A novel peptide derived from vascular endothelial growth factor prevents amyloid beta aggregation and toxicity.

Amyloid-ß oligomers (Aßo) are the most pathologically relevant Aß species in Alzheimer's disease (AD), because they induce early synaptic dysfunction that leads to learning and memory impairments. In contrast, increasing VEGF (Vascular Endothelial Growth Factor) brain levels have been shown to improve learning and memory processes, and to alleviate Aß-mediated synapse dysfunction. Here, we designed a new peptide, the blocking peptide (BP), which is derived from an Aßo-targeted domain of the VEGF protein, and investigated its effect on Aß-associated toxicity. Using a combination of biochemical, 3D and ultrastructural imaging, and electrophysiological approaches, we demonstrated that BP strongly interacts with Aßo and blocks Aß fibrillar aggregation process, leading to the formation of Aß amorphous aggregates. BP further impedes the formation of structured Aßo and prevents their pathogenic binding to synapses. Importantly, acute BP treatment successfully rescues long-term potentiation (LTP) in the APP/PS1 mouse model of AD, at an age when LTP is highly impaired in hippocampal slices. Moreover, BP is also able to block the interaction between Aßo and VEGF, which suggests a dual mechanism aimed at both trapping Aßo and releasing VEGF to alleviate Aßo-induced synaptic damage. Our findings provide evidence for a neutralizing effect of the BP on Aß aggregation process and pathogenic action, highlighting a potential new therapeutic strategy.

Study by optical spectroscopy and molecular dynamics of the interaction of acridine-spermine conjugate with DNA.

We report a spectroscopic and theoretical study of the interaction between double-stranded oligonucleotides containing either adenine-thymine or guanine-cytosine alternating sequences and N1-(Acridin-9-ylcarbonyl)-1,5,9,14,18-pentazaoctadecane, or ASC, which is formed by the covalent bonding of spermine and 9-amidoacridine moieties via a trimethylene chain. Solutions containing the oligonucleotides and the conjugate at different molar ratios were studied using complementary spectroscopic techniques, including electronic absorption, fluorescence emission, circular dichroism, and Raman spectroscopy. The spectroscopical properties of ASC at both the vibrational and the electronic levels were described by means of ab initio quantum-chemical calculations on 9-amidoacridine, used as a model compound. Molecular dynamics calculations, based on the QM/MM methodology, were also performed using previously docked structures of two oligonucleotide-ASC complexes containing the A-T and the G-C sequence. Our data, taken all together, allowed us to demonstrate that conjugation of spermine to acridine modulates and gives additional properties to the interaction of the latter with DNA. As the ASC molecule has a high affinity by the polyamine transport system, these results are promising for their application in the development of new anti-tumour drugs.

Structure-activity investigations of polyamine-anthracene conjugates and their uptake via the polyamine transporter.

A series of polyamine conjugates were synthesized and evaluated for their ability to target the polyamine transporter (PAT) in two Chinese hamster ovary (CHO) cell lines (PAT-active CHO and PAT-inactive CHOMG). This systematic study identified salient features of the polyamine architecture required to target and enter cells via the PAT. Indeed, the separation of charges, the degree of N-alkylation, and the spacer unit connecting the N(1)-terminus to the appended cytotoxic component (anthracene) were found to be key contributors to optimal delivery via the PAT. Using the CHO screen, the homospermidine motif (e.g., 4,4-triamine) was identified as a polyamine vector, which could enable the selective import of large N(1)-substituents (i.e., naphthylmethyl, anthracenylmethyl and pyrenylmethyl), which were cytotoxic to cells. The cell selectivity of this approach was demonstrated in B-16 murine melanoma cells and normal melanocytes (Mel-A). Three polyamine areas (recognition and transport, vesicle sequestration and polyamine-target interactions) were identified for future research.

Proteasome inhibitors as therapeutic agents: current and future strategies.

