Disease relevance of MITOGUAZONE

• Effectiveness of methyl-GAG (methylglyoxal-bis[guanylhydrazone]) in patients with advanced malignant lymphoma [1].
• The results are consistent with an alteration of polyamine biosynthesis by MGBG being involved in the antiproliferative toxicity of the drug [2].
• Methylglyoxal-bis(guanylhydrazone) in hormone-resistant adenocarcinoma of the prostate [3].
• Exponentially growing L1210 leukemia cells were prelabeled with [14C]thymidine, treated with MGBG for 1.5 to 16 hr, and then pulse labeled with [3H]-thymidine [4].
• Since some animal prostatic cancer tumor models are sensitive to cytotoxic drugs that produce polyamine inhibition, clinical trials of MGBG combined with other inhibitors of the polyamine pathway should be explored [3].

High impact information on MITOGUAZONE

• Recently, we identified a class of multivalent guanylhydrazone compounds that are effective inhibitors of proinflammatory cytokine synthesis in monocytes/macrophages [5].
• As a selective inhibitor of macrophage activation that prevents TNF production, this tetravalent guanylhydrazone could be useful in the development of cytokine-suppressive agents for the treatment of diseases mediated by overproduction of cytokines [6].
• Suppression of proinflammatory cytokines in monocytes by a tetravalent guanylhydrazone [6].
• METHODS: Inhibition of JNK and p38 MAPK activation with CNI-1493, a guanylhydrazone, was tested in vitro [7].
• In the present studies, we found that fetuin is necessary for macrophages to respond to CNI-1493, a tetravalent guanylhydrazone inhibitor of p38 mitogen-activated protein kinase phosphorylation [8].

Chemical compound and disease context of MITOGUAZONE

• Cisplatin, vinblastine, and mitoguazone chemotherapy for epidermoid and adenocarcinoma of the esophagus [9].
• MIME chemotherapy (methyl-GAG, ifosfamide, methotrexate, etoposide) as treatment for recurrent Hodgkin's disease [10].
• Decreased TAF7 expression, by RNA interference, in androgen-independent human prostate cancer LN-CaP104-R1 cells resulted in lower polyamine transport activity (25% of control) and resistance to MGBG-induced growth arrest [11].
• alpha-Difluoromethylornithine (DFMO), an enzyme-activated irreversible inhibitor of ornithine decarboxylase, was used alone and in combination with multiple doses of methylglyoxal-bis(guanylhydrazone) (MGBG) to treat mice with systemic L1210 leukemia [12].
• Methyl-glyoxal bis guanyl hydrazone (methyl-GAG, MGBG) in advanced breast cancer. A Phase II trial of the Southwest Oncology Group [13].

Biological context of MITOGUAZONE

• In contrast, the incorporation of [methyl-3H]thymidine into DNA and the rate of entry of the cells into mitosis are inhibited by 60% in the presence of MGBG [14].
• A haploid yeast strain was transformed with a genomic minitransposon- and lacZ-tagged library, and positive clones were selected for growth resistance to methylglyoxal bis(guanylhydrazone) (MGBG), a toxic polyamine analog [15].
• A 747-bp DNA fragment adjacent to the lacZ fusion gene rescued from one MGBG-resistant clone mapped to chromosome X within the coding region of a putative Ser/Thr protein kinase gene of previously unknown function (YJR059w, or STK2) [15].
• Exposure of cultured leukemia L1210 cells to 0.1 micron methylglyoxal-bis(guanylhydrazone) resulted in a concentration-dependent inhibition of cellular proliferation, beginning after about 1 to 2 generation times (12 to 24 hr) [16].
• Against L1210 leukemic cells and T24 bladder carcinoma cells, the compounds were slightly less effective than MGBG at inhibiting cell growth, with 50% inhibitory concentration values of 1 to 10 microM as compared with 0.5 and 1.1 microM, respectively, for MGBG [17].

