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At least 19 recordsLinked to original sources
PubMed1986

Phase II trial of nimustine (ACNU; 3-[4-amino-2-methyl-5-pyrimidinyl) methyl]-1-(2-chloroethyl)-1-nitrosourea hydrochloride) in patients with small cell carcinoma of the lung after failure on combination chemotherapy.

Thirty-nine previously treated patients received Nimustine in a phase II trial to test the therapeutic activity in refractory small cell lung cancer. Nimustine was given as a direct i.v. injection of 100 mg/m2 with treatments repeated every six weeks. Three partial remissions of 56, 123 and 355 days duration were noted among 34 evaluable patients. Thrombocytopenia was prominent with a median platelet nadir of 47,000/microliter. We conclude that Nimustine has minor antitumor-activity in heavily pretreated patients with small cell lung cancer. The definitive value of Nimustine in the treatment of small cell lung cancer, as well as its superiority over its parent compounds remains to be established.

Aged↗
PubMedDate not supplied

Modulation of O6-methylguanine-DNA methyltransferase-mediated nimustine resistance in recurrent malignant gliomas by streptozotocin--a preliminary report.

This trial is based on the strategy of reversing O6-methylguanine-DNA methyltransferase (MGMT)-mediated nimustine resistance by depleting MGMT activity with streptozotocin (STZ) pretreatment. Eight patients with recurrent malignant gliomas refractory to previous nimustine chemotherapy were entered in this study. Patients received STZ (2g/m2) followed one hour with nimustine (2-3 mg/Kg) via the ipsilateral carotid artery. After 1-2 cycles of therapy, 3 patients responded, 4 stabilized, and 1 failed. Toxic effects were generally tolerated. The preliminary results indicated that nimustine-resistant tumor cells in vivo could also be sensitized by modulation of MGMT activity.

Adult↗
PubMed1991

Phase II study of nimustine in metastatic soft tissue sarcoma. European Organization for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group.

The EORTC Soft Tissue and Bone Sarcoma Group has conducted a phase II trial in 33 eligible patients with metastatic soft tissue sarcoma with nimustine 100 mg/m2 every 6 weeks. In 31 evaluable patients there were 3 (10%) partial responses lasting 4.5, 6 and 7.5 months, and 5 cases of stable disease. 12 patients had progressive disease and 11 patients early progressive disease. Toxicity consisted mainly of leukopenia and thrombocytopenia and nausea and vomiting. It is concluded that nimustine has only minor activity in soft tissue sarcoma.

Adult↗
PubMed1990

Rapid and simple method for the determination of nimustine hydrochloride in human blood and brain by high-performance liquid chromatography.

A simple method for the determination of nimustine hydrochloride in blood and brain by high-performance liquid chromatography was developed. A pH 4.52 buffer was used in the extraction from blood and a pH 5.0 buffer was used for brain. A pre-packed Extrelut column was used to make the extraction procedure uncomplicated. At room temperature light-resistant test-tubes were unnecessary. The lower limit of detection was 50 ng/ml for blood and 100 ng/g for brain. This method may be useful for the determination of nimustine hydrochloride in blood and brain samples from patients.

Animals↗
PubMed1992

A phase II study of metastatic melanoma treated with a combination of interferon alfa 2b, dacarbazine and nimustine.

52 patients with metastatic melanoma have been treated with a combination of recombinant interferon-alfa-2b, dacarbazine and nimustine. The objective response rate was 23% with 9 complete responses (CR) and 3 partial responses (PR). The mean duration of the response was 18+ months for CR (6-31+ months) and 7 months for PR patients (4-10 months). The mean survivals were 24+ months (8-38 months) and 7 months (4-12 months), respectively. The mean duration of the response for patients with stable disease was 10+ months (2-48+ months) and the mean survival 17+ months (3-48+ months), while the patients with progressive disease died within 12 months (mean 4 months). The best responding sites were the lymph node, the lung and the subcutaneous metastases. Myelosuppression was the main adverse effect of the therapy. WHO grade 3-4 toxicity was seen in 27 patients leading to delay and reduced dosage of therapy; in 4 patients treatment was discontinued, 8 patients had no side effects. Combination therapy with interferon and dacarbazine and nimustine for metastatic melanoma offers no advantage over interferon and dacarbazine.