In cells, protein degradation is a key pathway for the destruction of abnormal or damaged proteins as well as for the elimination of proteins whose presence is no longer required. Among the various cell proteases, the proteasome, a multicatalytic macromolecular complex, is specifically required for the degradation of ubiquitinated proteins. In normal cells, the proteasome ensures the elimination of numerous proteins that play critical roles in cell functions throughout the cell cycle. Defects in the activity of this proteolytic machinery can lead to the disorders of cell function that is believed to be the root cause of certain diseases. Indeed, many proteins involved in the control of cell cycle transitions are readily destroyed by the proteasome once their tasks have been accomplished. Moreover, because proteasome inhibitors can provoke cell death, it has been suggested that proteasomes must be continually degrading certain apoptotic factors. For these reasons, proteasome inhibition has become a new and potentially significant strategy for the drug development in cancer treatment. The proteasome possesses three major peptidase activities that can individually be targeted by drugs. Different classes of proteasome inhibitors are reviewed here. In addition, we present new pseudopeptides with the enriched nitrogen backbones bearing a side chain and a modified C-terminal position that inhibit proteasome activity.

Dimethylsilane polyamines: cytostatic compounds with potentials as anticancer drugs. II. Uptake and potential cytotoxic mechanisms.

Dimethylsilane tetramines are structural analogues of spermine with a (CH3)2 Si-group incorporated into the central carbon chain. They have potential as anticancer drugs. Their cytotoxic effect was considered to rely mainly on their polyamine antagonist property. In order to obtain new ideas about cellular mechanisms, which are potential targets of the dimethylsilane polyamines, the effects of these compounds on some basic cell functions, such as protein and DNA synthesis, and calmodulin antagonism were studied. In addition, their mode of accumulation in cells was investigated. It became evident that the intracellular accumulation of dimethylsilane polyamines is almost exclusively achieved via the polyamine transport system. However, the exchange of a part of the intracellular natural polyamines against dimethylsilane polyamines has only a small effect on polyamine uptake. Binding to the endoplasmic reticulum and inhibition of protein synthesis are presumably important for the cytotoxic action of bis(11-amino-4,8-diazaundecyl)dimethylsilane, a hexamine, but seem of no importance for the tetramines. Calmodulin antagonism, however, is likely to contribute to their cytotoxic effect.

N-Benzylpolyamines as vectors of boron and fluorine for cancer therapy and imaging: synthesis and biological evaluation.

Cancer cells have high-affinity polyamine uptake systems with a low stringency for structural features. Putrescine, spermidine, and spermine have, therefore, been considered as potential vectors for the selective accumulation in tumors of therapeutically or diagnostically useful structures and elements. We envisaged N-benzyl derivatives of the polyamines as vectors of (10)B and (18)F for boron neutron capture therapy (BNCT) and tumor imaging by positron emission tomography (PET), respectively. In the present work, the synthesis, transport characteristics, DNA-binding properties, and cytotoxicity of several N-benzyl derivatives of putrescine and spermidine are described. The fluorinated spermidine derivative N-(3-[(4-aminobutyl)amino]propyl)[(4-fluorophenyl)methyl]amine (N(1)-4-Fbz-spd) may be useful for PET because of its high accumulation in cancer cells via the polyamine transport system. Among the boron-containing benzyl polyamines, N-(4-aminobutyl)([4-(dihydroxyboryl)phenyl]methyl)amine (4-Bbz-put) and N-(3-[(4-aminobutyl)amino]propyl)([4-(dihydroxyboryl)phenyl]methyl)amine (N(1)-4-Bbz-spd) should be suitable for BNCT, because their accumulation in B16 melanoma cells was more efficient than that of borocaptate and borophenylalanine, two reference compounds used in BNCT.

Antiproliferative and apoptotic effects of O-Trensox, a new synthetic iron chelator, on differentiated human hepatoma cell lines.

We investigated the effects of a new iron chelator, O-Trensox (TRX), compared with desferrioxamine (DFO), on proliferation and apoptosis in cultures of the human hepatoblastoma HepG2 and hepatocarcinoma HBG cell lines. Our results show that TRX decreased DNA synthesis in a time- and dose-dependent manner and with a higher efficiency than DFO. Mitotic index was also strongly decreased by TRX and, unexpectedly, DFO inhibited mitotic activity to the same extent as TRX, thus there is a discrepancy between the slight reduction in DNA synthesis and a large decrease in mitotic index after DFO treatment. In addition, we found that TRX induced accumulation of cells in the G(1) and G(2) phases of the cell cycle whereas DFO arrested cells in G(1) and during progression through S phase. These data suggest that the partial inhibition of DNA replication observed after exposure to DFO may be due to a lower efficiency of metal chelation and/or that it does not inhibit the G(1)/S transition but arrests cells in late S phase. The effects of both TRX and DFO on DNA synthesis and mitotic index were reversible after removing the chelators from the culture medium. An apoptotic effect of TRX was strongly suggested by analysis of DNA content by flow cytometry, nuclear fragmentation and DNA degradation in oligonucleosomes and confirmed by the induction of a high level of caspase 3-like activity. TRX induced apoptosis in a dose- and time-dependent manner in proliferating HepG2 cells. In HBG cells, TRX induced apoptosis in proliferating and confluent cells arrested in the G(1) phase of the cell cycle, demonstrating that inhibition of proliferation and induction of apoptosis occurred independently. DFO induced DNA alterations only at concentrations >100 microM and without induction of caspase 3-like activity, indicating that DFO is not a strong inducer of apoptosis. Addition of Fe or Zn to the culture medium during TRX treatment led to a complete restoration of proliferation rate and inhibition of apoptosis, demonstrating that Fe/Zn-saturated TRX was not toxic in the absence of metal depletion. These data show that TRX, at concentrations of 20-50 microM, strongly inhibits cell proliferation and induces apoptosis in proliferating and non-proliferating HepG2 and HBG cells, respectively.

