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At least 361 records · Page 20Linked to original sources
PubMed1990

Antiproliferative effect of hyperthermia and ACNU on cultured human malignant melanoma cells.

Human malignant melanoma cultured cells were treated either with ACNU (1-(4-amino-2-methyl-5-pyrimidinyl)methyl-3-(2-chlorethyl)-3-nitro sourea hydrochloride), hyperthermia, or the combination of ACNU and hyperthermia. The combination treatment inhibited the cell growth to a slightly synergistic degree compared to the respective single treatments. The present in vitro experimental results support in part the finding of our previous report that the combination treatment with ACNU and hyperthermia have a significantly synergistic antitumor effect to human melanoma transplanted to nude mice. However, the synergistic effect was much less intense in the present in vitro experiment. The difference may have resulted from the environmental differences between in vitro and in vivo experimental systems.

Cell Count↗
PubMed2000

Myelodysplastic syndrome following treatment of malignant melanoma with vincristine, ACNU, and dacarbazine.

Therapy-related myelodysplastic syndrome is a rare adverse effect in melanoma patients elicited by chemotherapy. We report a case of myelodysplastic syndrome following treatment of malignant melanoma with alkylating agents. Peripheral blood showed a remarkable suppression of three cell lineages, and the bone marrow was slightly hypercellular. However, no morphological abnormalities were detected in the peripheral blood or the bone marrow, and chromosomal analysis was normal.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1988

Pharmacokinetic approach to rational therapeutic doses for human tumor-bearing nude mice.

To improve clinical predictability from therapeutic results of various antitumor agents in human tumor/nude mouse models it seems to be important to use a dose pharmacokinetically equivalent to the clinical dose. Thus, we attempted to find the dose of a given drug that can reproduce in the nude mouse a plasma level similar to that seen in human patients treated with an effective dose of the drug based on comparative pharmacokinetic studies between man and nude mouse. As a result, those of 3 alkylating agents, mitomycin C, 3-[(4-amino-2-methyl-5-pyrimidinyl)methyl]-1-(2-chloroethyl)-1-nitrosourea (ACNU) and cyclophosphamide, and those of 2 antimitotic agents, vincristine and vinblastine, were estimated to be one-fourth or one-fifth of their maximum tolerated doses (MTD's). On the other hand, in the case of adriamycin, its MTD was approximately equivalent to its clinical dose pharmacokinetically. In contrast, clinically equivalent doses of 2 antimetabolites tested, 5-fluorouracil and methotrexate, were significantly greater than their MTD's; i.e., their plasma levels did not reach the effective clinical ones even when their MTD's were administered to the nude mice. These results suggest that the antitumor effects of most antitumor agents are over- or underestimated in this model when MTD's are used as a therapeutic dose, and indicate that the use of clinically equivalent doses determined pharmacokinetically is desirable.

Animals↗
PubMed1988

Responsiveness of human gastric tumors implanted in nude mice to clinically equivalent doses of various antitumor agents.

To reproduce clinical effects of various antitumor agents in the human tumor/nude mouse model, we investigated the responsiveness of 11 lines of human gastric tumor xenografts to doses of the agents pharmacokinetically equivalent to the respective clinical doses, which we designated the "rational dose" (RD). We found that the response rates to mitomycin C, 3-[(4-amino-2-methyl-5-pyrimidinyl]methyl-1-[2-chloroethyl]-1- nitrosourea (ACNU), adriamycin, 5-fluorouracil were 18%, and that to vinblastine was 30%; on the other hand, those to vincristine, methotrexate, and cyclophosphamide were poor. In contrast, in our previous study using the maximum tolerated doses, response rates to mitomycin C, ACNU, and vinblastine were as high as 64-82%, and those to adriamycin and 5-fluorouracil were 18%. When these results were compared with the clinical response rates of gastric tumors, as a whole, the results with RD's exhibited much better coincidence with the clinical data in terms of relative therapeutic potency, indicating the validity of the use of clinically equivalent doses instead of maximum tolerated doses in the human tumor model.

