المؤلفون: Ronald D. Snyder, Sangita Bhatt

المصدر: Cancer Letters. 72:83-90

مصطلحات موضوعية: Alkylating Agents, Cancer Research, Eflornithine, Mitoguazone, DNA Repair, DNA damage, Cell, Spermine, Biology, chemistry.chemical_compound, Polyamines, medicine, Humans, DNA, Neoplasm, Spermidine, medicine.anatomical_structure, Oncology, chemistry, Biochemistry, Cancer cell, Putrescine, Polyamine, Cell Division, DNA, DNA Damage, HeLa Cells

الوصف: Treatment of HeLa cells with the polyamine biosynthesis inhibitors difluoromethylornithine (DFMO) and/or methylglyoxal bis(guanylhydrazone) (MGBG) results in marked depression in levels of the cellular polyamines putrescine, spermidine and spermine. Cells in this polyamine-depleted state exhibited increased sensitivity to monofunctional alkylating agents, manifested as decreased cloning ability and retardation of the DNA excision repair process. DFMO treatment did not alter the initial level of interaction of radiolabeled alkylating agent with cellular DNA, but combined treatment with DFMO and MGBG reduced covalent binding, probably through effects on cell cycling. Polyamine supplementation had no effects on initial yield of DNA single-strand breaks in drug-treated cells. The repair defect appeared similar to that observed previously in polyamine-depleted cells following X-irradiation and UV irradiation, namely retarded sealing of DNA strand breaks. It was not possible to reverse the effects of these inhibitors by short periods of polyamine loading, despite the fact that all three polyamines could be restored to near-normal levels. These findings provide the first demonstration of altered response of polyamine-depleted cells to monofunctional alkylating agents and contribute to our understanding of altered responses of polyamine-depleted cancer cells to a variety of DNA-reactive chemotherapeutic drugs.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::e6bf728c0cfef589d34998c687ab4efcTest
https://doi.org/10.1016/0304-3835Test(93)90015-2

المؤلفون: Olle Heby, Lo Persson, Anders Ask

المصدر: Cancer Letters. 66:29-34

مصطلحات موضوعية: Male, Cancer Research, Eflornithine, Mitoguazone, Spermidine, Ratón, medicine.drug_class, Antibiotics, Mutant, Drug Resistance, Pharmacology, Biology, Tritium, Mice, chemistry.chemical_compound, Sex Factors, Polyamines, medicine, Extracellular, Animals, Carbon Radioisotopes, Leukemia L1210, Biological Transport, Anti-Bacterial Agents, Mice, Inbred C57BL, Oncology, chemistry, Biochemistry, Mice, Inbred DBA, Mutation, Putrescine, L1210 cells, Female, Spermine, Extracellular Space, Polyamine, medicine.drug

الوصف: When L1210 leukemia cells are inhibited in their polyamine synthesis by treatment with alpha-difluoromethylornithine (DFMO), their growth in culture is strongly suppressed. In striking contrast, the survival of L1210 leukemic mice is only marginally prolonged by DFMO treatment. This inconsistency is due to the fact, that in the mouse the tumor cells can utilize extracellular polyamines to compensate for the decrease in putrescine and spermidine synthesis caused by DFMO treatment. In the present study, we demonstrate that a reduction in the transport of polyamines into the tumor cells is a more effective means of increasing the therapeutic effect of DFMO than is a reduction in the supply of extracellular polyamines. DFMO treatment cured 30-75% of leukemic mice bearing mutant L1210-MGBGr cells deficient in polyamine uptake, but only slightly increased the survival time of leukemic mice bearing the parental L1210 cells despite the fact that the supply of extracellular polyamines was reduced (by feeding the mice a polyamine-deficient diet containing antibiotics). The effectiveness by which DFMO cured leukemic mice bearing L1210-MGBGr cells appeared to be sex dependent. Thus, 58% of the female mice, as compared to 30% of the male mice, were cured by DFMO treatment.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::9e51fc7ea68ca47c79cf249839b56d5eTest
https://doi.org/10.1016/0304-3835Test(92)90276-2

المؤلفون: W. Schulze, D. Behnke, K. Gase, W. Gutsche, J. Baumgart, J. Suehnel

المصدر: Cancer Letters. 54:119-124

مصطلحات موضوعية: Male, Cancer Research, Mitoguazone, Time Factors, Ambazone, medicine.medical_treatment, Melanoma, Experimental, Mice, Inbred Strains, Colony-Forming Units Assay, Mice, Random Allocation, chemistry.chemical_compound, In vivo, Antineoplastic Combined Chemotherapy Protocols, medicine, Animals, Humans, Cytotoxic T cell, Cytotoxicity, Tumor Necrosis Factor-alpha, business.industry, Melanoma, Drug Synergism, medicine.disease, Recombinant Proteins, In vitro, Cytokine, Oncology, chemistry, Immunology, Cancer research, Female, Tumor necrosis factor alpha, business, Neoplasm Transplantation