Polyamine deprivation alters formalin-induced hyperalgesia and decreases morphine efficacy.

Although the exact functions of polyamines in the nervous system remain still unclear, they are thought to have a physiological role in intracellular signal processing and neurotransmission. Polyamine deprivation which consists in the reduction of both the endogenous and exogenous sources of polyamines is a promising treatment for cancer. In a previous study we have shown that this treatment provokes an analgesic effect in rats submitted to brief phasic nociceptive tests. The present study examined the effect of polyamine deprivation on pain-related behaviors and spinal c-fos expression evoked in the formalin test presumed to better reflect clinical pain, using morphine as analgesia control. Polyamine deprivation per se altered the characteristic pain-related behaviors, reducing the interphase depression of pain, without inducing changes in the spinal Fos staining. In addition this treatment prevented the antinociceptive effect of morphine both on behavioral responses and on spinal c-fos expression. In polyamine-deprived rats, despite morphine injection, nociceptive scores remained dramatically high during the intermediate and the late phases of the response and the number of Fos immunoreactive neurons remained largely higher in deeper layers than in morphine control rats. Altogether these data support a modulatory role of polyamines both on the neuronal circuitry mediating sensory information, and on mechanisms underlying morphine analgesia.

Induction of Fos protein expression in spinal cord neurons of tumour-bearing rats.

The absence of discernible abnormal symptoms such as pain, often leading to delayed diagnosis in cancer patients, may be indicative of a dysregulation in sensory transmission between the tumour and the central nervous system. We explored expression of Fos protein in spinal cord neurons in rats, during the development of the MAT-LyLu prostatic adenocarcinoma grafted on the hind limb. The tumour triggered the densest Fos labelling in the L3-L5 lumbar segments, ipsilateral to the grafted limb. The labelling, detected at day 5, increased until day 10 and dropped off thereafter. The ventral horn (except lamina IX) was the most densely labelled region. Histological examination of the grafted limbs demonstrated that no inflammatory reaction accompanied the tumour growth. Rats exhibited no behavioural alterations either spontaneous or induced by handling. These results demonstrate that signals are sent to the central nervous system by the peripheral tumour. Considering both the behavioural and histological observations, it is unlikely that spinal activity reflects a painful state. The nature of these signals, inefficient to trigger the appropriate reaction of the organism against the tumour, remain to be determined with regard to the pharmacologically active compounds synthesized and released by the tumour cells.

Polyamine sulfonamides with NMDA antagonist properties are potent calmodulin antagonists and cytotoxic agents.

N1-Dansylspermine and related sulfonamides of the natural polyamines are very potent blockers of NMDA-type glutamate receptors. They exhibit pharmacological properties which were not predicted from the constituents of the conjugates. Cytotoxicity and calmodulin antagonism of N1-dansylspermine were especially impressive. Calmodulin antagonism implies that N1-dansylspermine prevents induction of ornithine decarboxylase and inhibits its own active uptake via the polyamine transport system. Structure-activity considerations demonstrated that an aromatic character of the substituent is not required; amide bond formation with an aliphatic sulfonic acid is sufficient to transform spermine into a highly toxic calmodulin antagonist. Cytotoxicity and calmodulin antagonism are properties which are intrinsic to spermine, but they are observed only at very high concentrations. Amide bond formation at N1 with a lipophilic residue appears to 'amplify' these normally latent properties. The use of polyamine conjugates structurally related to the amides described in this work for targeting tumours may be marred by their calmodulin antagonism.

