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At least 451 records · Page 25Linked to original sources
PubMed1990

Optic nerve degeneration caused by supraophthalmic carotid artery infusion with cisplatin and ACNU. Case report.

A 28-year-old woman with a left frontoparietal anaplastic astrocytoma was treated postoperatively with a combination of cisplatin and 1-(4-amino-2-methylpyrimidine-5-yl) methyl-3-(2-chloroethyl)-3-nitrosourea hydrochloride (ACNU). The drugs were infused via the left supraophthalmic internal carotid artery in an attempt to avoid ocular toxicity. The patient subsequently developed blindness in the left eye and a right temporal hemianopsia from marked degeneration of the left optic nerve and tract. It is apparent that the placement of a catheter into the supraophthalmic carotid artery does not exclude visual complications.

Adult↗
PubMed1990

Antiproliferative effect of trapidil, a platelet-derived growth factor antagonist, on a glioma cell line in vitro.

Platelet-derived growth factor (PDGF) is produced by glioma cells. However, there is heterogeneity among glioma cell lines in the production of PDGF. It has been demonstrated that U251MG cells produce a PDGF-like molecule while U105MG cells do not. Trapidil, a specific antagonist of PDGF, competes for receptor binding with PDGF. Therefore, the inhibitory effect of trapidil on the proliferation of glioma cells was investigated in vitro using two glioma cell lines. At 100 micrograms/ml, trapidil significantly inhibited the proliferation of U251MG cells (which produce the PDGF-like molecule). At the same trapidil concentration, the proliferation of U105MG cells (which do not produce the PDGF-like molecule) was not inhibited. The inhibitory effect of trapidil was remarkable on Days 3 and 4 of culture. After 4 days of incubation, the proliferation of U251MG cells was 46% of the control preparation. Trapidil enhanced the antitumor effect of 3-[4-amino-2-methyl-5-pyrimidinyl)ethyl)-1-(2-chloroethyl)-1-nitrosourea (ACNU) against U251MG cells. The enhancing effect was highest on Days 4 and 6 of culture. After 6 days of incubation in the presence of 100 micrograms/ml trapidil and 1 microgram/ml ACNU, the proliferation of U251MG cells was 18% of the control preparation. These findings suggest that trapidil interrupts the autocrine loop at the PDGF and PDGF-receptor level and that combination therapy with trapidil and ACNU may be useful in the treatment of glioma.

Animals↗
PubMed1991

Cross-resistance patterns in ACNU-resistant glioma sublines in culture.

Three ACNU-resistant clones (R1, R3, and R12) were isolated from 9L rat glioma cells under selection pressure of ACNU in vitro. The authors have investigated the mechanisms of resistance and characteristics of these clones at the cellular level by studying cross-resistance patterns to chemical and physical agents. Although these resistant sublines showed complete cross-resistance to methyl-chloroethylnitrosourea (MCNU), no cross-resistance was observed for other alkylating agents, while each of the resistant sublines showed partial cross-resistance to structurally dissimilar toxic agents (vinblastine, Adriamycin, and VP-16). No difference in ACNU uptake was observed between 9L and R3 cells, and resistance patterns among alkylating agents suggested that the mechanism of ACNU resistance was specific to bifunctional nitrosoureas. Based on a transport study, this multidrug resistance could be explained by reduced intracellular uptake of these drugs, but there seemed little possibility that membrane P-glycoprotein, which usually is observed in typical multidrug-resistant cells, was expressed in these ACNU-resistant cells because enhanced drug efflux was not found in ACNU-resistant sublines. Significant collateral sensitivity to L-asparaginase indicated that ACNU might disturb the asparagine synthetic pathways by its mutagenic action. The increased level of total glutathione in the resistant sublines may be one mechanism of radiation or ACNU resistance.

Animals↗
PubMed1991

Hypersensitivity of rat glioma sublines with acquired ACNU resistance to L-asparaginase.

