mitoguazone and Leukemia

Topics: Acetyltransferases; Adenosylmethionine Decarboxylase; Amine Oxidase (Copper-Containing); Carnitine; Cell Division; DNA Replication; Eflornithine; Energy Metabolism; Humans; Kinetics; Leukemia; Male; Mitochondria; Mitoguazone; Nucleic Acids; Ornithine; Oxidation-Reduction; Palmitic Acid; Palmitic Acids; Polyamines; Protein Biosynthesis; Putrescine; Virus Replication

Initial clinical trials of methyl-GAG (MGBG) showed that repetitive daily administration produced severe, occasionally fatal, toxic reactions. After two decades of neglect, recent studies have shown that doses of 500-600 mg/sq m administered every 7-14 days are very well tolerated. 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). The drug's mechanism of cytotoxic action and its toxic effects are not shared by most other cancer chemotherapeutic drugs. Furthermore, Phase II and Phase III evaluation are required to determine the therapeutic potential of this unique agent.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Chemical Phenomena; Chemistry; Clinical Trials as Topic; Colonic Neoplasms; Diarrhea; Dose-Response Relationship, Drug; Drug Eruptions; Drug Therapy, Combination; Eflornithine; Esophageal Neoplasms; Guanidines; Head and Neck Neoplasms; Humans; Kidney Neoplasms; Leukemia; Leukemia L1210; Lung Neoplasms; Mice; Mitoguazone; Muscular Diseases; Nausea; Neoplasms; Ornithine; Polyamines; Stilbamidines; Structure-Activity Relationship

Topics: Animals; Antimetabolites, Antineoplastic; Drug Administration Schedule; Drug Therapy, Combination; Eflornithine; Humans; Leukemia; Mitoguazone; Neoplasms, Experimental; Ornithine; Polyamines

Topics: Child; Clinical Trials as Topic; Drug Administration Schedule; Drug Evaluation; Humans; Leukemia; Lymphoma; Mitoguazone

Initial clinical trials of methyl-GAG (MGBG) showed that repetitive daily administration produced severe, occasionally fatal, toxic reactions. After two decades of neglect, recent studies have shown that doses of 500-600 mg/sq m administered every 7-14 days are very well tolerated. 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). The drug's mechanism of cytotoxic action and its toxic effects are not shared by most other cancer chemotherapeutic drugs. Furthermore, Phase II and Phase III evaluation are required to determine the therapeutic potential of this unique agent.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Chemical Phenomena; Chemistry; Clinical Trials as Topic; Colonic Neoplasms; Diarrhea; Dose-Response Relationship, Drug; Drug Eruptions; Drug Therapy, Combination; Eflornithine; Esophageal Neoplasms; Guanidines; Head and Neck Neoplasms; Humans; Kidney Neoplasms; Leukemia; Leukemia L1210; Lung Neoplasms; Mice; Mitoguazone; Muscular Diseases; Nausea; Neoplasms; Ornithine; Polyamines; Stilbamidines; Structure-Activity Relationship

A reversed-phase (C18) HPLC method with diode-array detection was developed for the separation and determination of methylglyoxal bis(amidinohydrazone) (mitoguazone) and seven closely related aliphatic analogs thereof, namely the bis(amidinohydrazones) of glyoxal, dimethylglyoxal, ethylmethylglyoxal, methylpropylglyoxal, butylmethylglyoxal, diethylglyoxal and dipropylglyoxal. The mobile phase consisted of a non-linear binary gradient of methanol and 0.03 M aqueous sodium acetate buffer (pH 4.3). Good separation of the eight congeners was achieved. On increasing the methanol content of the eluent, the bis(amidinohydrazones) eluted in the order of increasing number of carbon atoms in the side-chains. The method was also applied to the quantitative analysis of the compounds in aqueous solution and, combined with ultrafiltration, for the separation of the eight congeners in spiked human blood serum. A separate simplified method for the quantitative determination of each of the compounds in spiked human blood serum samples was also developed. The methods developed made for the first time possible the simultaneous HPLC analysis of more than one bis(amidinohydrazones). The results obtained indicate that the bis(amidinohydrazones) studied obviously have a distinct tendency to form ion associates with acetate ions and probably also other carboxylate ions in aqueous solution. This aspect may be of biochemical significance, especially concerning the intracellular binding of the compounds. Each one of the compounds studied invariably gave rise to one peak only, this result supporting the theory that the conventional synthesis of each of the compounds gives rise to one geometrical isomer only. This result is completely in agreement with the results of previous proton and carbon NMR spectroscopic as well as X-ray diffraction studies.