Adult↗
PubMed1989

Adjuvant intraarterial chemotherapy with nimustine in the management of World Health Organization Grade IV gliomas of the brain. Experience at the Department of Neurosurgery of Düsseldorf University.

A protocol with postoperative adjuvant intraarterial (ia) chemotherapy using nimustine (ACNU) was followed at the University of Düsseldorf (Federal Republic of Germany) after histologic confirmation of malignant glioma of the brain. The first iaACNU procedure was performed within 10 days of surgery, and immediately before postoperative irradiation. After radiotherapy further iaACNU courses were given. The study population consisted of 35 primarily treated malignant gliomas World Health Organization (WHO) Grade IV, i.e., glioblastomas (NIV). Of these tumors 11 showed early progressive disease (PD) (NIV primPD), whereas 24 had stable or responsive disease (NIV SD&RD). Seven patients with recurrent malignant gliomas WHO Grade IV (NIV recurrent) were also treated plus six patients with malignant gliomas WHO Grade III (NIII). Experience with 50 treated patients resulted from this study. The median survival time (MST) for the group NIV was 14.2 months; 41.0% of patients were long-term survivors. The MST for the group NIV primPD was 7.8 months; 9.1% of patients were long-term survivors. For the group NIV SD&RD a MST of 18.3 months and 66.7% of long-term survivors were determined. Patients with recurrent tumors on this treatment protocol had an additional MST of 6.1 months. The total MST after first surgery was 16.2 months. The incidence of complications was low. Systemic complications were infrequent or rare. Retinal disturbances were seen in two patients; leukoencephalopathy was not seen in our patients. In 10% of patients cerebral complications were found, which were irreversible in 2% of patients. Complications could not be assigned unequivocally to the nitrosourea. These results compare favorably with what is reported in the literature, demonstrate the potential value of iaACNU in the treatment of malignant gliomas WHO Grade IV, and should encourage the initiation of a randomized clinical trial of adjuvant iaACNU in the therapy of these tumors. The authors propose iaACNU as a valuable approach in the management of primarily diagnosed malignant gliomas WHO Grade IV, but cannot recommend the delay of iaACNU until the recurrence of a brain tumor.

Adult↗
PubMed1988

Cardiovascular anomalies produced by nimustine hydrochloride in the rat fetus.

The cardiovascular teratogenicity of nimustine hydrochloride (ACNU) was studied in rat fetuses. This drug is a nitrosourea derivative anticancer agent and produces alkylation of DNA. Pregnant Donryu rats were treated with single doses of 10, 11 or 13 mg/kg of the teratogen at various stages during gestation. Examination of the hearts was performed by microdissection after sacrificing the animals on the 20th day of gestation. The highest frequency of cardiovascular anomalies was found in the groups treated on the 8th day of gestation, but there was no difference in the rates induced by the three dosages of ACNU administered. The most common cardiovascular anomalies observed were ventricular septal defect (76.8%) and double outlet right ventricle (10.3%). A considerable number of affected fetuses (37/263) showed complex cardiac anomalies with atrioventricular (AV) malalignment and other AV valve anomalies. These anomalies include: double inlet left ventricle, straddling AV valve, atresia or stenosis of the AV valve, and dysplastic AV valve. ACNU appears to be a useful teratogenic agent for inducing complexes of cardiac anomalies which include AV malalignment.

Animals↗
PubMed1989

Pathogenesis of persistent truncus arteriosus induced by nimustine hydrochloride in chick embryos.

Nimustine hydrochloride (ACNU) is a nitrosourea derivative anticancer agent which has been shown to cause persistent truncus arteriosus in chick embryos. The objective of this study was to confirm the teratogenic effects of ACNU on the cardiovascular system of chick embryos and to determine whether ACNU induces persistent truncus arteriosus by interfering with neural crest cells. Various doses of ACNU ranging from 10 to 200 micrograms were injected under the chorioallantoic membrane of chick embryos on the third day of incubation. Saline solution was used as the control. After 10 to 11 days of incubation, 242 (46%) survivors of the 524 treated eggs were obtained. The survival rates of the embryos and the frequencies of cardiovascular anomalies were dose dependent. Of 146 embryos with cardiovascular anomalies, 104 (71%) had persistent truncus arteriosus. Ventricular septal defect and double-outlet right ventricle were seen in 37 (25%) and one (1%), respectively. Aortic arch anomalies were seen in 116 embryos (79%). Quail-chick chimeras (chick embryos with quail cardiac neural crest) were treated with 50 micrograms of ACNU and examined histologically 24 hours later. These chimeras showed dying neural crest cells in the pharyngeal arches. Dying cells were also noted in the neural tube, cranial ganglia, retina, and otocyst. These results suggest that persistent truncus arteriosus in chick embryos treated with ACNU is induced by neural crest cell death.