Solid phase organic synthesis of polyamine derivatives and initial biological evaluation of their antitumoral activity.

A series of N1-monosubstituted putrescine and spermine derivatives was synthesised using a solid phase methodology. We evaluated their cytotoxicity, calmodulin antagonism and polyamine uptake inhibition, pharmacological properties shared by some antitumoral agents.

Human monocyte-derived macrophages and dendritic cells are comparably effective in vitro in presenting HLA class I-restricted exogenous peptides.

Recent experimental data have shown that mice could be immunized efficiently, in particular against cancer, by the injection of antigen-loaded dendritic cells (DC) or macrophages (MPH). In the present work, these two antigen-presenting cells (APC) were prepared in humans from circulating mononuclear cells (MNC). MPH were obtained from MNC that were cultured in hydrophobic plastic bags and purified by elutriation. DC were from the culture of adherent elutriation-purified monocytes in the presence of granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-4 (IL-4). The two APC were prepared in parallel from the same donors and their phenotype and antigen-presenting capacity were compared. DC differed from MPH by a higher expression of HLA-DR and CD23 and a lower expression of CD14, CD64 and of adhesion molecules. DC and MPH were comparably effective in (a) enhancing the mitotic response of autologous lymphocytes to immobilized anti-CD3 (accessory function); (b) presenting melanoma peptides to specific cytotoxic T lymphocyte (CTL) clones; and (c) stimulating the generation of CTL directed against a myxovirus influenza peptide. However, DC were more effective than MPH in inducing the mitotic response of allogeneic peripheral blood leucocytes (PBL), possibly because of their higher expression of HLA class II molecules. In conclusion, DC and MPH prepared from blood MNC did not differ substantially in their ability to activate HLA class I-restricted T-cell responses by exogenous peptide presentation.

Flow cytometric analysis of in vivo polyamine deprivation in Lewis lung carcinoma (3LL) cells using the monoclonal antibody SPM8-2.

It has previously been shown that the monoclonal antibody SPM8-2 recognizes free spermine and spermidine as well as polyamines bound by an amide bond. In the present work it is demonstrated that this antibody also interacts with spermidine, spermine, and to a lesser extent N1- and N8-acetyl spermidine in an ELISA test where the polyamines are bound by reaction with formaldehyde. 3LL Lewis lung carcinoma cells from tumor-grafted mice were labeled with fluorescein-conjugated monoclonal antibody SPM8-2 and analyzed by flow cytometry. Both viable cells and formaldehyde-fixed and subsequently permeabilized cells showed fluorescent staining. However, most polyamines present in the cells are not directly available for antibody binding. Treatment of fixed cells with DNase or RNase greatly increased fluorescent staining, suggesting that some polyamines are co-localized with DNA and RNA. Antibody labeling of the cells was prevented by addition of free spermine. 3LL cells from tumors of mice treated by a polyamine depleting regimen had decreased intracellular spermidine levels and bound less antibody when compared to untreated controls. After digestion with RNase, the cells from treated mice bound considerably less fluorescent antibody than tumor cells from untreated mice, while their RNA content was similar. In contrast, fluorescent staining after DNase digestion was only slightly affected by the treatment with a polyamine depleting regimen. This suggests that the pools of polyamines which are co-localized with RNA are depleted more readily than those associated with DNA. Since only a small proportion of the intracellular polyamines is accessible to the bulky antibodies, treatment with hydrolytic enzymes (DNase, RNase) is necessary to reveal specific compartments of the polyamines and to demonstrate qualitative and semi-quantitative differences of their distribution within cells.

Bis(7-amino-4-azaheptyl)dimethylsilane: a new tetramine with polyamine-like features. Effects on cell growth.

Bis(7-amino-4-azaheptyl)dimethylsilane is a new type of aliphatic polycation with structural features resembling those of spermine. The elongation to a seven-membered carbon chain in which the central CH2-group was substituted by (CH3)2Si renders the molecule more lipophilic than spermine. Cells accumulate the compound via the polyamine transport system. Due to suppression of ornithine decarboxylase, de novo putrescine biosynthesis is impaired, and intracellular putrescine and spermidine concentrations are depleted. Depletion of intracellular spermidine together with binding to functionally important polyamine binding sites are considered the main features of the compound which cause cytostatic, and at high concentrations, cytotoxic effects.

