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Chemical Compound Review

NIMUSTINE     3-[(4-amino-2-methyl- pyrimidin-5...

Synonyms: Nimustin, Nimustina, Nimustinum, Lopac-N-8659, CHEMBL136737, ...
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Disease relevance of NIMUSTINE


High impact information on NIMUSTINE

  • The Neuro-Oncology Working Group (NOA) of the German Cancer Society therefore compared the efficacy of nimustine (ACNU) plus VM26 and ACNU plus cytarabine (Ara-C) chemotherapy in addition to standard radiotherapy in patients with newly diagnosed malignant glioma [3].
  • Gamma-glutamylcysteine synthetase (gamma-GCS) mRNA expression was coinduced with MRP by ACNU [5].
  • Our results also demonstrate that intermittent treatments of human glioma cells with ACNU can lead to the development of MRP-related multidrug resistance [5].
  • We made use of transgenic mice overexpressing human MGMT in their skin and the initiation-promotion protocol on treatment with 1-(4-amino-2-methyl-5-pyrimidinyl)methyl-3-(2-chloroethyl)-3-nitrosourea (ACNU, nimustine) that is representative of CNUs [6].
  • ACNU-induced skin tumors harbored mutations in the c-Ha-ras gene in both groups of mice [6].

Chemical compound and disease context of NIMUSTINE

  • To test the feasibility of intrathecal perfusion of ACNU (3-[(4-amino-2-methyl-5-pyrimidinyl)methyl]-1-(2-chloroethyl)-1-nitro sou rea hydrochloride) in the treatment of subarachnoid dissemination of malignant glioma, the neurotoxicity and pharmacokinetics of ACNU were studied in dogs [2].
  • 1-4-Amino-2-methylpyrimidin-5-yl)methyl-3-(2-chloroethyl)-3-nitrosourea (ACNU) is a water-soluble nitrosourea that has produced delayed hematological toxicity in man during Phase 1 clinical trials [4].
  • Hematologic toxicity was more prominent in the ACNU plus Ara-C arm [3].
  • 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 [7].
  • Three ACNU-resistant sublines (R1, R3 and R12) from rat glioma 9L cells showed cross-resistance to vinblastine, adriamycin, and VP-16 [8].

Biological context of NIMUSTINE


Anatomical context of NIMUSTINE


Associations of NIMUSTINE with other chemical compounds

  • Consequently a higher survival rate was obtained in the following experimental groups: (a) (CY 200 mg/kg, Days 0 and 1) + BMT greater than (CY 400 mg/kg, Day 0) + BMT, (ACNU 20 mg/kg, Days 0 and 1) + BMT greater than (ACNU 40 mg/kg, Day 0) + BMT [14].
  • Multiple short exposures (1 h) of ACNU following a long duration (1 week) of drug-free conditions resulted in the development of an ACNU-resistant population (designated A172R) that overexpressed MRP/gamma-GCS mRNA and had elevated transport activities for leukotriene C4 [5].
  • Moreover, 1-(4-amino-2-methylpyrimidine-5-yl)-methyl-3-(2-chloroethyl)-3-nitrosourea hydrochloride (ACNU) has been reported as possessing only minimal carbamoylating potential, as measured in vitro by a lysine assay [15].
  • 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 [16].
  • 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 [16].

Gene context of NIMUSTINE

  • Cells transduced with Ha-MDR-IRES-MGMT showed higher resistance to vincristine and lower resistance to ACNU than those transduced with Ha-MGMT-IRES-MDR [17].
  • In conclusion, the sensitivity to ACNU was not associated with hMLH1 status, but was found to depend only on the MGMT status [18].
  • We examined the mechanism of action of nitrosoureas as represented by 1-(4-amino-2-methyl-5-pyrimidinyl) methyl-3-(2-chloroethyl)-3-nitrosourea (ACNU) with respect to p53 and the G2M cell cycle checkpoint using two glioblastoma cell lines: U251MG and U373MG, with mutated p53 [19].
  • In both cell lines, the amount of Cdc2 protein phosphorylated at the tyrosine 15 residue was increased 2- to 6-fold by treatment with ACNU compared with untreated control cells [19].
  • The induction of WAF1 mRNA by ACNU was detected by northern blot analysis in these cells [20].