Cell lines resistant to 1-(4-amino-2-methyl-5-pyrimidinyl)methyl-3- (2-chloroethyl)-3-nitrosourea hydrochloride (ACNU) show a high degree of collateral sensitivity to L-asparaginase. The mechanism for this phenomenon was investigated by comparing the nutritional requirements and asparagine synthetase activity of the resistant sublines to those of parent cells. Nine ACNU-resistant sublines were isolated from rat glioma 9L cells after incubation with various concentrations of ACNU in Ham's F-12 medium. The 9L cells grew independently of asparagine, developing well in asparagine-deficient Dulbecco's modified Eagle's medium. In contrast, the growth rates of all nine ACNU-resistant sublines decreased under the same conditions and required the addition of 10(-4) M asparagine for maximum growth. Asparagine synthetase activity in the ACNU-resistant cells was much lower than in the 9L cells, suggesting that the requirement for asparagine in the resistant sublines was due to reduced activity of this enzyme. A growth-inhibition assay showed that the ACNU-resistant sublines were more sensitive to L-asparaginase than 9L cells by up to 2 x 10(5)-fold. These results suggest that L-asparaginase therapy has the potential to become a new approach for treating acquired ACNU resistance.

Animals↗
PubMed1992

Isolation and preliminary characterization of ACNU-resistant sublines of rat brain tumors in vivo.

Two variant cells lines resistant to the nitrosourea derivative ACNU ((1-4-amino-2-methyl-5-pyrimidinyl)-methyl-3-(2-chloroethyl)-3-nitrosourea hydrochloride), namely C6/ACNU and 9L/ACNU, were selected in vivo from rat brain tumors. Stable resistance to ACNU proved to be a characteristic of these cell lines, whether they were grown in vivo or in vitro. These cell lines exhibited a different pattern of cross-resistance to a wide range of chemotherapeutic agents with dissimilar chemical structures and mechanisms of action as compared with that of other ACNU-resistant cell lines established in vitro. Distinct cross-resistance was observed in both the C6/ACNU and 9L/ACNU cell lines to chloroethyl-nitrosoureas such as BCNU (carmustine), CCNU (lomustine), and methyl CCNU and, additionally, to vincristine, vinblastine, Adriamycin (doxorubicin), and arabinosylcytosine, but not to bleomycin, methotrexate, cis-platinum, and 5-fluorouracil. This might point to a multifactorial mechanism of drug resistance in ACNU-resistant cell lines derived from rat C6 and 9L brain tumor cells.

Animals↗
PubMed1992

Intrathecal chemotherapy with ACNU in a meningeal gliomatosis rat model.

Intrathecal administration of ACNU ((1-4-amino-2-methyl-5-pyrimidinyl)methyl-3-(2-chloroethyl)-3-nitroso urea hydrochloride) had a remarkable chemotherapeutic effect in a rat model of meningeal gliomatosis. This effect was evaluated in rats with meningeal gliomatosis induced by an intracisternal inoculation of rat C6 glioma cells. The median survival time of the rats treated with a single dose of intrathecal ACNU (1 mg/kg) on Day 1 or Day 3 after tumor inoculation was significantly prolonged by 35.7% to 42.9% or 25.0% to 28.6%, respectively, as compared with that of the control animals. Meningeal gliomatosis rat models treated intrathecally with ACNU (1 mg/kg) 5 days after tumor inoculation or intravenously with ACNU (15 mg/kg) both failed to prolong the survival time of the animals. These findings suggest that intrathecal chemotherapy with a low dose of ACNU is effective in the early stages of meningeal gliomatosis, whereas intravenous chemotherapy with a high dose of ACNU is always ineffective.

Animals↗
PubMed1994

Reversal of chemoresistance in malignant gliomas by calcium antagonists: correlation with the expression of multidrug-resistant p-glycoprotein.

Resistance to multiple drugs is often observed in malignant gliomas. The authors used a microtiter tetrazolium test to analyze primary in vitro chemoresistance and chemosensitivity of 15 early cultures of human malignant glioma exposed to 50 micrograms/ml (1,4-amino-2-methyl-5-pyrimidinyl)-methyl-3-(2-chloroethyl)-3-nitrosoure a (ACNU), 50 micrograms/ml cisplatin, 1 microgram/ml vincristine, or combinations of these chemotherapeutic agents. Primary chemoresistance was observed in 87% of tumors for ACNU, in 87% for cisplatin, and in 83% for vincristine. All tumors were examined for expression of multidrug-resistant p-glycoprotein, a transport protein of 170,000 D, by means of immunohistochemical staining with the JSB-1 antibody on paraffinized tumor sections. Eight of 15 specimens (53%) showed positive staining for the monoclonal antibody. Primary chemoresistance was overcome by addition of the calcium antagonists verapamil or nimodipine to the cultures if the original tumor expressed p-glycoprotein (p < 0.01 for verapamil, p < 0.05 for nimodipine). In tumors not expressing p-glycoprotein, addition of calcium antagonists to the cell cultures did not influence primary chemoresistance. It is concluded from these data that addition of calcium antagonists to the adjuvant chemotherapy of malignant gliomas might overcome primary chemoresistance in tumors expressing the multidrug-resistant phenotype.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2004

Induction of the DNA repair gene O6-methylguanine-DNA methyltransferase by dexamethasone in glioblastomas.

