Disease relevance of N-methylmethanamide

• To determine the relationship between polar solvent treatment and changes in membranes, we examined the effects of exposure to NMF on membrane fluidity in human colon cancer cells (DLD-1; clone A) [1].
• The growth of the murine TLX5 lymphoma is inhibited in vivo by administration of N-methylformamide (Gescher, A., et al., Br. J. Cancer, 45: 843-850, 1982) [2].
• The interactions of the iron-molybdenum cofactor, FeMoco, isolated from acid-treated Azotobacter vinelandii molybdenum-iron protein (Av1) with EDTA and thiophenol in N-methylformamide solution have been reinvestigated [3].
• Finally, we showed the susceptibility of RLECs to N-methyl formamide- and diethylnitrosamine-induced toxicity, suggesting metabolic activation by CYP2E1 [4].
• FeMoco, a low-M(r) metal cluster of probable composition Fe7MoS9 complexed with homocitrate, has been extracted with N-methylformamide from the MoFe protein of the nitrogenase enzyme from Klebsiella pneumoniae [5].

High impact information on N-methylmethanamide

• Clinical pharmacology of oral and i.v. N-methylformamide: a pharmacologic basis for lack of clinical antineoplastic activity [6].
• When N-methylformamide was removed from the cells, prior to commitment to differentiation, the levels of hsc70 were reestablished, whereas after 36 h of treatment there was no recovery [7].
• Immunoanalysis, using antibodies to either the stress-inducible heat shock protein hsp70 (4G4) or a pan-M(r) 70,000 heat shock protein antibody (3A3), showed that there was a striking reduction in the levels of the constitutive heat shock protein hsc70 when cells were incubated continuously with 170 mM N-methylformamide [7].
• Investigations of mechanisms of drug-induced changes in gene expression: N-methylformamide-induced changes in synthesis of the M(r) 72,000 constitutive heat shock protein during commitment of HL-60 cells to granulocyte differentiation [7].
• HL-60 cells were treated with the differentiating agent N-methylformamide and early changes in gene expression and protein content were investigated [7].

Chemical compound and disease context of N-methylmethanamide

• Polar organic solvents, such as N-methylformamide (NMF), N,N-dimethylformamide, and dimethyl sulfoxide, have been demonstrated to induce differentiation in a number of neoplastic cell lines, including human colon cancer cells [1].
• Pre-treatment of human osteosarcoma cells with N-methylformamide enhances P-glycoprotein expression and resistance to doxorubicin [8].
• Enhancement of the responses of human colon adenocarcinoma cells to X-irradiation and cis-platinum by N-methylformamide (NMF) [9].
• N-methylformamide and N-ethylformamide were equitoxic to the TLX5 lymphoma in vitro [10].
• A factor capable of activating apo-dinitrogenase (lacking the FeMo cofactor) from Azotobacter vinelandii was extracted from the alternative dinitrogenase protein with N-methylformamide [11].

Biological context of N-methylmethanamide

• When TLX5 cells were washed free of N-methylformamide after an exposure to 106 mM for 48 h and cultured in drug-free medium, the cells returned to exponential growth and to a normal cell cycle distribution [2].
• The observed membrane changes correlated well with the effect of NMF on differentiation in these cells as previously reported, as well as with cell growth rate and morphology in the present study [1].
• Continuous incubation of TLX5 murine lymphoma cells in vitro with N-methylformamide for 72 h, at concentrations of between 43 and 170 mM (0.25 and 1% v/v), brought about a concentration-dependent decrease in growth rate (50% inhibitory concentration = 68 mM) and viability [2].
• Here we report the large scale isolation and characterization of a species, designated MoFe cluster, that exhibits an S = 3/2 EPR signal, and the comparison of this entity to isolated FeMo cofactor in N-methylformamide and to the active site of the enzyme nitrogenase [12].
• Apoptosis was induced by 50 microM etoposide or 300 mM N-methylformamide (NMF), a nongenotoxic agent [13].