Animals↗
PubMed1990

Determinants of drug response in a cisplatin-resistant human lung cancer cell line.

To elucidate the mechanism(s) of cisplatin resistance, we have characterized a human non-small cell lung cancer cell line (PC-9/CDDP) selected from the wild type (PC-9) for acquired resistance to cisplatin. PC-9/CDDP demonstrated 28-fold resistance to cisplatin, with cross resistance to other chemotherapeutic drugs including chlorambucil (X 6.3), melphalan (X 3.7) and 3-[(4-amino-2-methyl-5-pyrimidinyl)]methyl-1-(2-chloroethyl)-1-nitros our ea (ACNU) (x 3.9). There was no expression of mdr-1 mRNA in either wild-type or resistant cells. The mRNA and protein levels of glutathione S-transferase (GST) pi were similar in the two lines. A GST-mu isozyme was present in equal amounts and the activities of selenium-dependent and independent glutathione peroxidase and glutathione reductase were unchanged. The mRNA level of human metallothionein IIA and the total intracellular metallothionein levels were reduced in the resistant cells. Significantly increased intracellular glutathione (GSH) levels were found in the resistant cells (20.0 vs 63.5 nmol/mg protein) and manipulation of these levels with buthionine sulfoximine produced a partial sensitization to either cisplatin or chlorambucil. Increased GSH probably also played a role in determining cadmium chloride resistance of the PC-9/CDDP, even though this cell line had a reduced metallothionein level. Also contributing to the cisplatin resistance phenotype was a reduced intracellular level of platinum in the PC-9/CDDP. Thus, at least two distinct mechanisms have been selected in the resistant cells which confer the phenotype and allow degrees of cross resistance to other electrophilic drugs.

Adenocarcinoma↗
PubMed1992

Antitumor effect of PSK at a distant site: tumor-specific immunity and combination with other chemotherapeutic agents.

The antitumor effect of PSK, a Coriolus preparation, was analyzed with the double grafted tumor system in which BALB/c mice received intradermal inoculations of syngeneic Meth-A fibrosarcoma in the right (primary tumor, 10(6) cells) and left (distant tumor, 2 x 10(5) cells) flanks. Intratumoral administration of PSK significantly inhibited the growth of not only the right but also the left tumor. PSK also inhibited the growth of a methylcholanthrene-induced fibrosarcoma BAMC-1, and a methylurethane-induced adenocarcinoma Colon 26 in the double grafted tumor system of syngeneic BALB/c mice. However, when the left distant tumor was different from the right Meth-A tumor, the intratumoral administration of PSK in the right tumor was unable to inhibit the growth of the left BAMC-1 or RL male-1 tumor. The PSK-induced immunity, therefore, is tumor-specific and T lymphocytes may play an important role in antitumor memory function. The enhancement of concomitant immunity by PSK treatment was completely impaired by previous intravenous administration of an alkylating agent, cyclophosphamide (CY). The enhancement of sinecomitant immunity by PSK treatment was also impaired by previous CY intravenous administration. The antitumor effect of PSK was suppressed by previous intravenous administration of another alkylating agent, ACNU. It is possible that alkylating agents suppress the function of effector T cells and granulocytes which are very important for the antitumor immune cascade reaction due to PSK treatment. On the other hand, the antitumor effect of PSK was enhanced by previous intravenous administration of an anti-metabolite, 5-fluorouracil.

Adenocarcinoma↗
PubMedDate not supplied

Prolongation of medium exchange is associated with a decrease in function but not expression of the P-glycoprotein pump in leukaemic cells.