Abnormalities, Drug-Induced↗
PubMed1992

Effects of granulocyte colony-stimulating factor, interleukin-1 alpha, and interleukin-6 on prolonged myelosuppression induced by nimustine hydrochloride in rats.

The myelorestorative effects of granulocyte colony-stimulating factor (G-CSF), interleukin-1 alpha (IL-1 alpha) and interleukin-6 (IL-6) were studied in F-344 rats which had been treated with cyclophosphamide (CY), carboplatin (CBDCA), or nimustine hydrochloride (ACNU). In CY- or CBDCA-pretreated rats, significantly higher peripheral white blood cell (WBC) count was observed in animals treated with G-CSF and IL-1 alpha, while the platelet (PLT) count was elevated by IL-6 treatment. All of the cytokines had little effect on the hemoglobin (HB) value. Animals treated with ACNU had prolonged myelosuppression. Treatment of these animals with G-CSF and IL-1 alpha significantly enhanced the recovery of HB value as well as WBC count. Higher PLT counts were observed in treated groups, but a statistical difference was not evident. Combination therapy with G-CSF and IL-1 alpha, G-CSF and IL-6, or IL-1 alpha and IL-6 did not have any significant beneficial effects on the peripheral blood cell count in ACNU-pretreated rats over single agent therapy. Conversely, the combination of IL-6 and G-CSF had an unfavorable effect on HB and PLT levels. In rats which received multiple doses of ACNU, G-CSF treatment exhibited a beneficial effect on WBC, HB, and PLT levels, the most prominent on the HB value. These findings suggest that treatment with hematopoietic cytokines may be most beneficial when combined with anticancer drugs which are known to cause prolonged myelosuppression.

Animals↗
PubMed1988

DNA lability induced by nimustine and ramustine in rat glioma cells.

The DNA labile sites induced by two nitrosoureas, nimustine (ACNU) and ramustine (MCNU) synthesised in Japan, have been examined in highly reiterated DNA sequences of rat glioma cells. Reiterated fragments of 167 and 203 base pairs (bp), obtained after Hind III and Hae III restriction endonuclease digestion of rat glioma cells DNA, were used as target DNA sequences to determine the labile sites. In vitro reaction with ACNU and MCNU resulted in scission products corresponding to the locations of guanine. Subsequent piperidine hydrolysis produced more frequent breaks of the phosphodiester bonds at guanine positions, thus forming alkali-labile sites.

Animals↗
PubMed1990

Thiol depletion and chemosensitization on nimustine hydrochloride by methionine-depleting total parenteral nutrition.

As an adjunct to cancer chemotherapy, we had succeeded in creating the methionine depletion in vivo, using the technique of total parenteral nutrition (TPN) by infusing an amino acid solution devoid of methionine and cysteine, as sole nitrogen source (Met-deplet. TPN). In Experiment 1, we demonstrated that the marked depletion of thiol was induced both in the liver and tumor tissues by Met-deplet. TPN in Sato lung carcinoma (SLC)-bearing rats. Then in Experiment 2, we also confirmed the presence of the enhancing effect on nimustine hydrochloride (ACNU) in Met-deplet. TPN to SLC. The tumor proliferation was inhibited significantly by Met-deplet. TPN even in conjunction with a small dose of ACNU, which showed no anti-tumor effect on the rats treated with methionine-containing amino acid solution, without apparent increase of the side effects in comparison with those in the control groups. On the other hand, to determine the carcinostatic effect on tumor-bearing animals, not only the size of the tumor but also its components, especially the percentage of necrotic tumor tissue (necrotic index), were considered to be important.