Topics: Adult; Antineoplastic Agents; Chromatography, High Pressure Liquid; Humans; Hydrazones; Isomerism; Leukemia; Male; Mitoguazone; Spectrophotometry, Ultraviolet

Fourteen patients with acute leukemia in relapse were treated with difluoromethylornithine (DFMO) alone or in combination with methylglyoxal-bis(guanylhydrazone) (MGBG) as part of Phase I studies. Five patients included in the trial exhibited morphologic evidence of cellular differentiation during the course of treatment. In one patient who exhibited no blasts and a normal white blood cell differential at the end of treatment the mononuclear cell content of all three polyamines declined after an initial increase in spermidine and spermine content. In the other patients in whom the cellular maturation was less pronounced the mononuclear cell polyamine levels remained stable or increased over the treatment time. No absolute difference was apparent between the cellular polyamine levels detected in patients at the times of the greatest increase in per cent circulating neutrophils as compared to the cellular levels present in patients whose circulating mononuclear cell number were increasing. Circulating mononuclear cell putrescine, spermidine, and spermine levels varied over two orders of magnitude from patient to patient and the range of values detected in each state completely overlapped those present in the other. It does not appear from the present study that there is a consistent human leukemic cell polyamine content at which cellular differentiation occurs.

Topics: Adolescent; Adult; Aged; Biogenic Polyamines; Bone Marrow; Bone Marrow Cells; Drug Evaluation; Eflornithine; Female; Humans; Leukemia; Leukocyte Count; Male; Middle Aged; Mitoguazone; Monocytes; Time Factors

The first systematic study on the acid-base properties of the antileukemic agents glyoxal bis(guanylhydrazone) (GBG) and methylglyoxal bis(guanylhydrazone) (MGBG) and of their non-antileukemic monoalkyl- and dialkylglyoxal analogs is reported. At physiological conditions (pH 7.4, 37 degrees C), the species distribution of GBG and MGBG differs remarkably from that of their inactive congeners, a noteworthy proportion of GBG (10.2%) and MGBG (4.0%) existing in the form of the free base while the corresponding proportion of their non-antiproliferative analogs is only 0.5% or less. Ethylglyoxal bis(guanylhydrazone) (EGBG), which has antiproliferative properties in vitro but is devoid of antileukemic activity in vivo, is intermediate between the two groups, 2.6% of it existing in the free base form. In contrast to what has been generally assumed, at physiological conditions, the predominant species of GBG, MGBG, and EGBG is the monocation form and not the dication. Considerable proportions of other congeners also exist in the monocation form. At slightly higher pH values that are of interest because of the known antimitochondrial effects of GBG and MGBG (and, in high concentrations, EGBG), the species distribution of GBG and MGBG differs even more remarkably from that of the dialkylglyoxal analogs. Thus, at pH 8.0 and 37 degrees C, as much as 36% of GBG and 19% of MGBG exist in the free base form, the corresponding proportion of EGBG being 14% and that of the other congeners studies only ca. 3-4%. On the basis of the results, it appears possible that the unusually strict structure-activity relationships of this class of antineoplastic agents may be based on the remarkable differences between the species distributions of the various congeners. The hypothesis is presented that the actual antiproliferative and antimitochondrial species of the compounds is the free base form. A compilation of pKa1 and pKa2 values, measured by potentiometric methods in 0.1 M NaCl (aq) at 25 degrees C and 37 degrees C, is given for six bis(guanylhydrazones). The species distribution curves of the compounds (at 37 degrees C) are given for the pH range 6-10.