Analytical, diagnostic and therapeutic context of NIMUSTINE

  • Although the level of cross-links for 9L cells had reached a maximum at 6 hours and then persisted at almost the same level as that at 24 hours after the treatment with ACNU, the level for 9L/R cells was very low at 6 hours and then gradually decreased at 24 hours after treatment with ACNU [21].
  • When 1 mg of ACNU, dissolved in 10 ml of artificial CSF, was perfused for a duration of 22 to 31 min, it started to appear in the lumbar CSF 10 to 15 min after the start of perfusion, reaching a maximum concentration of 13.88 to 22.31 micrograms/ml [2].
  • Western blot analyses revealed that levels of MRP in these ACNU-treated cells paralleled mRNA levels [5].
  • All the Mer- tumor xenografts were much more sensitive than tumors of Mer+ strains, including the clone 5'dD; after the highest ACNU dose (three injections of 50 mg/kg), some Mer- tumors disappeared completely and the growth of other tumors was severely retarded, whereas all Mer+ tumors continued to grow [22].
  • 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 [7].


  1. Chemoprotective effects of KF41399, a derivative of carbazole compounds, on nimustine-induced thrombocytopenia. Shiotsu, Y., Yamashita, K., Kanai, F., Ikuina, Y., Murakata, C., Teramura, M., Mizoguchi, H., Tamaoki, T., Akinaga, S. Blood (2000) [Pubmed]
  2. Neurotoxicity and pharmacokinetics of intrathecal perfusion of ACNU in dogs. Kochi, M., Kuratsu, J., Mihara, Y., Takaki, S., Inoue, N., Sueyoshi, N., Uemura, S., Ushio, Y. Cancer Res. (1990) [Pubmed]
  3. Neuro-Oncology Working Group 01 trial of nimustine plus teniposide versus nimustine plus cytarabine chemotherapy in addition to involved-field radiotherapy in the first-line treatment of malignant glioma. Weller, M., Müller, B., Koch, R., Bamberg, M., Krauseneck, P. J. Clin. Oncol. (2003) [Pubmed]
  4. A comparison of the biological and biochemical properties of 1-(4-amino-2-methylpyrimidin-5-yl)methyl-3-(2-chloroethyl)-3-nitrosourea and 2-[3-(2-chloroethyl)-3-nitrosoureido]-D-glucopyranose. Nagourney, R.A., Fox, P., Schein, P.S. Cancer Res. (1978) [Pubmed]
  5. Transient induction of the MRP/GS-X pump and gamma-glutamylcysteine synthetase by 1-(4-amino-2-methyl-5-pyrimidinyl)methyl-3-(2-chloroethyl)-3- nitrosourea in human glioma cells. Gomi, A., Shinoda, S., Masuzawa, T., Ishikawa, T., Kuo, M.T. Cancer Res. (1997) [Pubmed]
  6. The DNA repair protein O6-methylguanine-DNA methyltransferase protects against skin tumor formation induced by antineoplastic chloroethylnitrosourea. Becker, K., Gregel, C.M., Kaina, B. Cancer Res. (1997) [Pubmed]
  7. Experimental combination chemotherapy of ACNU and 5-FU against cultured glioma model (spheroid) and subcutaneous rat glioma. Kitahara, M., Katakura, R., Suzuki, J., Sasaki, T. Int. J. Cancer (1987) [Pubmed]
  8. Glutathione and cellular response of ACNU-resistant rat glioma sublines to drugs and radiation. Saito, Y., Nakada, Y., Hotta, T., Mikami, T., Kurisu, K., Yamada, K., Kiya, K., Kawamoto, K., Uozumi, T. Int. J. Cancer (1991) [Pubmed]
  9. Artificial control of nuclear translocation of DNA repair methyltransferase. Ishibashi, T., Nakabeppu, Y., Sekiguchi, M. J. Biol. Chem. (1994) [Pubmed]