Daunorubucin (DNR) accumulation studies as functional tests of the multidrug resistance (MDR1) gene product P-glycoprotein have produced diverging results when correlated to response to chemotherapy in acute leukaemia. To investigate possible reasons for this diversity a starvation experiment, based upon prolongation of medium exchange, was set up in the multidrug resistant cell line CEM/VBL100. DNR accumulation (1 microgram/ml) was measured flow cytometrically in the presence or absence of Verapamil (10 micromol/l). In cells permanently kept under ideal growth conditions, addition of Verapamil resulted in an average 90% increase in DNR enhancement in five successive experiments. In contrast, DNR accumulation increased by only 26% when the medium exchange was prolonged by 30 h to 42 h. This effect was not accompanied by changes in the MDR1 gene expression at the RNA or protein level. Consequently, 53 leukaemic blast samples of 30 newly diagnosed and 18 relapsed or refractory patients with acute leukaemia (ALL-18, AML-37) were processed without any delay and under the most stringent conditions possible. Evidence of the classical MDR phenotype was arbitrarily defined by a greater than 20% enhancement in DNR accumulation in response to Verapamil (10 micromol/l) or Cyclosporin A (3 micromol/l). Using this cutoff point for analysis of newly diagnosed leukaemia we found DNR uptake better correlated to response to treatment (p = 0.002) than P-gp detection by means of immunocytochemistry, using a panel of monoclonal antibodies (p = 0.03). We conclude that DNR accumulation studies are a sensitive method for predicting therapy outcome in acute leukaemia when performed with necessary precautions.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2006

Pegfilgrastim compared with filgrastim after high-dose melphalan and autologous hematopoietic peripheral blood stem cell transplantation in multiple myeloma patients.

We undertook a comparative study of Pegfilgrastim vs. Filgrastim after high-dose melphalan and autologous peripheral blood stem cell transplantation (APBSCT) in multiple myeloma (MM) patients. Thirty-seven consecutive patients were randomly assigned to receive a single 6 mg dose of Pegfilgrastim on day 1 post-transplant (n = 18 patients) vs. daily subcutaneous injections of Filgrastim 5 microg/kg (n = 19 patients) starting on day 5 post-transplant. The median duration of grade 4 neutropenia in the Pegfilgrastim and Filgrastim groups was 5 and 6 d, respectively (P = ns). The results for the two groups were also not significantly different for time to neutrophil and platelet recovery, but incidence of febrile neutropenia (61.1% vs. 100%, P = 0.003) and duration of febrile neutropenia (1.5 d vs. 4 d, P = 0.005), were lower in the Pegfilgrastim arm. After initial haematopoietic reconstitution, we observed significantly higher value of leukocytes x 10(9) L on day 15 (6.0 vs. 2.7, P = 0.004), in the Pegfilgrastim group compared with the Filgrastim group. This study shows that a single injection Pegfilgrastim can be used with safety and efficacy similar to those provided by daily injections of Filgrastim and it is associated with a decrease incidence of infectious events after APBSCT in MM patients.

Aged↗
PubMed2006

High-dose idarubicin, busulphan and melphalan for autologous stem cell transplantation in multiple myeloma responsive to DAV chemotherapy: comparison with a historical control.

Since 1997, 32 newly diagnosed multiple myeloma patients responsive to DAV chemotherapy were autografted with idarubicin-intensified busulphan-melphalan (ida-bu-mel). Main endpoints of the study were transplant-related toxicity, overall survival (OS) and progression-free survival (PFS). The results were compared with a historical control group of 38 patients treated with the 'standard' bu-mel regimen. Concerning time to engraftment, no significant difference was observed between the two groups, while toxicity was significantly higher in the intensive conditioning group, regarding grade IV mucositis, duration of profound neutropenia, incidence of infections and platelet requirement. Five-year OS and PFS are 73 versus 78% and 37 versus 48% for the intensive and standard regimen, respectively (p value not significant). The ida-bu-mel schedule appears to be a feasible and effective regimen for newly diagnosed multiple myeloma patients; nevertheless, no apparent benefit in OS and PFS arises from the comparison with a historical control treated with standard bu-mel, which is better tolerated and at least equally effective.

Adult↗
PubMed1984

High-dose 1-(4-amino-2-methyl-5-pyrimidinyl)-methyl-3-(2-chloroethyl)-3-nitro sou rea hydrochloride (ACNU) with autologous bone marrow rescue for patients with brain stem tumors.

