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At least 199 records · Page 11Linked to original sources
PubMed1982

AAAP (ACNU, adriamycin, methotrexate, prednisolone) therapy for adult erythroleukemia.

A new quadruple combination chemotherapy for acute leukemia with ACNU, Adriamycin, methotrexate, and prednisolone was developed and codenamed AAAP in 1978. We have obtained excellent chemotherapeutic results with AAAP for conventional chemotherapy-resistant leukemia in Japan. Recently we have treated three adults with erythroleukemia with an AAAP regimen. In Case I, a 45-year-old woman attained a complete remission after only one course of AAAP, which was maintained for 21 months. The patient has been alive for over 32 months. In Case 2, a 52-year-old woman, and Case 3, a 38-year-old man, a complete remission was achieved after two courses of AAAP. Both patients have been alive over 21 and 13 months, respectively, with an initial remission duration of 14 months and 11+ months respectively. We conclude that AAAP therapy would be useful for remission induction of erythroleukemia.

Adult↗
PubMed1993

Effects of high-dose chemotherapy with syngeneic bone marrow transplantation in experimental brain tumor in rats.

BACKGROUND: The clinical dose of 3-[(4-amino-2-methyl-5-pyrimidinyl)methyl]-1-(2-chloroethyl)-1-nitro- sourea hydrochloride (ACNU) is limited by the bone marrow suppression it produces. The authors investigated whether bone marrow transplantation (BMT) associated with a high dose of ACNU could alleviate marrow toxicity and achieve greater antitumor effects in Fischer rats. METHODS AND RESULTS: High doses of ACNU (20, 25, and 30 mg/kg) were administered on day 1, followed by injection of syngeneic bone marrow cells on day 3. Patterns of leukocyte recovery were compared in BMT and non-BMT groups. There was a significant benefit in leukocyte recovery in the BMT groups. A 9L glioma that was sensitive to ACNU was transplanted into the brain tissue of rats. Seven days later, the animals were divided into three groups based on the dose of ACNU (2, 10, and 25 mg/kg). The median survival time increased with larger ACNU doses. CONCLUSIONS: This suggested that high-dose ACNU chemotherapy with BMT could achieve greater antitumor effects and less bone marrow suppression than high-dose ACNU alone.

Animals↗
PubMed1987

Cell cycle perturbation of cultured C6 glioma cells following short-term contact with a low dose of ACNU.

The purpose of this study was to investigate the cell cycle perturbation of cultured C6 rat glioma cells induced by 1-(4-amino-2-methyl-5-pyrimidyl)methyl-3-(2-chloroethyl)3-nitrosourea hydrochloride (ACNU) using simultaneous flow cytometric measurements of DNA and bromodeoxyuridine (BrdU) content. A new graphic computer program permitted the quantification of cell density in hexagonal subareas and allowed the fraction of BrdU-labeled cells with mid-S phase DNA content (FLS) to be defined in a narrow window. The cell kinetic parameters such as cell cycle time (Tc) and S phase time (Ts) were estimated from a manually plotted FLS curve at 18 and 6 hr, respectively. The major effect of ACNU on the cell cycle was an accumulation of the cells in the G2M phase 12 to 24 hr posttreatment when compared to G2M traverse of untreated cells. For the two-dimensional analysis, cells were labeled with BrdU and then treated with ACNU, or treated with ACNU and then labeled with BrdU. It was concluded that the cells in the S and G2M phases at the time of ACNU administration progressed to mitosis but that the G1 phase cells accumulated in the subsequent G2M phase. Two-dimensional FCM analysis using BrdU provided a useful tool in studying cell cycle perturbation.

Animals↗
PubMed2003

O6-methylguanine-DNA methyltranspherase gene expression in gliomas by means of real-time quantitative RT-PCR and clinical response to nitrosoureas.

O(6)-methylguanine-DNA methyltransferase (MGMT) mRNA expressions were examined in 100 neuroepithelial tumors by real-time quantitative reverse transcription-polymerase chain reaction (RT-PCR) using SYBR Green I. The mean relative quantitation value of MGMTmRNA normalized to the level of beta2-microglobulin for 100 tumors was 5.3 +/- 11.2. The mean value of 41 glioblastomas was significantly higher than that for the other 59 tumors (p = 0.0008 by Student's t-test). In contrast, the means of 19 low-grade gliomas and 12 medulloblastomas were significantly lower than that of other tumors (p = 0.0282 and p = 0.0456 by Student's t-test). Among the 55 retrospective patients who had been treated with 1-(4-amino-2-methyl-5-pyrimidynyl)methyl-3-(2-chloroethyl)- 3-nitrosourea hydrochloride (ACNU), the value was a significant independent predictor of the effect of initial therapy with ACNU (p = 0.0007 by Mann-Whitney U-test) and the survival period (p = 0.0175 by Wald test). The value >or=1 was the most significant factor in predicting the initial effect of treatment by multi-variant regression analysis (p < 0.0001). These results suggest that our individual adjuvant therapy based on MGMTmRNA expression may be improved by the application of real-time quantitative RT-PCR.

