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PubMed2004

Polyamine catabolism in platinum drug action: Interactions between oxaliplatin and the polyamine analogue N1,N11-diethylnorspermine at the level of spermidine/spermine N1-acetyltransferase.

A great deal of experimental evidence connects induction of polyamine catabolism via spermidine/spermine N1-acetyltransferase (SSAT) to antiproliferative activity and apoptosis. Following our initial observation from gene expression profiling that platinum drugs induce SSAT, we undertook this present study to characterize platinum drug induction of SSAT and other polyamine catabolic enzymes and to examine how these responses might be enhanced with the well-known inducer of SSAT and clinically relevant polyamine analogue, N1,N11-diethylnorspermine (DENSPM). The results obtained in A2780 ovarian cancer cells by real-time quantitative RT-PCR and Northern blot analysis show that a 2-hour exposure of A2780 cells to platinum drugs induces expression of SSAT, a second SSAT (SSAT-2), spermine oxidase, and polyamine oxidase in a dose-dependent manner. At equitoxic doses, oxaliplatin is more effective than cisplatin in SSAT induction. The most affected enzyme, SSAT, increased 15-fold in mRNA expression and 2-fold in enzyme activity. When combined with DENSPM to further induce SSAT and to enhance conversion of mRNA to activity, oxaliplatin increased SSAT mRNA 50-fold and activity, 210-fold. Polyamine pools declined in rough proportion to levels of SSAT induction. At pharmacologically relevant oxaliplatin exposure times (20 hours) and drug concentrations (5 to 15 micromol/L), these responses were increased even further. Combining low-dose DENSPM with oxaliplatin produced a greater than additive inhibition of cell growth based on the sulforhodamine-B assay. Taken together, the findings confirm potent induction of polyamine catabolic enzymes, such as SSAT by platinum drugs, and demonstrate that these biochemical responses as well as growth inhibition can be potentiated by co-treatment with the polyamine analogue DENSPM. With appropriate in vitro and in vivo optimization, these findings could lead to clinically relevant therapeutic strategies.

Acetyltransferases↗

PubMed1987

[Detection of polyamines by an enzymatic assay. (6). Fundamental and clinical studies of a simple enzymatic method for determining total polyamines in blood].

A simple enzymatic method for determining total polyamines in human blood was established. Polyamines in trichloroacetic acid extract from 1 ml of blood were isolated on an anion-exchange column and measured spectrophotometrically by the end point assay using polyamine oxidase and putrescine oxidase. The recovery was as high as 98.4% and within-run precision (coefficient of variance: 1.82%), and the values obtained by this method were in fair agreement with those obtained by high performance liquid chromatography and the enzymatic differential assay methods previously reported. The polyamine levels were not changed when the blood was stored at -20 degrees C. Blood polyamine levels were measured in 108 patients with genitourinary cancers, 29 patients with benign prostatic hypertrophy, 18 patients with benign urological diseases and 25 normal subjects. Although polyamines were not significantly elevated in the low stage of cancer, elevation was observed at a high stage of malignancy. These results indicate that the determination of total polyamines may be useful to determine biochemically the malignancy of cancers.

Biomarkers, Tumor↗

PubMedDate not supplied

Polyamine oxidase activity and polyamine levels in human colorectal cancer and in normal surrounding mucosa.

BACKGROUND: Polyamine oxidase (PAO) is an enzyme involved in the interconversion pathway of polyamines, compounds required for cell proliferation and differentiation. As the role of PAO in tumor growth is unclear, and no data about PAO activity in human colorectal carcinoma are available, our aim was to investigate PAO activity and polyamine levels in this kind of tumor. METHODS: Polyamine levels and PAO activity were detected in 30 neoplastic colorectal samples and surrounding mucosa by HPLC. RESULTS: Free and N1-acetylated polyamine levels were higher in the neoplastic tissue than surrounding mucosa of the same patient. On the contrary, PAO activity was significantly lower in the neoplastic tissue than surrounding mucosa. CONCLUSION: It seems that PAO activity does not play an important role in the increased free polyamine levels in human colorectal carcinoma. Instead, the low PAO activity observed in our study let us to hypothesize that polyamine analogues can have an antitumoral effect on colorectal carcinoma.

Adult↗

PubMed1986

Factors affecting polyamine excretion from mammalian cells in culture. Inhibitors of polyamine biosynthesis.

Canavanine, diaminopropane, alpha-methylornithine and methylglyoxal bis(guanylhydrazone) decreased the intracellular polyamine concentrations in growing baby hamster kidney cells. Each of the inhibitors also prevented polyamine efflux into the extracellular medium. Concomitant with the decrease in polyamine excretion was a change in the distribution of polyamines in the extracellular medium. In each case there was a decrease in the amount of radioactivity present as free spermidine and an increase in that found as acetyl polyamines. The magnitude of this shift correlated with the degree of inhibition of excretion. It may be that acetyl polyamines play a role in the regulation of polyamine excretion.

Acetylation↗

PubMed2003

Transcription of ahpC, katG, and katE genes in Escherichia coli is regulated by polyamines: polyamine-deficient mutant sensitive to H2O2-induced oxidative damage.