Topics: Antineoplastic Agents; Hydrogen-Ion Concentration; Leukemia; Mitoguazone; Structure-Activity Relationship

Methylglyoxal-bis(cyclopentylamidinohydrazone) (MGBCP) has been synthesized as a multienzyme inhibitor for the polyamine-synthesizing pathway. This drug inhibited S-adenosylmethionine decarboxylase (EC 4.1.1.50), spermine synthase and spermidine synthase activities, competitively with S-adenosylmethionine, spermidine, and putrescine, respectively. MGBCP inhibited the growth of human leukemia Molt 4B and K 562 cells at 10 to 100 microM concentrations. Spermidine and spermine levels were markedly depressed in these MGBCP-treated leukemic cells, and the synthesis of protein, but not of DNA or RNA, was significantly diminished. In in vivo experiments, MGBCP depleted spermidine and spermine in the P388 leukemic ascites cells, and prolonged the survival time of mice bearing P388 leukemia. The S-adenosylmethionine decarboxylase-stabilizing effect of MGBCP in mouse liver, Molt 4B and K 562 cells was much less than that of the parent inhibitor methylglyoxal-bis(guanylhydrazone). Induction of ornithine decarboxylase activity by MGBCP in the cultured leukemic cells was also much less than that by methylglyoxal-bis(guanylhydrazone).

Topics: Adenosylmethionine Decarboxylase; Animals; Antineoplastic Agents; Biogenic Polyamines; Female; Humans; Leukemia; Mice; Mice, Inbred C57BL; Mice, Inbred DBA; Mitoguazone; Ornithine Decarboxylase; Spermidine Synthase; Spermine Synthase; Transferases; Tumor Cells, Cultured

Nine patients with hematological malignancies were treated with difluoromethylornithine and methylglyoxal bis(guanylhydrazone). The number of circulating blast cells decreased in all of the patients treated with DFMO and MGBG for longer than 1 wk. Morphological evidence of myeloid maturation was evident in four patients with leukemia and the circulating M Protein decreased in one patient with multiple myeloma. The polyamine content of the mononuclear cells in both the peripheral blood and bone marrow was transiently increased after the initial MGBG dose. During administration of DFMO decreases were achieved in the peripheral blood mononuclear cell putrescine levels in 7 patients, spermidine levels in 5 patients, and spermine levels in 4 patients. Alterations in bone marrow mononuclear cell polyamine levels were similar to those which occurred in the peripheral cells. An average of 9 days of DFMO treatment was required to lower mononuclear cell polyamine levels. Three of the 4 evaluable patients receiving multiple MGBG doses had an increased mononuclear cell content of MGBG after DFMO pretreatment. Enhancement of cellular MGBG levels was not directly correlated to the degree of cellular polyamine depletion.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow; Drug Evaluation; Eflornithine; Female; Humans; Leukemia; Leukocytes, Mononuclear; Male; Middle Aged; Mitoguazone; Polyamines

Eight patients who had refractory leukemia and 1 patient with refractory multiple myeloma were treated with the polyamine biosynthesis inhibitors methylgloxal bis(guanylhydrazone) (MGBG) and difluoromethylornithine (DFMO). After the first dose of MGBG there was an increase in polyamine content in the mononuclear cells of both the peripheral blood and the bone marrow despite the administration of DFMO in all patients with leukemia. Putrescine levels increased in the mononuclear cells of all patients, cellular spermidine levels increased in 4 and cellular spermine levels increased in 5 patients. The cellular polyamine levels remained elevated above the pretreatment levels for up to 1 week in some patients. Subsequent treatment with MGBG, administered after 1-2 weeks of DFMO treatment, also promoted increases in mononuclear cell polyamine concentrations. Since enhanced tumor cell uptake of MGBG after DFMO priming is hypothesized to be dependent on a decrease in cellular polyamine levels, the increase in cellular polyamines after MGBG has important implications for the scheduling of this drug combination. From these observations, withholding MGBG until DFMO treatment has produced a decrease in tumor cell polyamine concentrations would be the schedule most likely to enhance the uptake of MGBG.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Biogenic Polyamines; Bone Marrow; Drug Administration Schedule; Eflornithine; Female; Humans; Leukemia; Leukocytes, Mononuclear; Male; Middle Aged; Mitoguazone; Multiple Myeloma