Anatomical context of N-methylmethanamide

• Exposure of certain cell lines to the differentiation-inducing agent N-methylformamide (NMF) enhances their radiosensitivity [14].
• When HL-60 cells were incubated with 1 M N-methylformamide, a toxic concentration of this agent, or were heat shocked, the synthesis of both the Mr 70,000 and Mr 90,000 proteins was induced [15].
• Pretreatment of animals with 4-methylpyrazole (200 mg/kg intraperitoneally, once daily for 3 days) increased metabolism of N-methylformamide to 410% of control values in rat liver microsomes but was without effect on murine microsomal metabolism of N-methylformamide [16].
• Hepatocytes obtained from mice that had received acetone, an inducer of CYP2E1, were incubated for up to 4 hr with N-methylformamide (5 and 10 mM) [16].
• Detection of the N-methylcarbamoylating species was dependent on the presence in the incubation mixture of NMF, viable microsomes, NADPH, and a thiol-containing agent such as glutathione [17].

Associations of N-methylmethanamide with other chemical compounds

• Structure-activity studies of a series of polar organic compounds, including N,N-dimethylformamide, N-methylformamide, and related ureas and acetamides, were performed with regard to their ability to promote the terminal differentiation of the human promyelocytic leukemia cell line HL-60 to granulocyte-like cells [18].
• The enhancement of 5-FUra cytotoxicity appeared to be directly related to the degree of differentiation and to biochemical events that occur during the commitment to terminal cell division induced by N-methylformamide, DMSO, or HMBA [19].
• The rate of metabolism of N-methylformamide to S-(N-methylcarbamoyl) glutathione was determined in liver microsomes from six humans and correlated with extent of metabolic hydroxylation of chlorzoxazone, a CYP2E1 probe, and with amount of immunodetectable enzyme using an anti-rat CYP2E1 antibody (r = 0.81 and 0.80, respectively) [16].
• The assay is based upon liquid/liquid extraction of these compounds using dichloromethane at pH 10.2 (recovery between 63 and 98%), followed by a NACE separation performed within 8 min employing a 0.036 M borate buffer (apparent pH 9.9) in a mixture of methanol and N-methylformamide (1:3) and on-column absorbance detection at 280 nm [20].
• However, cells treated for 8 h with NMF did not undergo immediate apoptosis on the addition of DEX [21].

Gene context of N-methylmethanamide

• The hypothesis that the cytochrome P450 isozyme CYP2E1 catalyzes the metabolic toxification of N-methylformamide was tested [16].
• Collectively, these data show that N-methylformamide modulates the expression of some adhesion receptors, cell adhesion to laminin, collagen I, vitronectin and fibrinogen as well as the metastatic behaviour of M14 cells [22].
• Flow cytometric analysis of VLA2, VLA5, and VLA6 receptors showed that N-methylformamide increases the expression of the three integrins by 30 to 40 percent [23].
• To better understand the mechanism involved in N-methylformamide-mediated chemosensitization, we evaluated the N-methylformamide effect on cell volume and surface expression of some integrins molecules (VLA2, VLA5, and VLA6) of the HT-29 cell line [23].
• Reversible suppression of c-myc expression in a human colon carcinoma line by the anticancer agent N-methylformamide [24].

Analytical, diagnostic and therapeutic context of N-methylmethanamide

• The use of drugs such as monomethylformamide that can convert neoplastic cells to benign cells rather than kill the tumor cells represents an important conceptual departure from standard cytotoxic chemotherapy [25].
• N-methylformamide (NMF), a polar solvent, is currently being evaluated by the National Cancer Institute (NCI) as an antineoplastic agent because of its activity against colon, mammary, and lung tumor xenografts [26].
• It is concluded that the cessation of replication and the accumulation of cells in G1 of the cell cycle, after treatment with N-methylformamide, are probably not events representative of terminal differentiation but rather of cytostasis, which was accompanied by rapid cell death [2].
• These findings have resulted in the entry of monomethylformamide into phase I clinical trials in America and Europe. Preclinical work further suggests that polar solvents may be useful agents in combination with conventional treatment modalities [25].
• After continuous treatment of MOLT-4 human T lymphoblastoid cells with the topoisomerase II inhibitor etoposide (50 microM) and the nongenotoxic agent N-methylformamide (300 mM), apoptosis was confirmed by electron microscopy [27].

References