OBJECT: The DNA repair enzyme O6-methylguanine-DNA methyltransferase (MGMT) inhibits the cytotoxic effect of alkylating agents on tumor cells. The presence of two nonconsensus glucocorticoid-responsive elements in the human MGMT promoter region indicates the potential regulation of MGMT expression by glucocorticoid agents. This study was performed to elucidate whether dexamethasone affects the expression of MGMT in glioblastoma multiforme (GBM) cells, thereby limiting the benefit of chemotherapeutic alkylating agents. METHODS: Four GBM cell lines (A172, T98G, U138MG, and U87MG) were exposed to the alkylating agent 1-(4-amino-2-methyl-5-pyrimidinyl) methyl-3-(2-chloroethyl)-3-nitrosourea hydrochloride (ACNU) with or without dexamethasone. The expression levels of MGMT were correlated with the cytotoxic effects of ACNU in GBM cells. In the presence of ACNU alone, dexamethasone alone, and the combination of both agents, messenger RNA expression of MGMT was induced to varying degrees with the highest increases seen in the later conditions. This dexamethasone-dependent induction of the MGMT gene was even observed in U87MG cells in which the promoter is methylated, although the absolute expression of MGMT mRNA was the lowest in that cell line. The induction of MGMT by dexamethasone was associated with an increased resistance of these cells to ACNU. CONCLUSIONS: These results indicate that dexamethasone-mediated upregulation of MGMT limits the efficiency of alkylating agents in the treatment of malignant gliomas.

Antineoplastic Agents↗
PubMed1998

Therapeutic results of intra-arterial chemotherapy in patients with malignant glioma.

Thirty-three adult patients with anaplastic astrocytoma or glioblastoma multiforme, verified between 1990 and 1997, received postoperative intra-arterial ACNU chemotherapy and irradiation. Since our previous strategies to malignant gliomas had included intra-venous ACNU, the purpose of the present study is to evaluate the advantage of intra-arterial ACNU over its intra-venous counterpart as the historical control (37 patients). The median survival was 74.7 weeks for the former and 81.7 weeks for the latter. Although both groups were equivalent in survival, toxicity was less frequent in the intra-arterial group. Histopathological diagnosis, patient age and the Karnofsky's performance status related well with the survival.

Adult↗
PubMed1990

[High dose chemotherapy and autologous bone marrow transplantation for advanced germ cell tumor].

Six patients, with advanced germ cell tumor refractory to prior chemotherapy including cis-platinum and etoposide, were treated by high dose chemotherapy and autologous bone marrow transplantation. Etoposide (1200-1800 mg/m2), cyclophosphamide (120 mg/kg) and cis-platinum (60-120 mg/m2) were given and the autologous bone marrow was infused 72 hours after the last dose of chemotherapy. Two patients were treated by high dose chemotherapy three times. The regimen of the third high dose chemotherapy was etoposide (1800 mg/m2), cyclophosphamide (120 mg/kg), adriamycin (80 mg/m2), ACNU (200 mg/m2) and 254S (100 mg/m2). One patient died of cerebral hemorrhage 7 days after ABMT. Of the 5 patients evaluable for response, 4 responded: one patient obtained a complete response and 3 a partial response.

Adolescent↗
PubMed1999

[Expression and functions of adaptive response genes in Escherichia coli treated with mono- and bifunctional alkylating agents. Interference with SOS response].

The expression of genes belonging to the Ada regulon of Escherichia coli under the action of mono- and bifunctional alkylating agents--high-efficiency antitumor HMM, ACNU, and BCNU preparations--was studied. The functional specificity of the alkA, alkB, and aidB1 genes concerning both the structure and volume of DNA alkylation and the specificity of cell preadaptation was revealed. Additional experimental evidence for the role of the aidB1 gene as a unique "hazard gene", a component of the E. coli ada operon, was obtained. A phenomenon of positive interference between alternative SOS and Ada responses was observed for the first time upon gene expression.

