Disease relevance of Chlormethine

• Chloramine mutagenesis in Bacillus subtilis [1].
• RESULTS: Significant excesses of ANLL followed therapy with either prednimustine (RR = 13.4; 95% confidence interval [CI] = 1.1-156; P trend for dose < .05) or regimens containing mechlorethamine and procarbazine (RR = 12.6; 95% CI = 2.0-79; P < .05) [2].
• Immediate and delayed effects of nitrogen mustard (HN2) (0.1 mg/kg/day for 4 days) on the growth and cell proliferation patterns of the 3-methylcholanthrene-induced autogenous rat sarcoma were studied [3].
• There was no increase in lung cancer risk in relation to the number of cycles of chemotherapy or the cumulative doses of the drugs mechlorethamine and procarbazine [4].
• Immunologic studies were done on 47 long-term survivors of Hodgkin's disease who had been treated with MOPP chemotherapy (mechlorethamine, vincristine, procarbazine, and prednisone) [5].

Psychiatry related information on Chlormethine

• Specific treatments for mycosis fungoides, including electron beam irradiation, topical mechlorethamine, and psoralen plus ultraviolet A (PUVA) may be associated with the development of skin cancers after a variable latency period [6].
• Food deprivation, which induced the same weight loss as that found in NM-treated mice, was achieved by withholding food (fasted) during the oxygen exposure [7].
• Radioiodination of synthetic human secretin on its N-terminal histidyl residue was not difficult when a greater amount of Chloramine T and a longer reaction time were employed to achieve better incorporation of 125I [8].

High impact information on Chlormethine

• The present studies with nitrogen mustard (HN2) fail to demonstrate any effect of non-lethal concentrations of methylated xanthines (MXs) on removal of DNA damage or post-replication repair in conditions producing synergistic lethal effects [9].
• Some DNA-repair mutants appear to be more sensitive to chloramine, suggesting the involvement of DNA targets in bactericide [1].
• Chloramine (which occurs widely as a by-product of sanitary chlorination of water supplies) is shown to be a weak mutagen, when reversion of trpC to trpC in Bacillus subtilis is used as an assay [1].
• Mixed cultures recovered after treatment with DOX plus HN2 contained only P388/R cells [10].
• Synthetic human gastrin-17-I (G17) with a leucine substitution in the 15th position ( [Leu15]-G17) was iodinated by chloramine T; high saturable binding was found to enzyme-dispersed canine fundic mucosal cells [11].

Chemical compound and disease context of Chlormethine

• From 1989 to 1996, 533 eligible patients with stage IIIB/IV Hodgkin lymphoma (HL) were randomly assigned to receive 6 cycles of hybrid MOPP/ABV (mechlorethamine, vincristine, procarbazine, prednisone/Adriamycin [doxorubicin], bleomycin, vinblastine; n = 266) or ABVPP (doxorubicin, bleomycin, vinblastine, procarbazine, prednisone; n = 267) [12].
• The formation and removal of nitrogen mustard (HN2)- and melphalan-induced DNA cross-links (DNA interstrand and DNA-protein cross-links) in a human melanoma cell line (RPMI 8322), as determined by alkaline elution of DNA, was compared and related to the cytotoxic effect of each drug [13].
• The purpose of this study was to evaluate the influence of the number of mechlorethamine, vincristine, procarbazine, and prednisolone (MOPP) cycles and the extent of irradiation on the risk of secondary acute nonlymphocytic leukemia (SANLL) after a single combined treatment for Hodgkin's disease (HD) [14].
• These structure-activity studies demonstrate that conjugation of the mustard cytotoxic group to carbon 6 or carbon 2 of glucose produces an analogue that retains P388 antitumor activity significantly greater than that of HN2, with a concomitant reduction in murine bone marrow toxicity [15].
• Alkylating agents, mechlorethamine and N-methyl-N'-nitro-N-nitrosoguanidine, induce the production of plasminogen activator in U-87MG cells, an alkylation DNA repair deficient (Mer-) human glioblastoma strain [16].

Biological context of Chlormethine

• The percent labeled mitosis curves and DNA contents, before and 4 days after HN2 was given, were similar [3].
• Actinomycin D and mechlorethamine, however, had profound effects on inhibition of hCG-alpha production in excess of cell growth [17].
• The resistant phenotype was unstable and was maintained by weekly treatment of the cells with HN2 [18].
• The lengths of the breakage products of the DNA treated with HN2 were compared to the lengths of DNA scission products produced by chemical reactions used for DNA sequence determination [19].
• Using haploid Saccharomyces cerevisiae strains disrupted for genes central to the recombination, nonhomologous end-joining (NHEJ), and mutagenesis pathways, all these activities were found to be involved in the repair of nitrogen mustard (mechlorethamine)- and cisplatin-induced DNA ICLs, but the particular pathway employed is cell cycle dependent [20].