Adult↗
PubMed2005

O6-methylguanine-DNA methyltransferase methylation and TP53 mutation in malignant astrocytomas and their relationships with clinical course.

Epigenetic silencing of O(6)-methylguanine-DNA methyltransferase (MGMT) by promoter methylation can confer cancer cells with an increased sensitivity to alkylating chemotherapeutic agents and a higher susceptibility to TP53 transition mutations. The aim of our study was to assess the correlation of promoter methylation of the MGMT gene with TP53 mutations and the clinical characteristics of malignant astrocytomas. We analyzed the MGMT promoter methylation and TP53 mutations in 45 malignant astrocytomas (16 anaplastic astrocytomas and 29 glioblastomas multiforme) treated prospectively with 1-(4-amino-2-methyl-5-pyrimidinyl)methyl-3-2(2-chloroethyl)-3-nitrosourea, interferon-beta and radiation therapy, and evaluated their clinical usefulness. MGMT promoter methylation was found in 17 (38%) of the 45 newly diagnosed malignant astrocytomas. A clear trend existed between MGMT methylation and G:C to A:T transition mutations of TP53 (p = 0.0596). Patients with MGMT-methylated tumors displayed a greater chance of responding to adjuvant therapy as compared with those with MGMT-unmethylated tumors (p = 0.0393). TP53 mutation was not significantly associated with the clinical response (p = 0.1310). While neither MGMT methylation nor TP53 mutation had a significant effect on prognosis of the whole population, the presence of MGMT methylation emerged as a significant predictor of a longer survival when exclusively analyzing 29 patients with glioblastomas multiforme. These findings highlight the importance of MGMT methylation as a specific predictive factor for responsiveness to nitrosourea chemotherapy.

Adult↗
PubMed1986

Combined effect of ACNU and 5-FU on rat glioma cells in spheroids and monolayer cultures.

Combined effects of ACNU and 5-Fu on rat glioma clone-6 cells grown exponentially as monolayers and in multicell spheroids (500-600 micron in diameter) were analyzed by the colony-forming assay. Cells in spheroids with central necroses were more sensitive to ACNU than cells in monolayer, although a large fraction of the cells in these spheroids was resistant to 5-Fu. The effect of ACNU was enhanced by the combined treatment with 5-Fu for cells in both spheroids and monolayers, and was more remarkable when 5-Fu was administered 24 hr prior to ACNU treatment. The enhancement was mainly due to a decrease in the number of spheroid-cells resistant to 5-Fu. Isobologram analysis indicated that the enhancement was supra-additive when a low concentration of 5-Fu was combined with a high concentration of ACNU. It is suggested that a low dose of 5-Fu combined with a high dose of ACNU may preferentially kill more cells in solid tumors.

Animals↗
PubMed1987

Experimental combination chemotherapy of ACNU and 5-FU against cultured glioma model (spheroid) and subcutaneous rat glioma.

The effects of combination chemotherapy of ACNU and 5-FU on cells grown exponentially as monolayers, cells in multi-cell spheroids and in s.c. transplanted tumors of rat glioma clone-6 cells were analyzed by the colony-forming assay. The cytotoxic effect of ACNU on cells in spheroids was enhanced by continuous 5-FU pretreatment for several hours, but further enhancement was obtained only if the 5-FU pretreatment lasted for more than 12 hr. The combined effect was decreased by a drug-free interval due to recovery from potentially lethal 5-FU damage, but ACNU treatment immediately after 5-FU treatment suppressed PLD recovery. Analysis with sequential trypsinization of spheroids indicated that ACNU showed more marked cytotoxicity on cells in the deeper layers in spheroids than on those in the outer layers, whereas the effect of 5-FU decreased towards the deeper cell layers. Enhancement of treatment with ACNU combined with 5-FU was evident for cells in the outer layers, but was more remarkable in the deeper layers. The combined effect of ACNU and 5-FU on s.c. tumors was similar to that in spheroids. The effect of combined treatment of ACNU with 5-FU on increase in body weight was within the additive range of both drugs acting independently, but was more than additive for the growth delay of s.c. tumors.

