACNU-resistant phenotype was stable during an observation period of 13 weeks. The ACNU seemed to have a specific effect in inducing ACNU-resistant mutations, because no ACNU-resistant mutations were induced by treatment of the cells with other known mutagens, such as N-methyl-N'-nitro-N-nitrosoguanidine, methylmethanesulfonate, and ethylmethanesulfonate. The C6 rat glioma cells also showed a significant mutagenic response to ACNU, producing ACNU- and 5-fluorouracil-resistant mutants. The present results have the important therapeutic and mechanistic implication that ACNU is a potent mutagen and induces mutants that are resistant to ACNU and to other drugs.

Animals↗