4 patients with brain stem tumors were treated with high-dose ACNU with autologous bone marrow rescue. Hematologic and nonhematologic toxicities were not profound. There was objective evidence of response in 2 out of the 4. All were alive for 11-21 months from onset. Safe administration of high-dose ACNU with marrow rescue will warrant further control studies to determine its superiority over conventional doses.

Astrocytoma↗
PubMed1984

[Phase II study of the water-soluble nitrosourea compound ACNU in advanced colorectal carcinomas].

In a phase-II study 46 patients with advanced colorectal cancer were treated with the new nitrosourea ACNU [1-(2-chloroethyl)-1-nitroso-3 (4-amino-2-methyl-5-pyrimidinyl)methyl-3-nitrosourea]. From 43 evaluable patients, 86% presented distant metastases and 14% an unresectable primary tumour or a recurrent tumour. 24 patients presented a colon and 19 a rectal cancer. Prior anticancer drug treatment was given to 34 patients (79%), 11 (26%) were pretreated with a nitrosourea. ACNU was administered every 4-6 weeks as a single intravenous push injection of 100 mg/m2. Most patients received 2-3 courses. From 43 evaluable patients, one patient achieved a complete and 3 a partial remission (CR + PR 9%). 5 patients reached a minimal regression (tumour regression of less than 50%) and 5 a no change for at least 2 months. The median duration (time from beginning of ACNU therapy until tumour progression) of the 14 responders was 132 days. The median survival time was significantly longer for responders in comparison to patients with progressive disease (9.8 versus 4.1 months). The dose limiting toxicity was delayed bone marrow suppression predominantly in the form of thrombocytopenia. 22/42 patients (52%) presented a thrombocytopenia of under 50.000/mm3 with a nadir after 27 days. Leucocytopenia under 2.000/mm3 were observed in 22/40 patients (30%). A fall of haemoglobin of more than 2 g/dl was seen in 71%. Nausea or vomiting over 1-2 days were found in 59% of the treatment courses. Other drug related side effects were not encountered. ACNU has a similar activity in colorectal cancer as BCNU and CCNU.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenocarcinoma↗
PubMed1988

[Induction and intensive combined therapy of acute myeloid leukemia in adults].

In a prospective multicenter study the efficacy and toxicity of an induction therapy with daunorubicin, cytosine-arabinoside and VP 16-213, followed by an intensified consolidation with high-dose cytosine-arabinoside and daunorubicin, is evaluated in adult patients with acute myelogenous leukemia. The upper age limit for inclusion in the study was 50 years. Within the first two years of this study 91 patients were enrolled. In 84 patients who have finished the remission induction therapy the rate of complete remissions is 67%. The median survival time of all patients is 22 months and the probability of survival is 46% after 24 months. So far 34 patients in complete remission have been given one or two courses of the intensified consolidation therapy with high-dose cytosine-arabinoside and daunorubicin. The probability of relapse-free survival in these patients is 46% after 22 months and the median remission duration is 20 months.

Adolescent↗
PubMed1985

Enhanced nitrosourea cytotoxicity in cell culture by sodium butyrate.

In HeLa S3 cells, sodium butyrate was found to potentiate the cytotoxicity of chloroethylnitrosoureas and alkylating agents in vitro. Using a soft-agar colony-forming assay, 2.5 and 5.0 mM sodium butyrate pretreatment for 22 h increased the cell killing efficacy of both methyl- and chloroethylnitrosoureas by between 30 and 70%. The potentiation of cytotoxicity of bifunctional nitrogen mustards by butyrate was less than that of nitrosoureas, with a 15-30% increased cell kill at 5 mM butyrate. Sodium butyrate per se reduced plating efficiency and caused growth delay if residual levels (calculated at 100 microM for starting concentrations of 5 mM) were not removed by washing prior to plating.

Butyrates↗
PubMed1988

Carcinogenicity of 1-(4-amino-2-methylpyrimidine-5-yl)-methyl-3-(2-chloroethyl)-3- nitrosoureahydrochloride and three related N-nitroso derivatives following repeated intravenous administration to male Wistar rats.