Animals↗
PubMed1991

Glutathione and cellular response of ACNU-resistant rat glioma sublines to drugs and radiation.

Three ACNU-resistant sublines (R1, R3 and R12) from rat glioma 9L cells showed cross-resistance to vinblastine, adriamycin, and VP-16. Among these, the R3 subline also acquired radioresistance under aerobic conditions. Total glutathione levels in these sublines were elevated 2- to 3-fold. Treatment of the cells with BSO, a specific inhibitor of GSH synthesis, resulted in decreased intracellular total glutathione levels in all 4 cell lines to about 10% of control levels. However, sensitivity to radiation or to chemicals did not change accordingly. Treatment of 9L cells with OTZ, a precursor of cysteine, resulted in a rise in intracellular GSH levels but it did not correlate with sensitivity to X-ray or to ACNU. These results suggest that, in terms of cellular sensitivity to radiation or ACNU, total glutathione level alone cannot serve as a predictive indicator.

Animals↗
PubMed1993

Influence of O6-methylguanine-DNA methyltransferase activity on chloroethylnitrosourea chemotherapy in brain tumors.

Chloroethylnitrosoureas (CENUs) alkylate DNA at specific sites and inhibit DNA replication in tumor cells. O6-Alkylguanine moieties resulting from alkylation of guanine bases are thought to be one of most lethal adducts in living cells. Effectiveness of CENUs is known to relate well with an enzymic activity of the DNA repair enzyme O6-methylguanine-DNA methyltransferase (MGMT), which recognizes and removes O6-alkylguanine. To improve therapeutic results of CENUs, we have measured MGMT activity of human brain tumors and studied the relationship between MGMT activity and clinical responsiveness to I-(4-amino-2-methyl-5-pyrimidinyl)methyl-3-(2-chloroethyl)-3-nitrosourea hydrochloride (ACNU). Thirty-seven patients with brain tumors were entered into the study. The neoplasms included gliomas, non-glial tumors, and brain metastases. The MGMT activity of gliomas was significantly lower than that of non-glial tumors and brain metastases. No significant difference in the enzyme activity was noted between low- and high-grade gliomas. Out of the 22 gliomas 5 tumors indicated a value below 60 fmol/mg, suggestive of a methyl excision repair minus (Mer-) tumor. Two out of 3 evaluable patients with a Mer- tumor responded well to post-operative ACNU adjuvant chemotherapy. Our results suggest that brain tumors include a certain percentage of Mer- phenotype tumors, and that CENUs such as ACNU should be applied selectively on tumors with a low MGMT activity in order to increase the therapeutic effectiveness.

Adolescent↗
PubMed1994

Enhancing effect of O6-alkylguanine derivatives on chloroethylnitrosourea cytotoxicity toward tumor cells.

O6-Alkylguanine derivatives are well known as chemical modulators of the DNA repair enzyme O6-methylguanine-DNA methyltransferase (MGMT). Depletion of the enzyme by these derivatives leads to increase sensitivity of tumor cells to chloroethylnitrosoureas. We tested the effect of O6-methylguanine, O6-benzylguanine, O6-(p-methylbenzyl)guanine, O6-(p-chlorobenzyl)guanine, O6-(p-methoxybenzyl)guanine, O6-methylhypoxanthine and O6-benzylhypoxanthine on the sensitivity of tumor cell lines to 1-(4-amino-2-methyl-5-pyrimidinyl)methyl-3-(2-chloroethyl)-3- nitrosourea hydrochloride (ACNU) using a colorimetric cytotoxicity assay. The sensitivity of MGMT-proficient tumor cells including HeLA S3, C6-1, C6-2/ACNU, U-138 MG and U-373 MG cells was greatly enhanced by 2 hr pretreatment of 10-100 microM O6-benzylguanine, O6-(p-methylbenzyl)guanine and O6-(p-chlorobenzyl)guanine, but not by O6-methylguanine or O6-methylhypoxanthine. O6-(p-methylbenzyl)guanine moderately sensitized the 2 cell lines, HeLa S3 and C6-1, tested in our study to ACNU cytotoxicity. O6-Benzylhypoxanthine at the high concentration (100 microM) sensitized, to some extent, 3 MGMT-proficient cell lines. Lesser degrees of enhancement by the O6-benzylguanine derivatives were noted in MGMT-deficient tumor cells. Biological effects of O6-alkylguanine derivatives on enhancing ACNU cytotoxicity of tumor cells suggest that the exocyclic 2-amino and O6-benzyl groups in O6-benzylguanine skeleton are both essential for the inhibition of MGMT activity.