Amino Acids↗
PubMed1987

Effects of combined treatment with nimustine hydrochloride and radiation on solid FM3A tumor in mice.

Female C3H/HeN mice bearing solid FM3A tumors were treated with a combination of ACNU (or Nimustine hydrochloride) and radiation in order to investigate the antitumor effects and also to determine the optimal treatment schedule of ACNU in such combined therapy. ACNU was intravenously injected either twice with an interval of 2 weeks and a dose of 30 mg/kg (intermittent large-dose treatment), or as 4 weekly doses of 15 mg/kg (fractionated small-dose treatment). Local irradiation (5 Gy) at the tumor site was performed twice with an interval of 2 weeks between the doses. Synergistic effects were obtained by the combination of ACNU and radiotherapy in terms of tumor growth inhibition and prolongation of survival. Histology also revealed much greater reduction of viable tumor cells in the case of combination treatment. With either treatment with ACNU alone or in combination with irradiation, the intermittent large-dose injections resulted in better inhibition of tumor growth than did the fractionated small-dose injections, but the survival times with the intermittent treatments were not as prolonged as would be expected from the direct effects. Loss of body weight and depression of WBC number were also much more severe in the intermittent treatment group. Thus, it may be concluded that when ACNU is combined with radiotherapy, the intermittent large-dose regimen is not necessarily superior to the fractionated small-dose one.

Animals↗
PubMed1987

Protective effect of nimustine hydrochloride against radiation-induced pulmonary injury in mice.

Female C3H/HeN mice were irradiated in the thorax at a dose ranging from 10 to 25 Gy with or without ACNU (nimustine hydrochloride) treatment in order to determine whether the chemotherapeutic agent would lead to an enhancement of radiation-induced lung damage. ACNU given intravenously at 15 mg/kg immediately prior to irradiation reduced the mortality of mice irradiated with a low dose; mortality with either radiation alone or radiation plus ACNU was 4/10 (40%) or 0/10 (0%) at 13.1 Gy, and 9/10 (90%) or 6/10 (60%) at 15 Gy, respectively. The presence of ACNU during thoracic irradiation also prolonged the survival time of mice approximately 2-fold over that of animals given radiation alone. Histological examination of mice sacrificed 80 days after treatments revealed that the combination of drug and irradiation produced no radiation pneumonitis, which was predominant in mice given radiation alone. It is unexpectedly concluded that ACNU may have a protective effect against radiation-induced lung injury.

Animals↗
PubMed1986

[Combination chemotherapy with cyclophosphamide, adriamycin, cisplatin, nimustine, and methotrexate (EACAM) in advanced adenocarcinoma of the lung].

Twenty-eight patients with advanced adenocarcinoma of the lung were treated with the combination chemotherapy "EACAM" consisting of cyclophosphamide (333 mg/m2 X 1), adriamycin (27 mg/m2 X 1), cisplatin (25 mg X 5), nimustine (33 mg/m2 X 1), and methotrexate (27 mg/m2 X 3). This regimen was repeated once every 4 or 5 weeks. One complete response (CR) and 10 partial responses (PR) were obtained in 27 evaluable patients and the response rate was 40.7%. The 50% survival time for all of the evaluable cases was 64 weeks. The 50% survival time for the responding patients (93 weeks) was significantly superior (p = 0.002) to that of the nonresponding patients (52 weeks). Alopecia, myelosuppression and mild G I trouble were observed, but these presented no obstacle to the continuation of the therapy. The combination chemotherapy "EACAM" is therefore considered to be a very effective and tolerable treatment for advanced adenocarcinoma of the lung, and can help in achieving our aim of prolonging the survival time of such patients.

Adenocarcinoma↗
PubMed1986

[The treatment of psoriasis. Critical study of the use of ACNU (nimustine hydrochloride)].

