Disease relevance of NIMUSTINE

• More important, KF41399 did not affect the antitumor activity of ACNU against mouse Sarcoma180 and human lung cancer LC-6 [1].
• Oral administration of KF41399 ameliorated thrombocytopenia induced by ACNU and accelerated the rate of platelet recovery in a dose-dependent fashion [1].
• These findings suggest the feasibility of intrathecal perfusion of ACNU in the treatment of patients with subarachnoid dissemination of glioma [2].
• The toxicity profile favors ACNU plus VM26 for further evaluation [3].
• ACNU is highly active against murine L1210 leukemia [4].

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

• Neurotoxicity and pharmacokinetics of intrathecal perfusion of ACNU in dogs [2].
• We obtained evidence that the methyltransferase must repair the DNA damage as soon as the DNA is exposed to ACNU, in order to avoid cell cycle arrest at the G2 phase [9].
• This study examined the effects of full-length p16 gene transfer by recombinant adenovirus on cell growth and on sensitivity to CDDP or ACNU chemotherapies [10].
• A proliferation assay employing MTT showed that AxCA-hp16 infection induced chemoresistance, preventing CDDP-induced cell death (11- to 15-fold) and ACNU-induced cell death (80- to 92-fold) [10].
• Our results suggest that brain tumors include a certain percentage of Mer- phenotype tumors, and that CENUs such as ACNU should be applied selectively on tumors with a low MGMT activity in order to increase the therapeutic effectiveness [11].

Anatomical context of NIMUSTINE

• Another ACNU-sensitive mutant, CNU1, was slightly more sensitive to UV than the parent cell line [12].
• ACNU [1-2 mg dissolved in 10-20 ml of lactated Ringer's solution or artificial cerebrospinal fluid (CSF)] was administered via the right lateral ventricle by constant drip infusion and CSF was drained by lumbar puncture [2].
• ACNU was not detected in lumbar CSF after bolus injection into the lateral ventricle [2].
• Histological examination of the brain and spinal cord revealed only mild denudation of ependyma in the wall of the ventricles in a dog treated three times with 2 mg ACNU (perfusion twice, bolus injection once) and in 2 dogs perfused with 1 mg ACNU once a week for 10 weeks [2].
• This value exceeded the known rate of ACNU decomposition in aqueous solution (28 to 29 min), implying that the disappearance of ACNU from CSF was due to hydrolytic decomposition and cellular entry and/or transcapillary loss across central nervous system capillaries [13].

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].

References