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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↗
PubMed1999

Dacarbazine, nimustine hydrochloride, cisplatin and tamoxifen combination chemotherapy for advanced malignant melanoma.

Melanoma is an uncommon disease in Japan. The incidence, however, has been gradually increasing in the last two decades, as in many other countries worldwide. Ten patients with metastatic malignant melanoma were treated between March of 1997 and April of 1998 in the Department of Dermatology, National Cancer Center Hospital, with a combination chemotherapy consisting of dacarbazine (DTIC), nimustine hydrochloride (ACNU), cisplatin (CDDP), and tamoxifen (TAM). The patients characteristics were as follows: four were males and six females; the age range was 33-70 years; all were Japanese; sites of primary disease: extremities 4, primary unknown 3, nasal cavity 1, anus 1, scalp 1; sites of metastases: lymph nodes 6, pulmonary system 5, skin 2, liver 3, gall bladder 1, adrenal gland 1. The chemotherapy regimen included DTIC 220 mg/m2/i.v. on days 1 through 3, ACNU 60 mg/m2/i.v. on day 1, cisplatin 25 mg/m2/i.v. on days 1 through 3, and tamoxifen 10 mg p.o. twice daily. One patient achieved a complete response and 3 showed partial responses. The response rate was 40%. The four responders included those with metastases to the nodes, lung, and liver. The main toxicities were nausea, vomiting, leucopenia, anemia, and thrombocytopenia. This regimen is a fairly effective combination against metastatic melanoma.

Adult↗
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↗
PubMed2006

Glioblastoma multiforme with oligodendroglial component (GBMO): favorable outcome after post-operative radiotherapy and chemotherapy with nimustine (ACNU) and teniposide (VM26).

BACKGROUND: The presence of an oligodendroglial component within a glioblastoma multiforme (GBM) is considered a prognostically favorable factor, but the clinical outcome of patients with glioblastoma multiforme with oligodendroglial component (GBMO) after combined post-operative radiotherapy and chemotherapy has rarely been reported. METHODS: We analyzed overall and progression-free survival in a group of ten consecutive patients initially diagnosed with GBMO between 1996 and 2004 (4.2% of all GBM patients). Median (range) age was 54 (34-73) years, 90% were resected and median radiotherapy dose was 54 (45-60.6) Gy. 80% of patients received post-operative chemotherapy with nimustine (ACNU) and VM26 (teniposide) for a median of 3.5 (1-6) cycles, the remainder were treated with post-operative radiotherapy alone. All specimens were reviewed by an experienced neuropathologist. RESULTS: Neuropathological re-evaluation revealed GBM with an oligodendroglial component of 30% or less in five cases, predominant oligoastrocytic tumors with focal areas of GBM in four patients and WHO grade III oligoastrocytoma with questionable transition to GBM in one patient. Four of ten patients were alive at at 40, 41, 41 and 82 months. The median overall survival (Kaplan-Meier) was 26 months, the 2-year survival rate was 60% (progression-free survival: 9.8 months and 40%, respectively). CONCLUSION: In conclusion, patients with GBMO treated with post-operative radiotherapy and chemotherapy with ACNU/VM26 had a better prognosis than reported for GBM in modern chemoradiation series.

Adult↗
PubMed1998

Effects of treatment with nimustine (ACNU), a bifunctional alkylating anticancer agent, on cultured resting L1210 cells.

Resting L1210 cells were treated with nimustine (ACNU), a bifunctional alkylating anticancer agent, for 2 h in a nutrient-depleted medium. The cells were then transferred to a fresh medium and incubated for a further 48 h. Functions of the cells thus prepared were examined in terms of the dye-exclusion of the membrane, 2,3-bis(2-methoxy-4-nitro-5-sulfophenyl)-5-[(phenylamino)carbonyl] -2H-tetrazolium hydroxide, inner salt, sodium salt (XTT)-reducing ability of the mitochondria, and heat generation due to vital metabolism as the measure of cell viability. The cells treated with ACNU were functioning normally in all the cell functions examined but were completely devoid of proliferating capacity. These results suggest the possibility that ACNU might impair the proliferative capacity of the resting cell population inside a solid tumor without causing such impairment to the cells of normal organs and tissues composed of intrinsically non-proliferative cells.

Animals↗
PubMed2000

Pharmacokinetics of cytosine arabinoside, methotrexate, nimustine and valproic acid in cerebrospinal fluid during cerebrospinal fluid perfusion chemotherapy.