The present study deals with the results of topical treatment of psoriasis with ACNU (nimustine hydrochloride), a water-soluble derivative of nitrosourea developed in Japan. Solutions at concentrations of 0.1 p. 100, 0.2 p. 100 and 0.4 p. 100 were obtained by dissolving ACNU in water and alcohol. An 0.4 p. 100 ointment was prepared by mixing ACNU with polyethylene glycol. Seventeen patients (12 male and 5 female), ranging in age from 19 to 68 years, were treated. Improvement of the skin lesions was observed in all 10 patients treated with the solution and in 6 of the 7 patients treated with the ointment. Clinical and histological pictures of the 4 main cases are shown with photographs. Compared with other treatments, the ACNU solution and ointment have the same effect as corticosteroid ointments of moderate strength or Goeckerman therapy. Side-effects included papules, redness, pigmentation and irritation. ACNU has been used for the treatment of mycosis fungoides, but we were the first to use this drug in psoriasis. This treatment has some side-effects, but they are less severe than those of other anti-cancer drugs. ACNU is relatively expensive and unsuitable for long term use. Thus, topical applications of ACNU may be of some value in cases where conventional treatments have failed.

Adult↗
PubMed1985

[Combination chemotherapy with cyclophosphamide, adriamycin, cisplatin, nimustine(ACNU), and methotrexate (EACAM) in advanced adenocarcinoma of the lung].

Twenty-two patients with advanced adenocarcinoma of the lung were treated with the combination chemotherapy "EACAM" consisting of cyclophosphamide (333mg/m2 X 1), adriamycin (27mg/m2 X 1), cisplatin (25mg X 5), nimustine (33mg/m2 X 1), and methotrexate (27mg/m2 X 3). This regimen was repeated once every 4 or 5 weeks. One complete response (CR) and 8 partial responses (PR) were obtained in 21 evaluable patients and the response rate was 42.9%. It has not been possible to calculate the median survival time for all of the evaluable cases, since 13 of them are still alive up to the present time. The side effects observes were as follows: nausea and vomiting (81.8%), alopecia (81.8%), stomatitis (22.7%), leukocytopenia less than 2,000/mm3 (45.5%), and thrombocytopenia less than 5 X 10(4)/mm3 (18.2%). Apart from strong myelosuppression, no severe infection or bleeding tendency was noticed. A mild elevation of serum createnine was observed in one patient, and no patients developed renal insufficiency. The combination chemotherapy "EACAM" is therefore considered to be a very effective and tolerable treatment for adenocarcinoma of the lung.

Adenocarcinoma↗
PubMed1986

[Clinical or experimental use of an anticancer drug-oil suspension and its characteristics].

The anticancer agent, Nimustine, which is a derivative of Nimustine hydrochloride (Sankyo CC, Ltd), was suspended in an oil, Lipiodol, using an ultrasonic suspender and used in experimental animals and human subjects with malignant tumor. The use of Lipiodol facilitates the fluoroscopic demonstration of the site into which the suspension has been injected. The Nimustine-Lipiodol suspension was almost stable in room air over 7 days and diffusion of suspended Nimustine into saline in vitro was still noted 4 weeks later. Remarkable regression of tumor size was observed when the Nimustine-Lipiodol suspension was locally injected into the lesion of Lewis lung cancer subcutaneously inoculated into mice. Moreover, a marked regression of tumor size and improvement of CEA level in serum were also obtained when arterial injection of the Nimustine-Lipiodol suspension was carried out in patients with metastatic liver cancer. Therefore, local or arterial injection of Nimustine-Lipiodol suspension is considered to be effective as a method of cancer targeting therapy.

Animals↗
PubMed1989

Evaluation of antitumor activity in a human breast tumor/nude mouse model with a special emphasis on treatment dose.

Eight lines of human breast tumors implanted in nude mice were treated with various antitumor agents at two different doses, maximum tolerated doses (MTD) and rational doses (RD) that were pharmacokinetically equivalent to the clinical doses; the response rates to both doses were compared. With MTD, the response rates to mitomycin C and vinblastine were 100%, and those to other agents including cyclophosphamide, nimustine (a water-soluble nitrosourea), vincristine, Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH), 5-fluorouracil (5-FU), and methotrexate were 30%-50%, indicating high responsiveness to the former two agents. In contrast, when the RD were used, the response rates to the majority of these agents were 25%-40%, and those to vincristine and nimustine were 13% and 0%, respectively. These results agree with the reported clinical results compared with those with MTD, suggesting the importance of the use of clinically equivalent doses in the evaluation of antitumor efficacy in a human tumor/nude mouse system.

Animals↗