Disease relevance of MP 655

• A eukaryotic 3-methyladenine DNA glycosylase gene, the Saccharomyces cerevisiae MAG gene, was shown to prevent N-(2-chloroethyl)-N-nitrosourea toxicity [1].
• Extracts of E. coli cells that contain and express the MAG gene released 7-hydroxyethylguanine and 7-chloroethylguanine from N-(2-chloroethyl)-N-nitrosourea-modified DNA in a protein- and time-dependent manner [1].
• N'-(2-Chloroethyl)-N-(2-(methylsulfonyl)-ethyl)-N'-nitrosourea (cystemustine) is a chloroethylnitrosourea that has been used in the treatment of human melanoma [2].
• Differences in DNA alkylation products formed in sensitive and resistant human glioma cells treated with N-(2-chloroethyl)-N-nitrosourea [3].
• Differential potentiation of 1,3-bis(2-chloroethyl)-1-nitrosourea by alpha-difluoromethylornithine in chloroethylnitrosourea-sensitive and -resistant 9L rat brain tumor cells in vitro [4].

High impact information on MP 655

• The chloroethylnitrosourea (CNU) alkylating agents are commonly used for cancer chemotherapy, but their usefulness is limited by severe bone marrow toxicity that causes the cumulative depletion of all hematopoietic lineages (pancytopenia) [5].
• Disruption of the MAG gene by insertion of the URA3 gene increased the sensitivity of S. cerevisiae cells to N-(2-chloroethyl)-N-nitrosourea, and the expression of MAG in glycosylase-deficient Escherichia coli cells protected against the cytotoxic effects of N-(2-chloroethyl)-N-nitrosourea [1].
• PURPOSE: 2-Chloroethyl-3-sarcosinamide-1-nitrosourea (SarCNU) is a novel chloroethylnitrosourea that demonstrates selective cytotoxicity in athymic mice bearing human glioma [6].
• N'-[2-chloroethyl]-N[2-(methylsulfonyl) ethyl]-N'-nitrosourea (cystemustine),a chloroethylnitrosourea antineoplastic drug, provokes cellular proliferation inhibition and redifferentiation, but there was no cell death in B16 melanoma tumors [7].
• N-(2-chloroethyl)-N-nitrosourea tethered to lexitropsin induces minor groove lesions at the p53 cDNA that are more cytotoxic than mutagenic [8].

Chemical compound and disease context of MP 655

• Aerobic and hypoxic toxicity of a new class of mixed-function drugs associating nitroimidazoles and chloroethylnitrosourea in nitrosourea-sensitive (Mer-) and -resistant (Mer+) human tumor cells [9].
• alpha-Difluoromethylornithine, an enzyme-activated, irreversible inhibitor of ornithine decarboxylase, inhibited the growth of both chloroethylnitrosourea-sensitive and -resistant 9L rat brain tumor cells in vitro [4].
• The sensitivities of Escherichia coli K-12 strain AB1157, its uvrA-deficient mutant AB1886, and its recA mutant AB2463 to N,N'-bis(2-chloroethyl)-N-nitrosourea, N-(2-chloroethyl)-N-nitrosourea, and N-ethyl-N-nitrosourea have been determined [10].
• Fotemustine is a chloroethylnitrosourea with antitumor activity in disseminated melanoma and adult primary brain tumors [11].
• PCNU, a chloroethylnitrosourea with high alkylating activity, low carbamoylating activity, optimal octanol: water partition coefficient and broad activity in animal systems, was administered to 32 evaluable patients with measurable metastatic melanoma by brief intravenous infusions every six weeks [12].

Biological context of MP 655

• Many human tumor cells are resistant to chloroethylnitrosourea-induced DNA interstrand cross-linking and cell kill due to their high levels of the DNA repair protein O6-alkylguanine DNA alkyltransferase [13].
• Cytotoxicity, as measured by colony formation assays, and DNA damage caused by M&B 39565 were compared with those caused by a breakdown product of M&B 39565, 5-[3-(2-chloroethyl)triazen -1-yl]imidazole-4-carboxamide (MCTIC) and also with 1-(2-chloroethyl)-1-nitrosourea (CNU) [14].
• The resistant cell line is 5-fold less sensitive to the cytotoxic effects of N-(2-chloroethyl)-N-nitrosourea and 8-fold less sensitive to sister chromatid exchange than the sensitive cell line [3].
• We had previously shown that transfection of this plasmid into Chinese hamster ovary (CHO) cells results in the expression of MGMT and in increased cellular resistance to N-methyl-N'-nitro-N-nitrosoguanidine and 1-(2-chloroethyl)-1-nitrosourea (CNU) but not N-nitroso-N-ethylurea (ENU) [15].
• CONCLUSIONS: The present study identified hMLH1 methylation status as a predictor of the clinical response of malignant astrocytomas to chloroethylnitrosourea-based adjuvant therapy [16].