Animals↗
PubMed1995

Differential inactivation of O6-methylguanine-DNA methyltransferase activity by O6-arylmethylguanines.

Activity of O6-methylguanine-DNA methyltransferase (MGMT) is well related with drug resistance of tumor cells to chloroethylnitrosoureas (CENUs), because MGMT removes CENU-induced O6-alkylguanines in DNA by accepting the alkyl group at a cysteine moiety. Inactivation of MGMT is a feasible way to overcome MGMT-related resistance of tumor cells to CENUs. O6-Benzylguanine is known to be a strong depleter of MGMT. We previously reported the potentiation effect of O6-arylmethylguanine derivatives on cytotoxicity of 1-(4-amino-2-methyl-5-pyrimidinyl)methyl-3-(2-chloroethyl)-3-nitrosourea hydrochloride (ACNU), a CENU, for HeLa S3 cells. In this study, we tested the activity of these O6-arylmethylguanine derivatives as depleters of MGMT using HeLa S3 cell-free extract. The O6-arylmethylguanine derivatives tested were O6-benzylguanine (1), O6-(4-, 3-, and 2-fluorobenzyl)guanines (2-4), O6-(4, 3-, and 2-trifluoromethylbenzyl)guanines (5-7), O6-(4-, 3-, and 2-pyridylmethyl)guanines (8-10), and O6-(2- and 1-naphtylmethyl)guanines (11,12). Among these, compounds 1-3, 5, 8, 9 and 11 showed a strong MGMT depletion activity, whereas compounds 4, 6, 7, 10 and 12 were inactive. These inactive compounds, except for 6, have a substituent at the alpha position of the benzyl group (4, 7, 12) or are an alpha nitrogen analogue of 1 (10). There was a good relation (r = -0.856, p < 0.001) between the MGMT depletion activity of O6-arylmethylguanine derivatives and their potentiation activity of ACNU cytotoxicity. These results suggest that the alpha position of the benzyl group plays an important role in the interaction of O6-arylmethylguanine derivatives with MGMT to result in the inactivation of MGMT. Potent MGMT inactivators (1-3, 5, 8, 9, 11) sensitize tumor cells to CENU chemotherapy.

Antineoplastic Agents↗
PubMed1984

Selective effects of Lipiodolized antitumor agents.

Lipiodol Ultra-Fluid (Lipiodol) remains selectively in the tumor for an extended time when applied through arteries feeding the tumor. Although lipophilic antitumor drugs are selective when combined with Lipiodol, wide application of common hydrophilic agents is limited, as these compounds are insoluble in oil. We propose "Lipiodolization" of water-soluble agents using as an intermediate Urografin, a water-soluble contrast medium. Thirteen patients with primary hepatocellular carcinoma were treated with this Lipiodol-Urografin system containing antitumor agents. Marked decrease in serum alpha-fetoprotein (AFP) levels, decrease in tumor size in the hepatic imaging, and histologic studies of the resected specimen revealed this mode of therapy to be effective in 10 of 13 patients (77%) with hepatocellular carcinoma. Lipiodolization of antitumor agents is a new approach to selective cancer chemotherapy.

Adult↗
PubMed1986

Effects of cyclophosphamide, cis-platinum, nitrosourea (ACNU), melphalan, and dacarbazine on a cytogenetically highly malignant neuroblastoma xenograft.

The effects of eight different chemotherapeutic agents were studied on a human neuroblastoma xenograft, designated TNB9, according to the standard Battelle Columbus Laboratories protocol. Cytogenetically and molecular-cytogenetically, this xenograft is known to have a homogeneously staining region (HSR) on chromosome 20 and to exhibit 60- to 80-fold amplification of clone #8 (1.75 kb) and N-myc (2.1 kb) in the HSR. Our previous analyses of cytogenetic and phenotypic characteristics on nine human neuroblastoma xenografts demonstrated that TNB9 is one of the most malignant strains of neuroblastoma. The in vivo chemotherapeutic sensitivity assessment disclosed that cyclophosphamide, cis-platinum, nitrosourea (ACNU), melphalan, and dacarbazine (DTIC) are effective, while aclarubicin, vincristine, and cytosine arabinoside are quite ineffective against this neuroblastoma xenograft.

