mitoguazone and pimagedine

The prostate is a rich factory of polyamine production. In spite of this, the prostate is also able to accumulate polyamines from the circulation. Intracellular polyamine depletion has been observed to enhance the accumulation of diamines such as putrescine. This needs to be taken advantage of either as a means for imaging prostatic tumour spread to the lymph nodes or as a means of targeting toxins to the prostatic tumour. Putrescine is a small molecule that may prove difficult for use for synthesizing stable toxin derivatives that can take advantage of the targeting potential of the polyamine transporter. The cloning and sequencing characterization of the transporter is under way. When the prostatic transporter is identified, it will be possible to understand the role of the transporter in normal and cancerous prostatic cell growth and functioning and should serve to aid our understanding of how we can better optimize agents to use the transporter for delivery of antitumour agents.

Topics: Aziridines; Biological Transport; Cell Division; Dihydrotestosterone; Eflornithine; Guanidines; Humans; Male; Mitoguazone; Ornithine Decarboxylase; Polyamines; Prostate; Prostatic Neoplasms; Putrescine

To evaluate the putative importance of digestive luminal polyamines, we investigated the role of oxidation in putrescine uptake and transport in differentiated Caco-2 cells grown in monolayer.. Our results confirm a putrescine uptake system located both at the apical and basolateral cell membrane. Putrescine is efficiently transported and excreted in the apical-to-basolateral direction.. These results suggest (i) a diamine oxidase controlled catabolic oxidative excreting pathway and (ii) a paracellular route for putrescine transport. This catabolic route seems to proceed by converting putrescine into gamma-aminobutyraldehyde which is then rapidly excreted from the cell at the basolateral membrane since no gamma-aminobutryraldehyde was detected in the cell. This putative basolateral excreting mechanism is inhibited in the presence of the diamine oxidase inhibitor, aminoguanidine.

Topics: Biological Transport, Active; Caco-2 Cells; Cystamine; Enzyme Inhibitors; Guanidines; Humans; In Vitro Techniques; Mitoguazone; Putrescine; Spermidine; Spermine

Polyamines are known to play a central role in processes such as growth and development. Virtually nothing is known about their importance in tooth development, an attractive and frequently used experimental model for studies of developmental processes. A polyamine-depleted state was created in tooth cells in an organ culture system. First lower molar germs from 16-and 17.5-day old mouse fetuses were used. alpha-difluoromethylornithine (DFMO) and methylglyoxal bis-(guanylhydrazone) (MGBG) were used to deplete the cells from their polyamine content. Polyamine interconversion and catabolism were prevented by aminoguanidine sulfate (AG). In day-16 germs cultured in serum-containing medium, DFMO reduced the frequency of cycling cells as shown by [3H]thymidine incorporation, and induced a delay of odontoblast differentiation of about 24 h. Under the same conditions, MGBG induced an arrest of histo-morphogenesis, correlated to a significant decrease in the rate of cell proliferation. Addition of polyamines prevented DFMO- and MGBG-induced delay of tooth differentiation. Interestingly, MGBG did not delay the terminal differentiation of odontoblasts and ameloblasts in cultured day-17.5 molars; in these, cells at the tip of the cusps are only a few hours before their withdrawal from the cell cycle. In serum-deprived medium, dental cytodifferentiations did not occur. Addition of putrescine or spermidine to serum-free media, however, allowed for tooth morphogenesis and cytodifferentiation. Tooth explants in a serum-deprived medium reacted to DFMO in a cytocidal fashion, whereas MGBG showed only a mild toxicity in some cell types. Addition of putrescine to DFMO-containing medium prevented its cytotoxic effect. Addition of spermidine to MGBG-containing medium not only prevented its mild toxicity but also allowed for predentin secretion by differentiated odontoblasts. The results are discussed with regard to the well-established developmental events of tooth germs cultured in vitro and with respect to present knowledge of polyamine metabolism and their involvement in cellular processes.

Topics: Animals; Cell Differentiation; Cell Division; Culture Media; DNA; Eflornithine; Guanidines; Mice; Mitoguazone; Odontoblasts; Odontogenesis; Organ Culture Techniques; Polyamines; Putrescine; Spermidine; Time Factors; Tooth

Methylglyoxal-bis(guanylhydrazone) (MGBG), a potent inhibitor of the spermidine and spermine biosynthetic enzyme S-adenosyl-L-methionine decarboxylase, enhanced the cytotoxicity of 1,3-bis-(2-chlorethyl)-1-nitrosourea in 9L rat brain tumor cells in vitro, as measured by a colony-forming efficiency assay, by an amount that was approximately the same as the potentiation caused by the ornithine decarboxylase inhibitor alpha-difluoromethylornithine. Dose enhancement ratios at 10, 1 and 0.1% survival levels were approximately 1.3 for both inhibitors. 9L cells that were treated for 48 hr with 40 microM MGBG had putrescine, spermidine and spermine levels that were 112, 41 and 21%, respectively, of polyamine levels in control cells. MGBG treatment does not increase intracellular levels of decarboxylated S-adenosyl-L-methionine (AdoMet) as alpha-difluoromethylornithine treatment does. Elevated levels of decarboxylated AdoMet could modify intracellular methylation reactions and could affect the cytotoxicity of a chloroethylnitrosourea. Despite the fact that MGBG treatment caused a slight increase in intracellular levels of AdoMet, it is unlikely that this elevation will increase the amount of intracellular methylation. Thus it appears that effects caused by the decrease in polyamine levels are responsible for the potentiation of chloroethylnitrosourea cytotoxicity against 9L cells.

Topics: Adenosylmethionine Decarboxylase; Animals; Brain Neoplasms; Carboxy-Lyases; Carmustine; Cell Survival; Cells, Cultured; Dose-Response Relationship, Drug; Drug Synergism; Guanidines; Mitoguazone; Putrescine; Rats; Spermidine; Spermine

Treatment of mice bearing L1210 leukaemia with 2-difluoromethylornithine, a specific inhibitor of ornithine decarboxylase (EC 4.1.1.17), produced a profound depletion of putrescine and spermidine in the tumour cells. Sequential combination of methylglyoxal bis(guanylhydrazone), an inhibitor of adenosylmethionine decarboxylase (EC 4.1.1.50), with difluoromethylornithine largely reversed the polyamine depletion and led to a marked accumulation of cadaverine in the tumour cells. Experiments carried out with the combination of difluoromethylornithine and aminoguanidine, a potent inhibitor of diamine oxidase (EC 1.4.3.6), indicated that the methylglyoxal bis(guanylhydrazone)-induced reversal of polyamine depletion was mediated by the known inhibition of diamine oxidase by the diguanidine. In spite of the normalization of the tumour cell polyamine pattern upon administration of methylglyoxal bis(guanylhydrazone) to difluoromethylornithine-treated animals, the combination of these two drugs produced a growth-inhibitory effect not achievable with either of the compounds alone.

Topics: Amine Oxidase (Copper-Containing); Animals; Antineoplastic Agents; Drug Therapy, Combination; Eflornithine; Female; Guanidines; Leukemia L1210; Mice; Mice, Inbred DBA; Mitoguazone; Ornithine; Polyamines