Anatomical context of MP 655

• Isolation of two chloroethylnitrosourea-sensitive Chinese hamster cell lines [17].
• Comparisons between sensitive and resistant human tumor cell lines regarding effects of polyamine depletion on chloroethylnitrosourea efficacy [18].
• We wish to report that pretreatment of Mer+ cells (HT-29 human colon carcinoma cells and IMR-90 normal human fibroblasts) with the DNA methylating agent MNNG, under conditions which should inactivate O6-methyl-transferase, apparently saturates the monoadduct repair system, and allows CNU to form interstrand crosslinks in these cells [19].
• Cell cultures challenged by a conditioned medium of CENU-treated cells underwent growth inhibition, cytoskeleton disorders, cytokinesis retardation, metabolite alterations, glutathione decrease and phosphoethanolamine increase, without ROS elicitation [20].
• Enhancement by O6-benzyl-N-acetylguanosine derivatives of chloroethylnitrosourea antitumor action in chloroethylnitrosourea-resistant human malignant melanocytes [21].

Associations of MP 655 with other chemical compounds

• Treatment of chloroethylnitrosourea-resistant cells with streptozotocin (STZ) prior to bis-chloroethylnitrosourea (BCNU) exposure has been shown to result in a depletion of O6-methylguanine DNA methyltransferase (MGMT) activity, increased BCNU-induced interstrand cross-linking, and a 2-3 log enhancement of BCNU cytotoxicity in vitro [22].
• Alkylation of DNA by chloroethylnitrosourea (CNU) at the guanine N7 position has been shown to occur in a sequence-selective fashion [23].
• Administration of serum from CENU-treated tumor-bearing donors arrested tumor proliferation, decreased vessel formation and induced tumor metabolite alterations encompassing glutathione decrease and polyunsaturated fatty acid and phosphoethanolamine increase [20].
• Fotemustine is a novel chloroethylnitrosourea, that readily penetrates the blood brain barrier [24].
• We present a novel dynamic flow cytoenzymological demonstration of the potent inhibition by the antitumour chloroethylnitrosourea BCNU of the intracellular hydrolysis of fluorescein diacetate by esterases of viable, intact murine and human tumour cells in vitro [25].

Gene context of MP 655

• Consequently, tumors expressing low levels of MGMT are sensitive to CENU chemotherapy, and any mechanism that can be used to reduce MGMT levels could sensitize resistant tumors [26].
• However, part of the chloroethylnitrosourea resistance in SKI-1 cells is not secondary to decreased accumulation [27].
• That TPA-mediated induction of MGMT caused increased cellular resistance to 2-chloroethyl-N-nitrosourea suggests a therapeutic significance for PKC-mediated MGMT modulation [28].
• Correlation of chloroethylnitrosourea resistance with ERCC-2 expression in human tumor cell lines as determined by quantitative competitive polymerase chain reaction [29].
• Cross-linking of DNA induced by chloroethylnitrosourea is presented by O6-methylguanine-DNA methyltransferase [30].

Analytical, diagnostic and therapeutic context of MP 655

• A dose-response relation for the cytotoxic activity of chloroethylnitrosourea cancer chemotherapeutic agents in cell culture has been developed [31].
• 2-Chloroethyl-3-sarcosinamide-1-nitrosourea, a novel chloroethylnitrosourea analogue with enhanced antitumor activity against human glioma xenografts [32].
• The alkylation of phosphates in DNA by therapeutically active haloethylnitrosoureas was studied by reacting N-chloroethyl-N-nitrosourea (CNU) with dTpdT, separating the products by HPLC, and identifying them by co-chromatography with authentic markers [33].
• We previously found that 2-chloroethyl-3-sarcosin-amide-1-nitrosourea (SarCNU), a new chloroethylnitrosourea analogue presently in phase I clinical trials, is a selective cytotoxin that enters cells via the extraneuronal transporter for monoamine transmitters (EMT) [34].
• Three isomeric forms of a cystamine-containing chloroethylnitrosourea, N,N'-bis[N-(2-chloroethyl)-N-nitrosocarbamoyl]cystamine (CNCC), have been identified and separated by high pressure liquid chromatography [35].

References