Adolescent↗
PubMed1995

Treatment combined with bone marrow transplantation for advanced neuroblastoma: an analysis of patients who were pretreated intensively with the protocol of the Study Group of Japan.

One hundred and ten patients with advanced neuroblastoma were treated with the protocol of the Study Group of Japan between January 1985 and March 1991. Patients received six cyclic courses of regimen A1, consisting of cyclophosphamide (1,200 mg/m2), vincristine (1.5 mg/m2), tetrahydropyranyl adriamycin (40 mg/m2), and cisplatin (90 mg/m2). Primary tumors and regional lymph node metastases were removed some time during the first six cycles of regimen A1. After six cycles of A1, the patients were divided into three groups. Patients in group 1 received alternating treatment with regimen B (cyclophosphamide and ACNU) and intensified A1, and those in group 2 were treated with alternating administration of regimen C (cyclophosphamide and DTIC) and intensified A1. Patients in group 3 were treated with supralethal therapy and bone marrow transplantation (BMT). Event-free survival rates at five years were 38.8% in the chemotherapy group (groups 1 and 2) and 50.0% in the transplant group (group 3). Because of the study design that was not in truly randomized fashion and because of the small number of patients in each risk group, it is indicated, though not concluded, that the transplant group had a better prognosis than the chemotherapy group in the cases with stage III disease or with amplified N-myc oncogene, based on the statistical calculations. Differences in survival rates for patients who underwent BMT when complete remission (CR) was achieved and for those who achieved CR but who did not undergo marrow transplant were statistically insignificant. BMT-related death occurred in 3 of 31 cases (9.7%) undergoing marrow transplant, and the causes of the death included hemorrhagic pneumonia, myocardial disturbance and hemorrhagic uremia.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1996

Elevated expression of DNA polymerase beta gene in glioma cell lines with acquired resistance to 1-(4-amino-2-methyl-5-pyrimidinyl)methyl-3-(2-chloroethyl)-3- nitrosourea.

We investigated the expression of DNA polymerase beta (beta-pol) and O6-methylguanine-DNA methyltransferase (MGMT) in human glioma cells with acquired resistance to 1-(4-amino-2-methyl-5-pyrimidinyl)-methyl-3-(2-chloroethyl)-3-nitrosoure a (ACNU) and in the parent cells. ACNU-resistant T430 (T430R) and A172 (A172R) glioma cell lines were established following repeated exposure to ACNU. The level of MGMT mRNA expression was elevated in T430R, but not in A172R. In contrast, the level of beta-pol mRNA expression and the level of beta-pol protein were elevated in A172R, compared with the parent cells. While the mechanism of MGMT repair has been considered to be important in the drug resistance of human brain tumors to ACNU, our present results demonstrate that beta-pol may also play an important role in the acquisition of tumor cell resistance to ACNU in human gliomas.

Antineoplastic Agents↗
PubMed1997

Posttranscriptional regulation of MRP/GS-X pump and gamma-glutamylcysteine synthetase expression by 1-(4-amino-2-methyl-5-pyrimidinyl) methyl-3-(2-chloroethyl)-3-nitrosourea and by cycloheximide in human glioma cells.

Treatment of human glioma A172 cells with 1-(4-amino-2-methyl-5-pyrimidinyl) methyl-3-(2-chloroethy-3-nitrosourea (ACNU) for 2 to 4 hr resulted in a 2- to 3-fold increase in steady-state levels of multidrug resistance-associated protein (MRP) and gamma-glutamylcysteine synthetase (gamma-GCS) mRNA. Nuclear run-on assays revealed a less than 0.5-fold increase in transcription rates of these genes under the same treatment conditions, suggesting that posttranscriptional regulation plays an important role for the increased mRNA levels. In the absence of ACNU, rates of MRP and gamma-GCS mRNA degradation were similar in A172 cells as determined by incubating cells with the RNase inhibitor, Actinomycin D. ACNU treatments resulted in increased MRP mRNA stability. Induction of MRP and gamma-GCS mRNA by ACNU apparently did not require de novo protein synthesis as determined by the use of protein synthesis inhibitor cycloheximide (CHX). However, CHX alone could induce accumulation of gamma-GCS mRNA, also by posttranscriptional mechanism. Taken together, these results demonstrate that (i) posttranscriptional regulation is primarily involved in the induction of MRP and gamma-GCS expression by ACNU and CHX in human glioma cells; and (ii) despite the fact that these two genes have been reported to be frequently co-expressed, their responses to the treatments of RNA and protein synthesis inhibitors are not the same.

ATP-Binding Cassette Transporters↗