الوصف: Dihydroambazone (DHA) is a water-soluble derivative of the experimental anticancer drug ambazone [8]. In vitro, a combination of DHA and human recombinant tumor necrosis factor alpha (TNF) exerted a strong synergism of cytotoxicity against both mouse melanoma B16K cells and the TNF-sensitive mouse fibroblast line L-M (S). Furthermore, in a colony-forming assay with B16K cells a combination of TNF and DHA inhibited colony-formation much more severely than either drug alone. An increased antiproliferative efficiency was also confirmed in vivo against established subcutaneous melanoma B16 tumors of C57BL/6 mice.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::ed0af08573f061369c78a8e92f7834e5Test
https://doi.org/10.1016/0304-3835Test(90)90032-s

المؤلفون: D. Wilkie, L.L. Cheng, D.C. Collier

المصدر: Cancer Letters. 51:213-220

مصطلحات موضوعية: Glycerol, Keratinocytes, Cancer Research, Mitoguazone, Antioxidant, Cell Survival, Glutamine, medicine.medical_treatment, Guinea Pigs, Saccharomyces cerevisiae, Mitochondrion, Biology, Antioxidants, chemistry.chemical_compound, medicine, Animals, Drug Interactions, Cells, Cultured, Methylglyoxal, Glutathione, Yeast, Mitochondria, Cytosol, Glucose, Oncology, chemistry, Biochemistry, Spectrophotometry, Cell culture, Mutation, Energy source, Cell Division

الوصف: Mitochondria of yeast cells were primary targets of methylglyoxal bis (guanylhydrazone) (MGBG) from the following criteria: (1) selective inhibition of growth of cells utilizing a nonfermentable energy source, (2) inhibition of mitochondrial protein synthesis compared with cytosolic protein synthesis and (3) selective mutagenesis of the mitochondrial genome compared with nuclear mutagenesis. Evidence of primary antimitochondrial activity of MGBG in mammalian cells was provided by greater potency of the drug in guinea pig keratinocyte cultures utililizing glutamine as carbon and energy source compared with fermentable glucose. Cell death was used as a measure of drug toxicity in both yeast and mammalian systems. The antioxidants glutathione, vitamin E and vitamin C reversed toxicity and antimitochondrial activity to a large extent implying that toxic free radical metabolites of the drug are of significance in cellular activity of MGBG.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::0cec25d859f09abe94a664363662191fTest
https://doi.org/10.1016/0304-3835Test(90)90105-7

المؤلفون: Leena Alhonen-Hongisto, Juhani Jänne, Pauli Seppänen

المصدر: Cancer Letters. 18:1-10

مصطلحات موضوعية: Ornithine, Cancer Research, medicine.medical_specialty, Eflornithine, Mitoguazone, Time Factors, Antineoplastic Agents, Spleen, Guanidines, Mice, chemistry.chemical_compound, Bone Marrow, Internal medicine, medicine, Animals, Tissue Distribution, Leukemia L1210, business.industry, Methylglyoxal, medicine.disease, Small intestine, Leukemia, medicine.anatomical_structure, Endocrinology, Oncology, chemistry, Mice, Inbred DBA, Immunology, Drug Therapy, Combination, Female, Bone marrow, business, medicine.drug

الوصف: Mice were treated with daily injections of methylglyoxal bis(guanyl-hydrazone) (MGBG) without or with concurrent administration of 2-difluoromethylornithine (DFMO) in drinking water for 15 days. Analysis of 10 different tissues for their MGBG content during the treatment revealed little evidence for a tissue specific cumulative accumulation of the drug given either alone or in combination with DFMO. On the contrary, tissue MGBG levels tended to increase until the 4th to 7th day of the treatment, whereafter a gradual decline or a plateau was obvious in most tissues. The concomitant DFMO treatment produced a consistent elevation of tissue MGBG concentrations in bone marrow cells and possibly also in intestinal tissue. In L1210 leukemia-bearing DBA mice, MGBG was most actively taken up by the ascitic leukemia cells. A priming of the tumor-bearing mice with DFMO for a few days before the start of MGBG injections resulted in a strikingly enhanced accumulation of the latter drug in the leukemia cells and also in the spleen, which was apparently heavily infiltrated by tumor cells. In liver, small intestine and in bone marrow cells of tumor-bearing animals the concentration of MGBG was not influenced by the DFMO treatment. In DBA mice without the L1210 tumor, DFMO only insignificantly increased the level of MGBG in bone marrow cells whereas no increase was seen in the spleen, in contrast to the same organ obtained from tumor-bearing mice. This combined treatment, in comparison with DFMO or MGBG alone, also produced the best therapeutic response as revealed by marked reduction of the tumor mass.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::df287bd03f81c9cfa685afe26f9e4f6dTest
https://doi.org/10.1016/0304-3835Test(83)90111-8