Anatomical context of Chlormethine

• The neutrophil-derived, membrane-permeating oxidant, NH2Cl, (but not the non-membrane-permeating chloramine, taurine-NHCl) induced detachment of fetal mouse cardiac myocytes and other cell types (fibroblasts, epithelial cells, and endothelial cells) from the culture dish, concomitant with cell shrinkage ("peeling off") [21].
• Immediate and delayed neurotoxicity after mechlorethamine preparation for bone marrow transplantation [22].
• The role of NER and recombination in the repair of ICLs induced by nitrogen mustard (HN2) was investigated using Chinese hamster ovary mutant cell lines [23].
• Compared to human neutrophils, the monocyte could generate similar amounts of chloramine when stimulated with phorbol myristate acetate, but far less if opsonized zymosan particles were used as the trigger [24].
• However, DSF had little if any effect on the modulation of HN2 cytotoxicity to normal hematopoietic cell spleen colony-forming units (NCFU) [25].

Associations of Chlormethine with other chemical compounds

• Recombinant interleukin-2 (IL2) was labelled with iodine-123 by a modified chloramine T method [26].
• Our results show that caffeine potentiates the lethality of the nitrogen mustard 2-chloro-N-(2-chloroethyl)-N-methylethanamine (HN2) by inducing damaged cells to undergo mitosis before properly repairing lesions in their DNA [27].
• Here we demonstrate that in the yeast Saccharomyces cerevisiae, photolyase also binds to DNA damaged by the anticancer drugs cis-diamminedichloroplatinum (cis-DDP) and nitrogen mustard (HN2) and by the alkylating agent N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) [28].
• Heinz body test with acetylphenylhydrazine became positive in HN2-treated cells, and rabbit red cell survival was shortened considerably in the concentration range used to inhibit sickling [29].
• Transport of HN2, hydrolyzed derivative of HN2 and choline by L5178Y lymphoblasts in vitro was not competitively inhibited by any of the other alkylating agents, suggesting that transport of these compounds was by an independent mechanism [30].

Gene context of Chlormethine

• Apoptosis and long term enterocyte survival were examined in vivo after exposure to three cytotoxic agents (Cisplatin, Nitrogen Mustard and N-methyl-N-nitrosourea (NMNU/MNU)) within mice either singly or doubly mutant for p53 and Msh2 [31].
• RESULTS: Of 26 agents screened, BRCA1 and BRCA2 mRNA reductions were observed in both cell lines after exposure to adriamycin (ADR), camptothecin (CPT), sodium selenite (SLN), and ultraviolet radiation (UV), while nitrogen mustard (HN2) caused mRNA reduction in DU-145 but not in Tsu-Prl [32].
• DNA sequence analysis of HN2-induced SUP4-o mutations suggested that RAD52 contributed to the production of basepair substitutions at G.C sites [33].
• HN2 had no discernible effect on the S phase activity of cyclin A- or cdk2-immune complexes [34].
• In addition, we found that HCT-116/p21-/- cells were much more susceptible to HN2-induced cell cycle delay than parental cells [35].

Analytical, diagnostic and therapeutic context of Chlormethine

• The final preparation contained two species: (a) a approximately 13,000 Mr band on reducing or nonreducing SDS-PAGE and on autoradiograms after radioiodination with chloramine T, and (b) a 66,000 Mr species ranging from approximately 5% to approximately 50% of the protein detectable by silver strain [36].
• The labeling index fell from 36.4 to 14.0% and the mitotic index from 0.88 to 0.67% after two treatments with HN2 [3].
• Repair synthesis was shown to continue during the G2 arrest by using synchronized cells pulse labeled with [3H]thymidine after HN2 treatment and autoradiography [27].
• These cells were arrested in G2 shortly after treatment with HN2 as shown by flow microfluorimetry and autoradiography [27].
• We undertook a phase II study of combination chemotherapy with mechlorethamine (nitrogen mustard) 6 mg/m2 intravenously day 1 and day 8, vincristine 2 mg intravenously day 1 and day 8, and procarbazine 100 mg/m2 orally days 1 through 14 (MOP) in adults with recurrent high-grade glioma [37].

References