This report investigates the pharmacokinetics of cytosine arabinoside (Ara-C), methotrexate (MTX), nimustine (ACNU) and valproic acid (VPA) in cerebrospinal fluid (CSF) during CSF perfusion chemotherapy. A 28-year-old Japanese woman with disseminated glioblastoma was, on admission, on a stable oral regimen of prolonged-release VPA tablets (Depakene-R), 400 mg twice a day, for seizure control. Twelve courses of CSF perfusion chemotherapy with Ara-C, MTX, and ACNU were administered. Plasma samples and CSF samples via Ommaya reservoirs were obtained during the eleventh course of treatment. The Ara-C and ACNU concentrations were measured by HPLC. The MTX and VPA concentrations were measured by fluorescence polarization immunoassay. During CSF perfusion chemotherapy, the highest CSF concentrations of Ara-C, MTX, and ACNU were observed at the end of the perfusion and decreased in a monoexponential pattern. The half-lives of Ara-C, MTX, and ACNU were 2.65, 3.52, and 0.71 h, respectively. No anticancer drugs were detectable in plasma during CSF perfusion chemotherapy. Before CSF perfusion chemotherapy, the free VPA concentration in plasma was 14.4% of the total VPA concentration. The mean total and free VPA concentrations in plasma were 78.0+/-0.8 and 10.9-0.3 microg/ml, respectively. The free VPA concentrations in plasma and in CSF were of similar values. At the end of perfusion, the lowest free VPA concentration in CSF was 30.3% of that at the initiation of perfusion. The free VPA concentrations in CSF at 3, 7, 23, and 47 h after the end of perfusion were 79.8, 94.5, 100.9, and 100.9% respectively of that at the initiation of perfusion. During CSF perfusion chemotherapy, the ratio of free VPA concentrations to the total VPA in CSF was 86.3+/-6.9%. The VPA concentrations in CSF rapidly decreased during the CSF perfusion but recovered to pre-treatment levels within 7 h.

Adult↗
PubMed2001

Pharmacokinetics of nimustine, cytosine arabinoside, and methotrexate in cerebrospinal fluid during cerebrospinal fluid perfusion chemotherapy.

This report investigates the pharmacokinetics of nimustine (ACNU), cytosine arabinoside (Ara-C), and methotrexate (MTX) in cerebrospinal fluid (CSF) during CSF perfusion chemotherapy. A 47-year-old Japanese man with spinal cord, cerebellum and brain stem dissemination of oligo-astrocytoma received nine courses of CSF perfusion chemotherapy with ACNU, Ara-C, and MTX. A CSF perfusion chemotherapy solution was perfused via an Ommaya reservoir in the ventricle, and was discharged by drainage though another Ommaya reservoir in the lumbar spinal canal. CSF samples via Ommaya reservoirs in the lumbar spinal canal were obtained during the fifth and eighth courses of treatment. The concentrations of ACNU and Ara-C in CSF were measured by HPLC, and the MTX concentrations by fluorescence polarization immunoassay. In the fifth course of treatment, a CSF injection chemotherapy solution, consisting of 5 mg of ACNU dissolved in 20 ml of artificial CSF, was injected over a few minutes using the Ommaya reservoir. Next, a CSF perfusion chemotherapy solution, consisting of 10 mg of Ara-C and 5 mg of MTX dissolved in 100 ml of artificial CSF, was perfused over 2 h. In the eighth course of treatment, a CSF perfusion chemotherapy solution, consisting of 5 mg of ACNU, 10 mg of Ara-C and 5 mg of MTX dissolved in 100 ml of artificial CSF, was perfused over 2 h. In both treatments, the highest concentrations of Ara-C and MTX in CSF were observed 1 or 2 h after the end of perfusion, with the values of each drug being similar. The CSF AUCs of Ara-C and MTX in each treatment were of similar values. Although the highest concentration of ACNU in CSF was observed in the fifth treatment 1 h after injection (an injection chemotherapy of ACNU plus a perfusion chemotherapy of Ara-C and MTX), the concentration of ACNU in CSF was undetectable in the eighth treatment (a perfusion chemotherapy of ACNU, Ara-C and MTX). We were successful in administering all anticancer drugs, and reaching a level of over 1.0 microg/ml concentration in CSF of the lumbar spinal canal, using an injection chemotherapy of ACNU plus a perfusion chemotherapy of Ara-C and MTX; this was done even though the drugs, in particular ACNU, underwent some perfusion-period dependent decomposition.

Adult↗
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↗
PubMed2000

Chemoprotective effects of KF41399, a derivative of carbazole compounds, on nimustine-induced thrombocytopenia.