المؤلفون: D.L. Dewey

المصدر: Cancer Letters. 6:247-250

مصطلحات موضوعية: chemistry.chemical_classification, Adenosylmethionine Decarboxylase, Cancer Research, Amine oxidase, Mitoguazone, Monoamine Oxidase Inhibitors, Spermidine, Cell Cycle, Acrolein, Spermidine metabolism, Guanidines, chemistry.chemical_compound, On cells, Enzyme, Oncology, Biochemistry, chemistry, Methyl glyoxal, Putrescine, Animals, Cell Division, Cells, Cultured

الوصف: Spermidine inhibits many cells in culture because amine oxidase in the serum converts spermidine to toxic products. Methyl glyoxal bis guanylhydrazone (Methyl GAG) inhibits cells in culture because it is a specific inhibitor of S-adenosylmethionine decarboxylase, preventing the conversion of putrescine to spermidine. When both spermidine and methyl GAG were added together, no inhibition was observed. The effect could be explained by the finding that methyl GAG was a powerful non-competitive inhibitor of the enzymatic oxidation of spermidine to acrolein.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::fee5f980146da0aa1d5a8824b15ffe07Test
https://doi.org/10.1016/s0304-3835Test(79)80041-5

المؤلفون: Tetsuya Tsukada, Hiroshige Hibasami, Kunio Nakashima, Satoru Maekawa

المصدر: Cancer Letters. 30:17-23

مصطلحات موضوعية: Male, Adenosylmethionine Decarboxylase, Cancer Research, Mitoguazone, Carboxy-Lyases, Spermine, Cell Line, chemistry.chemical_compound, Polyamines, Animals, Humans, Methionine, biology, Methylglyoxal, Rats, Inbred Strains, Rats, Spermidine, Liver, Oncology, chemistry, Biochemistry, Enzyme inhibitor, Adenosylmethionine decarboxylase, Putrescine, biology.protein, Leukemia, Erythroblastic, Acute, Polyamine

الوصف: Methylglyoxal bis(butylamidinohydrazone) (MGBB) inhibited S -adenosylmethionine decarboxylase (SAMDC) activity competitively with S -adenosylmethionine (SAM) showing the K i value of 1.8 × 10 −5 M. MGBB showed less SAMDC-stabilizing effect in rat liver in vivo than did methylglyoxal bis(guanylhydrazone) (MGBG). MGBB inhibited the growth of human erythroid leukemia K 562 cells. Putrescine, spermidine and spermine concentrations in MGBB-treated cells were depressed to 56%, 58% and 88% of the values of control cells, respectively. [ 35 S]Methionine incorporation into trichloroacetic acid-insoluble fraction was decreased in the inhibitor-treated cells.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::48cb9ff13ffc93210c0933b4be349106Test
https://doi.org/10.1016/0304-3835Test(86)90127-8

المؤلفون: Olle Heby, Gunnar Andersson

المصدر: Cancer Letters. 3:59-63

مصطلحات موضوعية: Adenosylmethionine Decarboxylase, Cancer Research, Mitoguazone, Cell division, Cell growth, Methylglyoxal, DNA, Neoplasm, Biology, Cell cycle, Guanidines, Polyamine Synthesis Inhibitor, Kinetics, chemistry.chemical_compound, Oncology, Biochemistry, chemistry, In vivo, Adenosylmethionine decarboxylase, Cancer research, Animals, Carcinoma, Ehrlich Tumor, Cell Division

الوصف: Population kinetics of Ehrlich ascites tumor cells grown in vivo were studied following treatment with methylglyoxal-bis(guanylhydrazone) (MeGAG; NSC-32946), a potent chemotherapeutic agent and a specific polyamine synthesis inhibitor. MeGAG-treatment resulted in a continuous accumulation of cells in the S and G2 phases of the cell cycle, and, as a consequence, the rate of cell proliferation decreased. This finding emphasizes the importance of the polyamines for progression through the cell cycle.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::6d14e422aeca0fd897315a7859eb01fdTest
https://doi.org/10.1016/s0304-3835Test(77)94150-7