Biochemical and cellular effects of roscovitine, a potent and selective inhibitor of the cyclin-dependent kinases cdc2, cdk2 and cdk5.

Cyclin-dependent kinases (cdk) play an essential role in the intracellular control of the cell division cycle (cdc). These kinases and their regulators are frequently deregulated in human tumours. Enzymatic screening has recently led to the discovery of specific inhibitors of cyclin-dependent kinases, such as butyrolactone I, flavopiridol and the purine olomoucine. Among a series of C2, N6, N9-substituted adenines tested on purified cdc2/cyclin B, 2-(1-ethyl-2-hydroxyethylamino)-6-benzylamino-9-isopropylpurine (roscovitine) displays high efficiency and high selectivity towards some cyclin-dependent kinases. The kinase specificity of roscovitine was investigated with 25 highly purified kinases (including protein kinase A, G and C isoforms, myosin light-chain kinase, casein kinase 2, insulin receptor tyrosine kinase, c-src, v-abl). Most kinases are not significantly inhibited by roscovitine. cdc2/cyclin B, cdk2/cyclin A, cdk2/cyclin E and cdk5/p35 only are substantially inhibited (IC50 values of 0.65, 0.7, 0.7 and 0.2 microM, respectively). cdk4/cyclin D1 and cdk6/cyclin D2 are very poorly inhibited by roscovitine (IC50 > 100 microM). Extracellular regulated kinases erk1 and erk2 are inhibited with an IC50 of 34 microM and 14 microM, respectively. Roscovitine reversibly arrests starfish oocytes and sea urchin embryos in late prophase. Roscovitine inhibits in vitro M-phase-promoting factor activity and in vitro DNA synthesis in Xenopus egg extracts. It blocks progesterone-induced oocyte maturation of Xenopus oocytes and in vivo phosphorylation of the elongation factor eEF-1. Roscovitine inhibits the proliferation of mammalian cell lines with an average IC50 of 16 microM. In the presence of roscovitine L1210 cells arrest in G1 and accumulate in G2. In vivo phosphorylation of vimentin on Ser55 by cdc2/cyclin B is inhibited by roscovitine. Through its unique selectivity for some cyclin-dependent kinases, roscovitine provides a useful antimitotic reagent for cell cycle studies and may prove interesting to control cells with deregulated cdc2, cdk2 or cdk5 kinase activities.

Polyamine deprivation prevents the development of tumour-induced immune suppression.

Mice grafted with the 3LL (Lewis lung) carcinoma exhibit immune suppression: spleen cells showed decreased spontaneous interleukin 2 (IL-2) production and T-CD4+ and T-CD8+ lymphocyte populations; in addition the polyamine content in the spleen was increased. By treating the mice with a polyamine-deficient diet containing neomycin, metronidazole and inhibitors of ornithine decarboxylase and polyamine oxydase, tumour growth was reduced and the immune abnormalities were reversed. The spleen cells overproduced IL-2 by reducing exogenous sources of polyamines, but total blockade of all major polyamine sources was necessary to obtain an optimal effect both on IL-2 production and on spleen polyamine content. Irrespective of whether polyamine deprivation was started at an early or at an advanced stage of tumour growth, T-lymphocyte populations were restored to normal values, demonstrating that polyamine deprivation not only prevents tumour-induced immune suppression, but reverses established immunological disorders. In contrast to what was observed regarding IL-2 production by spleen cells and natural killer (NK) cell activity, the polyamine oxidase (PAO) inhibitor did not enhance the number of T lymphocytes. These findings are consistent with a direct effect of the polyamines on immune effector cell metabolism. They suggest an important role of the gastrointestinal polyamines and of PAO activity in the regulation of IL-2 production.

Bis(7-amino-4-azaheptyl)dimethlysilane and bis(7-ethylamino-4-azaheptyl)dimethylsilane: inhibition of tumor cell growth in vitro and in vivo.