We examined the chemoprotective effects of KF41399, a novel derivative of carbazole compounds, on severe thrombocytopenia induced by nimustine (ACNU, 45 mg/kg administered for 2 consecutive days intravenously) in mice. Administration schedule studies revealed that pretreatment of mice with KF41399 was necessary to improve thrombocytopenia. Oral administration of KF41399 ameliorated thrombocytopenia induced by ACNU and accelerated the rate of platelet recovery in a dose-dependent fashion. In addition, KF41399 pretreatment improved the decrease in body weight and spleen weight and in the colony-forming activity of bone marrow mononuclear cells (MNC). Oral administration of KF41399 to normal mice induced G(0)/G(1)-phase accumulation of MNC as well as hematopoietic progenitor cells (lineage negative cells [Lin(-)]) and reduced the colony-forming activity of MNC. In Lin(-) cells derived from KF41399-treated mice, up-regulation of Bcl-2 and down-regulation of cyclin E and cyclin A proteins were observed. In the same cells, a decrease in the phosphorylated form of Rb protein and an increase in the p130 protein were observed without changes in the protein level of cell cycle-dependent kinase 2 (Cdk2), Cdk4, and Cdk6. More important, KF41399 did not affect the antitumor activity of ACNU against mouse Sarcoma180 and human lung cancer LC-6. However, 25-mg/kg KF41399 treatment reduced the antitumor activity of ACNU against human lung cancer Lu-65, and 5 mg/kg KF41399 caused a slight reduction of the antitumor activity of ACNU without inducing thrombocytopenia. These results suggest that KF41399 might be useful as a chemoprotective agent to improve chemotherapy-induced thrombocytopenia and types of other toxicity. (Blood. 2000;95:3771-3780)

Adenocarcinoma↗
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↗
PubMed2003

Relationship between expression of O6-methylguanine-DNA methyltransferase, glutathione-S-transferase pi in glioblastoma and the survival of the patients treated with nimustine hydrochloride: an immunohistochemical analysis.

Drug resistance is one of the important factors that determine tumor response to chemotherapy. Several candidates for resistance to various chemotherapeutic agents have been elucidated. O6-methylguanine-DNA methyltransferase (MGMT) removes methylation damage induced by nitrosourea from the O6 position of DNA guanines before cell injury. Glutathione-S-transferase (GST) pi is also involved in nitrosourea resistance. We examined the expression of MGMT and GST pi in 18 glioblastomas (GBM) using immunohistochemistry and compared the results with patients' survival after administration of 1-(4-amino-2-methyl-5-pyrimidinyl) methyl-3-(2-chloroethyl)-3-nitrosourea hydrochloride (ACNU)-based chemotherapy. According to the Kaplan-Meier's method, although median progression free survival (PFS) of eight patients whose tumors retained high MGMT (3+ approximately 2+), and 10 patients whose tumors showed low MGMT expression (1+ approximately 0) were nine and 15 months, respectively (p = 0.09), median overall survival (OS) of the two groups were 12 and 22 months, respectively, which were significantly different (p = 0.01). GST pi expression in GBM was not a prognostic factor. It is suggested that GBM with strong staining of MGMT activity may show more resistance to ACNU-based chemotherapy compared to that with low MGMT. The simple immunohistochemical analysis of MGMT in GBM can be a useful method to determine whether ACNU or another treatment regimen should be recommended.

Adult↗
PubMedDate not supplied

Comparative cytotoxicity of carmustine (BCNU), nimustine (ACNU) and elmustine (HeCNU) after depletion of O6-alkylguanine-DNA alkyltransferase (O6-AGT).

BCNU was reported to have about a 6- to 8- fold lower cytotoxic potency than ACNU in cell lines naturally deficient in O6-AGT. In seven tumor cell lines with an O6-AGT activity ranging from 40 to 360 fmol/mg the cytotoxic potency of BCNU, ACNU and HeCNU, without and after O6-AGT depletion by O6-BG, was determined. Without O6-AGT depletion, BCNU was superior to both other drugs in tumor cells with high O6-AGT activity. After O6-AGT depletion, the cytotoxic potency (comparison of IC50 values) of ACNU was higher than that of BCNU (p=0.016) or that of HeCNU (p=0.016) in all tumor cell lines. We conclude that (without O6-AGT depletion) BCNU is the drug of choice especially in tumor cells with high transferase activity. The higher cytotoxic potency of ACNU after O6-AGT depletion as compared to BCNU after O6-AGT depletion is countered by the higher toxicity of ACNU in patients necessitating a clinical dose reduction as compared to BCNU. Thus, we would not expect superiority of ACNU + O6-BG over BCNU+ O6-BG after systemic administration.

Antineoplastic Agents, Alkylating↗
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↗