Anatomical context of MITOGUAZONE

• In both cell lines, polyamines and MGBG share a common transport system [18].
• After removal of MGBG, damaged mitochondria in 90 to 95% of cells recovered near-normal ultrastructure within 1 to 2 days; in some cells, mitochondrial recovery from severe damage could be monitored following a lag period of up to 5 days [19].
• Moreover, current results indicate that MGBG has useful antitumor activity in patients with advanced malignant lymphoma and carcinomas of the head and neck, esophagus, and lung (non-small cell) [20].
• DBI was found to increase markedly the inhibitory effect of either 4,4'-diacetyldiphenylurea-bis(guanylhydrazone) or MGBG on respiration of isolated rat liver mitochondria [21].
• Polyamines and biosynthetic enzymes in the rat intestinal mucosa and the influence of methylglyoxal-bis(guanylhydrazone) [2].

Associations of MITOGUAZONE with other chemical compounds

• The Km and Vmax values for spermidine and MGBG measured 10 sec after addition (initial permeation) were not affected by DFMO pretreatment in either cell line [18].
• Ethylglyoxal bis(guanylhydrazone) (EGBG) was compared as an inhibitor of polyamine biosynthesis with methylglyoxal bis(guanylhydrazone) (MGBG) in bovine small lymphocytes stimulated by concanavalin A [22].
• Proliferation of 9L cells was only slightly inhibited by treatment with 40 microM MGBG alone, but when used in combination with 0.5 mM alpha-difluoromethylornithine (DFMO), an irreversible inhibitor of ornithine decarboxylase, proliferation was much more effectively inhibited [18].
• In contrast to MGBG, CGP 48664 displays attenuated antimitochondrial activity as indicated by a lack of effect on pyruvate oxidation and mitochondrial DNA levels under treatment conditions which inhibit cell proliferation [23].
• As with MGBG and 4,4'-diacetyldiphenylurea-bis(guanylhydrazone), the potassium cationophore, valinomycin, increased the sensitivity of mitochondrial respiration to DBI [21].

Gene context of MITOGUAZONE

• CNI-1493, a tetravalent guanylhydrazone, is an inhibitor of macrophage activation including the synthesis of TNF and other cytokines [24].
• Taken together, these results reveal a physiological function of TAF7 as a basal regulator for mammalian polyamine transport activity and MGBG-induced apoptosis [11].
• In the studies reported here, it was found that inhibitors of polyamine biosynthesis, methylglyoxal-bis[quanylhydrazone] (MGBG) and difluoromethylornithine (DFMO), prevent mitogen-induced accumulation of mRNAs encoding major cytoskeletal components, beta-actin and alpha-tubulin, in mouse splenocytes [25].
• The induction of ODC activity by TPA was specifically blocked by methylglyoxal bis(butylamidinohydrazone) (MGBB), a competitive inhibitor of ODC and S-adenosylmethionine decarboxylase, but not by the analog methylglyoxal bis(guanylhydrazone) (MGBG) [26].
• In vitro, treatment with DL-alpha-difluoromethylornithine (DFMO) or methylglyoxal bis-(guanylhydrazone) (MGBG) led to an increase in AdoMetDC [27].

Analytical, diagnostic and therapeutic context of MITOGUAZONE

• MGBG-treated and control cultures initiate DNA synthesis at the same time and show the same percentage of labeled cells by autoradiography [14].
• The low degree of toxicity, unique mechanism of action, and minimal myelosuppressive effects suggest that methyl-GAG will prove useful in future trials of combination chemotherapy regimens for the treatment of lymphoma [1].
• Methylglyoxal-bis(guanylhydrazone) (MGBG) is a polycationic drug which is useful in the chemotherapy of lymphoid and myeloid proliferative disorders [4].
• Excised tumor tissue and plasma were assayed for MGBG by high-pressure liquid chromatography [28].
• The fate of mitochondrial DNA (mtDNA) both during (24 to 48 hr) and following (7 hr to 7 days) MGBG treatment was monitored by ultrastructural, electron autoradiographic, pulse-labeling, gradient centrifugation, restriction cleavage, and electrophoretic methods [19].

References