المؤلفون: Jan Lindemans, M. Schoester, A. C. M. Kroes, A. A. M. Ermens, J. Abels

المصدر: Cancer Letters. 41:295-305

مصطلحات موضوعية: Male, Adenosylmethionine Decarboxylase, S-Adenosylmethionine, Cancer Research, Mitoguazone, Nitrous Oxide, Spermine, chemistry.chemical_compound, Biosynthesis, Rats, Inbred BN, Polyamines, Animals, Cycloleucine, Leukemia, Experimental, Methionine, Proteins, DNA, Rats, Spermidine, Oncology, chemistry, Biochemistry, Polyamine, Intracellular

الوصف: Decarboxylated S-adenosylmethionine (SAM) is an aminopropyl donor in the synthesis of the polyamines, spermidine and spermine. The decarboxylation of SAM is inhibited by the toxic cytostatic drug methylglyoxalbis-(guanylhydrazone) (MGBG). To achieve more specific and less toxic effects of MGBG, this drug was combined with cycloleucine, which inhibits SAM synthesis, and with nitrous oxide, which inhibits methionine synthetase. This treatment thus aimed at sequential inhibition of the synthesis of decarboxylated SAM, and was studied in a rat leukemia model (BNML). Combined treatment further decreased the level of spermine, but not of spermidine, in leukemic cells, compared to the effects of MGBG alone. The therapeutic effects of this combination were additive or less than additive, however. MGBG was not very effective in reducing leukemic growth and severely toxic, although less with combined treatment. Another inhibitor of SAM decarboxylase, berenil, was also used, and although this drug was about equally active in inhibition of leukemic growth, alterations in intracellular polyamines were not observed. The combination of nitrous oxide and cycloleucine, which effectively reduced leukemic growth at non-toxic dosages, selectively inhibited spermine synthesis, and therefore may be used to interfere with polyamine metabolism. The relevance of this polyamine deprivation to the treatment of leukemia could not be demonstrated.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::04619aa9db068205ad5397a14bab4a70Test
https://doi.org/10.1016/0304-3835Test(88)90291-1

المؤلفون: Leena Alhonen-Hongisto, Raija Laine, Hannu Elo, Ilpo Mutikainen, Juhani Jänne

المصدر: Cancer letters. 41(1)

مصطلحات موضوعية: Cancer Research, Adenosylmethionine Decarboxylase, Magnetic Resonance Spectroscopy, Mitoguazone, Carboxy-Lyases, Antineoplastic Agents, Antileukemic agent, 03 medical and health sciences, chemistry.chemical_compound, Structure-Activity Relationship, 0302 clinical medicine, X-Ray Diffraction, Polyamines, 030304 developmental biology, 0303 health sciences, biology, Ornithine, 3. Good health, Oncology, chemistry, Ornithine Decarboxylase Inhibitor, Biochemistry, Enzyme inhibitor, Adenosylmethionine decarboxylase, 030220 oncology & carcinogenesis, Putrescine, biology.protein, Amine Oxidase (Copper-Containing), Diamine oxidase, Polyamine, Cell Division

الوصف: Diethylglyoxal bis(guanylhydrazone) (DEGBG), a novel analog of the antileukemic agent methylglyoxal bis(guanylhydrazone) (MGBG) was synthesized. It was found to be the most powerful inhibitor of yeast S-adenosylmethionine decarboxylase (AdoMetDC) so far studied (Ki approx. 9 nM). This property, together with the finding that the compound is a weaker inhibitor of intestinal diamine oxidase than are MGBG and its glyoxal, ethylglyoxal and ethylmethylglyoxal analogs, makes the compound a promising candidate as a polyamine antimetabolite for chemotherapy studies. DEGBG was also found to potentiate the antiproliferative effect of the ornithine decarboxylase inhibitor alpha-difluoromethyl ornithine against mouse L1210 leukemia cells in vitro. DEGBG increased several-fold the intracellular putrescine concentration of cultured L1210 cells, just as MGBG and its ethylglyoxal analog are known to do. The results strongly suggest that DEGBG is worth further studies. Combined with previous studies, they also made possible the construction of some empirical rules concerning the structure-activity relationships of bis(guanylhydrazone) type inhibitors of AdoMetDC. The identity of DEGBG was confirmed by a single-crystal X-ray analysis and by 1H- and 13C-NMR spectroscopy. It consisted of the same isomer as MGBG and several of its analogs are known to consist of.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::4cc71329da2e648dc70d30596f16fc9eTest
https://pubmed.ncbi.nlm.nih.gov/3134121Test