Adaptation, Physiological↗
PubMedDate not supplied

Management of small cell lung cancer in elderly.

BACKGROUND: There is increasing interest in the treatment of elderly small cell lung cancer (SCLC) patients, however the patients enrolled in clinical studies are strictly selected elderlies. MATERIALS AND METHODS: We retrospectively reviewed the treatment of consecutive unselected patients more than 70 years of age in whom SCLC were diagnosed over the past 22 years. RESULTS: In patients who received cisplatin-containing chemotherapy, response rate(RR) and mean survival time(MST) were 53.8% and 9 months. Whereas, in patients who were treated with carboplatin-containing chemotherapy, RR and MST were 72.0% and 7 months. The latter group included the patients whose doses of carboplatinum was reduced 20 to 50% in the first course of treatment. There was no difference found in RR, survival, and incidence of toxicity between these chemotherapy groups. CONCLUSION: Our results showed that in elderly SCLC patients, carboplatin could be substituted for cisplatin without apparent loss of therapeutic efficacy.

Aged↗
PubMed2000

[Roles of p53 in chemotherapy of glioblastoma].

LN382, a glioblastoma cell line, has a temperature-sensitive mutant p53. At the permissive temperature (34 degrees C), arrest of cell growth at the G1 phase occurred with recovered p53's transcriptional activity, and restored p53 protein turnover. In order to understand the influence of the functional status of p53 on the sensitivity to anticancer agents in glioblastoma cells, I analyzed responses of LN382 cells and U251MG cells with a mutant p53 as a control at 34 degrees C and 37 degrees C to etoposide, paclitaxel, and cisplatin, and 1-(4-amino-2-methyl-5-pyrimidinyl)methyl-3-(2-chloroethyl)-3-nitrosourea hydrochloride (ACNU). Restoration of p53 protein function in LN382 cells at 34 degrees C reduced the cytotoxicity of etoposide and paclitaxel, whereas that of cisplatin and ACNU was not affected. In contrast, the temperature shift to 34 degrees C did not alter the cytotoxicity of etoposide, paclitaxel, cisplatin, or ACNU in U251MG cells. Transduction of wild-type p53 in LN382 cells also reduced the sensitivity of the cells to etoposide. Cell cycle analysis using flow cytometry revealed that this decrease in sensitivity was associated with an impaired transition to the G2M phase subsequent to the addition of etoposide or paclitaxel. These results indicate that cell cycle arrest induced by wild-type p53 function may abrogate the cytotoxic effects of etoposide and paclitaxel, which are dependent on G2M-associated apoptosis.

Antineoplastic Agents↗
PubMed2000

The ability in adhesion and invasion of drug-resistant human glioma cells.

Drug-resistance is critical in treating malignant tumors, and a variety of treatments are given to control it. Little study has been done, however, on biological changes in tumor cell activity in the course of acquiring drug-resistance. We used a glioma cell line to study changes in cell adhesion and invasion on acquiring drug-resistance. Human glioma culture cell line IN157 was used to establish the cell lines resistant to etoposide (VP-16), vincristine sulfate (VCR), and doxorubicin hydrochloride (DOX). Expressions of integrin alpha2, alpha3, alpha5, and beta1, neuronal cell adhesion molecule (NCAM), and matrix metalloproteinases (MMPs) were examined by flow cytometry. In drug-resistant cells, integrin expression was enhanced and NCAM expression was reduced. Adhesions to the extracellar matrix (ECM) proteins (laminin, fibronectin or type IV collagen) were studied. The adhesive ability of all cell lines increased in a concentration-dependent manner. Adhesion of drug-resistant cells was significantly stronger than that of IN157. The cell invasion of drug-resistant cell lines to the basal membrane was significantly lower than that of IN157. The cell invasion of IN157 was significantly suppressed by adding anti-NCAM antibody. In the case of IN157 with the acquisition of drug-resistance, an increase in the expression of integrins may have enhanced the adhesion to ECM proteins. This finding may be concerned with the decreased activity of drug-resistant cell lines in invading the basement membrane. NCAM expression in drug-resistant cell lines was reduced and anti-NCAM antibody abated invasion of IN157, suggesting that NCAM is involved in IN157 invasion.

Animals↗