Long-term toxic evaluation of 1-(4-amino-2-methylpyrimidine-5-yl)-methyl-3- (2-chloroethyl)-3-nitrosoureahydrochloride (ACNU), 1-(2-chloroethyl)-1-nitroso-3-(methylene-2-pyridylium)-urea- hydrochloride (CNMPU), 1-(2-chloroethyl)-1-nitroso-3-(4-thiomorpholino)-urea (CNTMU) and 4-[N-(2-chloroethyl)-N-nitrosocarbamoyl]-morpholine (CNCM) which were administered each at five dosages, adapted to the clinical situation, revealed significantly increased tumor risks for the first three agents in the lung and the adrenal gland. Additionally, CNTMU and ACNU induced a significant rise in the tumor load of the neurogenic tissue; the latter compound, being in clinical use, was associated with a significantly increased number of mammary tumors as well. CNCM, however, did not exhibit significantly elevated carcinogenic activity, although the overall tumor load was up to 2.4-fold increased compared to controls. The results indicate no advantage of the newly developed ACNU with respect to its inherent carcinogenic risk as compared to clinically established 2-chloroethyl-N-nitroso derivatives.

Animals↗
PubMedDate not supplied

Treatment of malignant gliomas: a new approach.

The aim of this study is to describe the authors' experience with intra-arterial ACNU chemotherapy of malignant gliomas. The prognosis of cerebral malignant gliomas remains poor, whatever traditional therapy is applied. ACNU is a well tolerated nitrosourea with a strong antimitotic effect on neurogenic cells both in vitro and in vivo; this drug has enhanced efficacy when used at high concentrations, particularly as an intraarterial infusion. Seventy-six patients have been studied to date, 68 of whom are evaluable; these patients were treated by intra-arterial infusion of ACNU (100 mg/m2) every 6 weeks, with a mean of 2.5 courses per patient. The objective response (OR) was 28% and analysis of pretreatment factors revealed that survival was influenced by histological grade, other types of therapy applied, and age. In general IAC is well tolerated and the response and survival appear to be better than with systemic chemotherapy.

Adult↗
PubMed2005

Hypofractionated stereotactic re-irradiation: treatment option in recurrent malignant glioma.

BACKGROUND: Hypofractionated stereotactic radiotherapy (HFSRT) is one salvage treatment option in previously irradiated patients with recurrent malignant glioma. We analyzed the results of HFSRT and prognostic factors in a single-institution series. METHODS: Between 1997 and 2003, 19 patients with recurrent malignant glioma (14 glioblastoma on most recent histology, 5 anaplastic astrocytoma) were treated with HFSRT. The median interval from post-operative radiotherapy to HFSRT was 19 (range 3-116) months, the median daily single dose 5 (4-10) Gy, the median total dose 30 (20-30) Gy and the median planning target volume 15 (4-70) ml. RESULTS: The median overall survival (OS) was 9.3 (1.9-77.6+) months from the time of HFSRT, 15.4 months for grade III and 7.9 months for grade IV tumors (p = 0.029, log-rank test). Two patients were alive at 34.6 and 77.6 months. OS was longer after a total dose of 30 Gy (11.1 months) than after total doses of <30 Gy (7.4 months; p = 0.051). Of five (26%) reoperations, none was performed for presumed or histologically predominant radiation necrosis. Median time to tumor progression after HFSRT on imaging was 4.9 months (1.3 to 37.3) months. CONCLUSION: HFSRT with conservative total doses of no more than 30 Gy is safe and leads to similar OS times as more aggressive treatment schemes. In individual patients, HFSRT in combination with other salvage treatment modalities, was associated with long-term survival.

Antineoplastic Agents↗
PubMed2004

Treatment of low-grade oligodendroglial tumors without radiotherapy.

The authors prospectively treated 18 consecutive patients with low-grade oligodendroglial tumors without postoperative radiotherapy. The treatment strategy was as follows: follow-up after total resection and chemotherapy after subtotal resection or biopsy. All patients were alive and 17 patients (94%) were progression-free after a median follow-up of 4.7 years. The results suggested that radiotherapy could be postponed until clinical progression in the treatment of low-grade oligodendroglial tumors.

Adult↗