  10. Adenovirus-mediated p16 gene transfer prevents drug-induced cell death through G1 arrest in human glioma cells. Hama, S., Heike, Y., Naruse, I., Takahashi, M., Yoshioka, H., Arita, K., Kurisu, K., Goldman, C.K., Curiel, D.T., Saijo, N. Int. J. Cancer (1998) [Pubmed]
  11. Influence of O6-methylguanine-DNA methyltransferase activity on chloroethylnitrosourea chemotherapy in brain tumors. Mineura, K., Izumi, I., Watanabe, K., Kowada, M. Int. J. Cancer (1993) [Pubmed]
  12. Isolation of two chloroethylnitrosourea-sensitive Chinese hamster cell lines. Hata, H., Numata, M., Tohda, H., Yasui, A., Oikawa, A. Cancer Res. (1991) [Pubmed]
  13. Central nervous system toxicity and cerebrospinal fluid pharmacokinetics of intraventricular 3-[(4-amino-2-methyl-5-pyrimidinyl)ethyl]-1-(2-chloroethyl)-1-nitro soureas and other nitrosoureas in beagles. Levin, V.A., Byrd, D., Campbell, J., Giannini, D.D., Borcich, J.K., Davis, R.L. Cancer Res. (1985) [Pubmed]
  14. Most effective route of administration and utilization of high-dose chemotherapy with bone marrow transplantation in rats. Mizushima, Y., Morikage, T., Sasaki, K., Yano, S. Cancer Res. (1989) [Pubmed]
  15. Selective cytotoxicity of haloethylnitrosoureas in a carcinoma cell line resistant to bifunctional nitrogen mustards. Tew, K.D., Wang, A.L. Mol. Pharmacol. (1982) [Pubmed]
  16. Enhancing effect of O6-alkylguanine derivatives on chloroethylnitrosourea cytotoxicity toward tumor cells. Mineura, K., Izumi, I., Watanabe, K., Kowada, M., Kohda, K., Koyama, K., Terashima, I., Ikenaga, M. Int. J. Cancer (1994) [Pubmed]
  17. Retroviral coexpression of two different types of drug resistance genes to protect normal cells from combination chemotherapy. Suzuki, M., Sugimoto, Y., Tsukahara, S., Okochi, E., Gottesman, M.M., Tsuruo, T. Clin. Cancer Res. (1997) [Pubmed]
  18. The effect of o6-methylguanine-DNA methyltransferase (MGMT) and mismatch repair gene (hMLH1) status on the sensitivity to alkylating agent 1-(4-amino-2-methyl-5-pyrimidinyl)methyl-3-(2-chloroethyl)-3-nitrosourea(ACNU) in gallbladder carcinoma cells. Sato, K., Kitajima, Y., Koga, Y., Miyazaki, K. Anticancer Res. (2005) [Pubmed]
  19. Suppression of Cdc2 dephosphorylation at the tyrosine 15 residue during nitrosourea-induced G2M phase arrest in glioblastoma cell lines. Nakamizo, A., Inamura, T., Inoha, S., Amano, T., Ochi, H., Ikezaki, K., Fukui, M. J. Neurooncol. (2002) [Pubmed]
  20. p53-independent WAF1 induction by ACNU in human glioblastoma cells. Aoki, H., Ohnishi, K., Wang, X., Takahashi, A., Ohnishi, T., Nakamura, M., Sakaki, T. Mol. Carcinog. (1998) [Pubmed]
  21. Significance of DNA cross-links on 1-(4-amino-2-methylpyrimidin-5-yl)methyl-3-(2-chloroethyl)-3- nitrosourea (ACNU)-induced cytotoxicity against ACNU-sensitive and -resistant lines of 9L rat glioma cells. Kokunai, T., Tamaki, N., Matsumoto, S. J. Natl. Cancer Inst. (1987) [Pubmed]
  22. Hypersensitivity of human tumor xenografts lacking O6-alkylguanine-DNA alkyltransferase to the anti-tumor agent 1-(4-amino-2-methyl-5-pyrimidinyl)methyl-3-(2-chloroethyl)-3-nitros ourea. Fujio, C., Chang, H.R., Tsujimura, T., Ishizaki, K., Kitamura, H., Ikenaga, M. Carcinogenesis (1989) [Pubmed]
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