Difluoromethylornithine (DFMO) is a nonreversible inhibitor of ornithine decarboxylase (ODC), the initial rate-limiting enzyme in the polyamine biosynthetic pathway. When HL60 leukemic cells were incubated in the presence of concentrations of DFMO from 0.05 mM to 5 mM, there was a concentration-dependent inhibition of ODC activity apparent within 24 h. Likewise, cellular polyamine levels were reduced by the presence of DFMO in a concentration-dependent manner after 4 days. The growth of cells incubated with 0.5 mM or greater was inhibited after 3-4 cell doublings. When the concentration of DFMO was less than 0.5 mM, growth was not inhibited. Methylglyoxal-bis(guanylhydrazone) (MGBG) uptake was enhanced in cells treated with concentrations of 0.05-0.5 mM DFMO, but not enhanced in cells treated with DFMO concentrations of 1 mM or greater. DFMO-induced cellular polyamine depletion does enhance MGBG uptake into HL60 cells, but treatment with high concentrations of DFMO, which deplete polyamines to the extent that growth is inhibited, negate this effect.

Topics: Cell Division; Cells, Cultured; Eflornithine; Female; Humans; Leukemia; Mitoguazone; Ornithine Decarboxylase; Polyamines; Putrescine

Topics: Guanidines; Humans; Leukemia; Leukocytes; Methods; Mitoguazone

Methylglyoxal-bis(guanylhydrazone) (MGBG; NSC 32946), a competitive inhibitor of S-adenosyl-L-methionine decarboxylase (EC 4.1.1.50), currently being reevaluated for its clinical antileukemic activity. MGBG labeled with 14C in the guanylhydrazone moiety was administered i.v. (150 microCi; specific activity, 1.9 microCi/mumol; 20 mg total) to six patients with leukemia. All patients in the study had normal renal and hepatic function. [14C]MGBG underwent no in vivo metabolism; it disappeared from the plasma with an average terminal t 1/2 of 4.1 hr. The 72-hr cumulative urinary excretion was only 14.5 +/- 2.2% (S.E.M.) of the total radioactive dose. The apparent volume of distribution was 661 ml/kg and the total clearance rate was 21.2 ml/kg/min. The low urinary excretion rate and the relatively rapid plasma clearance suggest that MGBG may be sequestered in the body. Therefore, if MGBG is administered by a frequent treatment schedule, the prolonged biological half-life in humans may significantly contribute to its clinical toxicity.

Topics: Drug Evaluation; Guanidines; Humans; Kinetics; Leukemia; Metabolic Clearance Rate; Mitoguazone

Topics: Drug Therapy; Guanidines; Humans; Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Mercaptopurine; Mitoguazone; Pyruvaldehyde; Toxicology

Topics: Guanidines; Humans; Leukemia; Leukemia, Myeloid; Mercaptopurine; Mitoguazone; Pyruvaldehyde; Toxicology

Topics: Antimetabolites; Antineoplastic Agents; Biomedical Research; Blood Chemical Analysis; Dermatology; Gastroenterology; Guanidines; Humans; Leukemia; Leukemia, Experimental; Leukemia, Monocytic, Acute; Leukemia, Myeloid; Mitoguazone; Pyruvaldehyde; Toxicology

Topics: Animals; Antineoplastic Agents; Guanidine; Guanidines; Leukemia; Leukemia, Experimental; Mice; Mitoguazone; Pyruvaldehyde; Stilbamidines

Topics: Antineoplastic Agents; Child; Glyoxal; Leukemia; Mitoguazone

Topics: Amidines; Antineoplastic Agents; Humans; Hydrazines; Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Mitoguazone; Pyruvaldehyde

Topics: Animals; Glyoxal; Hydrazines; Leukemia; Leukemia, Experimental; Mice; Mitoguazone