Bis(7-amino-4-azaheptyl)dimethylsilane (AzhepSi) and its bis(ethyl) derivative [bis(7-ethylamino-4-azaheptyl)dimethylsilane] (EtAzhepSi) are the first examples of a new type of aliphatic tetramine with a dimethylsilane group incorporated into the central carbon chain. AzhepSi shares certain properties with the natural polyamines, but in contrast with spermidine and spermine it inhibits the growth of L1210 leukemia cells in culture at micromolar concentrations. The bis(ethyl) derivative of AzhepSi was made, in analogy to bis(ethyl) spermine, a polyamine derivative, which gained much attention during the last decade as a potential anticancer drug. Chinese hamster ovary (CHO) cells accumulate the dimethylsilyl tetramines considerably more and are more sensitive to these drugs than are CHO-MG cells, a polyamine uptake-deficient mutant. This and related observations demonstrate that AzhepSi and EtAzhepSi are preferentially taken up by a polyamine transport system. Both tetramines inhibit the growth of a variety of tumor cells at micromolar concentrations. AzhepSi turned out to be either equipotent or more potent, but in no case less potent than EtAzhepSi. When given alone at daily doses of 25 micromol/kg, the compounds did not prolong the survival time of L1210 leukemia mice. However, in combination with 2-(difluoromethyl)ornithine and neomycin, AzhepSi had a significant effect on the life span of the animals. The growth rate of 3LL Lewis lung carcinoma was reduced by both compounds at daily doses of 25 micromol/kg. The observations presented in this work suggest that the dimethylsilyl tetramines are antiproliferative agents in vitro and in vivo. Due to enhanced general toxicity, the introduction of N-ethyl substituents was of no advantage in the case of these polyamine analogues.

Accumulation of hydroxyspermidine in red blood cells, a potential index of tumor proliferation rate.

It has previously been demonstrated that during Lewis Lung carcinoma growth, red blood cell spermidine levels increase concomitantly with tumor volume. If [14C] putrescine or 2-methylputrescine are administered, [14C] spermidine and methylspermidine, respectively, accumulate in red blood cells in proportion with the tumor volume. In the present work the metabolic transformation of 2-hydroxyputrescine, a natural derivative of putrescine, to hydroxyspermidine, was studied in tumor bearing mice. After a single i.p. injection of 2-hydroxyputrescine, higher concentrations of hydroxyspermidine were found in the tumor than in liver. In the red blood cells of Lewis lung carcinoma-bearing mice, hydroxyspermidine was detected between 24 hours and 96 hours after i.p. injection of 2-hydroxyputrescine. The concentration of hydroxyspermidine found in red blood cells was proportional to the tumor volume. Hydroxyspermidine has potential as a marker of malignant cell proliferation in human oncology.

Polyamine transport in mammalian cells. An update.

The uptake and release of the natural polyamines putrescine, spermidine and spermine by mammalian cells are integral parts of the systems that regulate the intracellular concentrations of these biogenic amines according to needs. Although a general feature of all tissues, polyamine uptake into intestinal mucosa cells is perhaps the most obvious polyamine transport pathway of physiological and pathophysiological importance. Mutant cell lines lacking the ability to take up polyamines from the environment are capable of releasing polyamines. This indicates that uptake and release are functions of two different transport systems. The isolation of a transporter gene from a mammalian cell line is still lacking. Overaccumulation of polyamines is controlled by release and by a feedback regulation system that involves de novo synthesis of antizyme, a well known protein that also regulates the activity of ornithine decarboxylase. Recent work has demonstrated that Ca(2+)-signalling pathways are also involved. Although there is consensus about the importance of polyamine uptake inhibitors in the treatment of neoplastic disorders, a practically useful uptake inhibitor is still missing. However, the attempts to target tumours, and to increase the selectivity of cytotoxic agents by combining them with the polyamine structure, are promising. New, less toxic and more selective anticancer drugs can be expected from this approach.

Observations with an S-adenosylmethionine decarboxylase inhibitor in rats with prostatic adenocarcinoma.

CGP 48664A (2-(4-aminoiminomethyl)-2,3-dihydro-1H-inden-1-ylidene dihydrochloride, CAS 149400-88-4) is a new potent inhibitor of S-adenosylmethionine decarboxylase with antitumor properties. In view of the eminent clinical problems in the treatment of non hormone dependent prostatic cancer, the antiproliferative potency of this compound was tested in Dunning MAT-LyLu rat prostatic adenocarcinoma. The compound proved inefficient in preventing the growth of this tumor, even at a near toxic dose. A reason for the lacking effect is presumably the inadequate accumulation of the drug in the tumor cells due to the excessive growth rate of the MAT-LyLu xenografts. Tumor growth seems not to be accompanied by a proportionally rapid vascularization of the tumor mass. CGP 48664A was found to be a potent inhibitor of polyamine oxidase. This property of the drug may have contributed to the activation of the phagocytic capacity of peritoneal macrophages from tumor-bearing rats.