Polyamines (putrescine and spermidine) are present in almost all living organisms and participate in numerous cellular processes. In this study, we report the protective roles of polyamines against hydrogen peroxide (H2O2)-induced oxidative stress. All of ahpC, katG, and katE genes, known to participate in the antioxidant defense mechanism against H2O2-induced stress in Escherichia coli, failed to induce in the absence of polyamines during normal aerobic growth. The induction of both oxyR and rpoS gene expression, whose products are essential to induce ahpC, katG, and katE genes, was also absolutely dependent on polyamines. Polyamine-deficient E. coli mutant has increased susceptibility to exogenous H2O2, and this cell cytotoxicity was relieved to a wild-type level by addition of putrescine or spermidine (1mM), which restored the transcriptional induction of ahpC, katG, and katE genes. H2O2-removing capacity was measured in the mutant, showing a significantly low H2O2-removing capacity compared to the wild type when polyamines were not present. We concluded that the increased susceptibility of the polyamine-deficient E. coli mutant to H2O2 treatment resulted from an intracellular low level of H2O2-removing capacity through the failure of their regulons, ahpC, katG, and katE induction, as well as the failure of oxyR and rpoS induction.

Antioxidants↗

PubMed2003

Defining the molecular requirements for the selective delivery of polyamine conjugates into cells containing active polyamine transporters.

Several N(1)-substituted polyamines containing various spacer units between nitrogen centers were synthesized as their respective HCl salts. The N(1)-substituents included benzyl, naphthalen-1-ylmethyl, anthracen-9-ylmethyl, and pyren-1-ylmethyl. The polyamine spacer units ranged from generic (4,4-triamine, 4,3-triamine, and diaminooctane) spacers to more exotic [2-(ethoxy)ethanoxy-containing diamine, hydroxylated 4,3-triamine, and cyclohexylene-containing triamine] spacers. Two control compounds were also evaluated: N-(anthracen-9-ylmethyl)-butylamine and N-(anthracen-9-ylmethyl)-butanediamine. Biological activities in L1210 (murine leukemia), alpha-difluoromethylornithine (DFMO)-treated L1210, and Chinese hamster ovary (CHO) and its polyamine transport-deficient mutant (CHO-MG) cell lines were investigated via IC(50) cytotoxicity determinations. K(i) values for spermidine uptake were also determined in L1210 cells. Of the series studied, the N(1)-benzyl-4,4-triamine system 6 had significantly higher IC(50) values (lower cytotoxicity) in the L1210, CHO, and CHO-MG cell lines. A cellular debenzylation process was observed in L1210 cells with 6 and generated "free" homospermidine. The size of the N(1)-arylmethyl substituent had direct bearing on the observed cytotoxicity in CHO-MG cells. The N(1)-naphthalenylmethyl, N(1)-anthracenylmethyl, and N(1)-pyrenylmethyl 4,4-triamines had similar toxicity (IC(50)s: approximately 0.5 microM) in CHO cells, which have an active polyamine transporter (PAT). However, this series had IC(50) values of >100 microM, 66.7 microM, and 15.5 microM, respectively, in CHO-MG cells, which are PAT-deficient. The observed lower cytotoxicity in the PAT-deficient CHO-MG cell line supported the premise that the conjugates use PAT for cellular entry. In general, moderate affinities for the polyamine transporter were observed for the N-arylmethyl 4,4-triamine series with their L1210 K(i) values all near 3 microM. In summary, the 4,4-triamine motif was shown to facilitate entry of polyamine conjugates into cells containing active polyamine transporters.

Animals↗

PubMed2004

N1-substituent effects in the selective delivery of polyamine conjugates into cells containing active polyamine transporters.

Several N(1)-arylalkylpolyamines containing various aromatic ring systems were synthesized as their respective HCl salts. The N(1)-substituents evaluated ranged in size from N(1)-benzyl, N(1)-naphthalen-1-ylmethyl, N(1)-2-(naphthalen-1-yl)ethyl, N(1)-3-(naphthalen-1-yl)propyl, N(1)-anthracen-9-ylmethyl, N(1)-2-(anthracen-9-yl)ethyl, N(1)-3-(anthracen-9-yl)propyl, and pyren-1-ylmethyl. The polyamine architecture was also altered and ranged from diamine to triamine and tetraamine systems. Biological activities in L1210 (murine leukemia), Chinese hamster ovary (CHO), and CHO's polyamine transport-deficient mutant (CHO-MG) cell lines were investigated via IC(50) cytotoxicity determinations. K(i) values for spermidine uptake were also determined in L1210 cells. The size of the N(1)-arylalkyl substituent as well as the polyamine sequence used had direct bearing on the observed cytotoxicity profiles. N(1)-Tethers longer than ethylene showed dramatic loss of selectivity for the polyamine transporter (PAT) as shown in a CHO/CHO-MG cytotoxicity screen. In summary, there are clear limits to the size of N(1)-substituents, which can be accommodated by the polyamine transporter. A direct correlation was observed between polyamine-conjugate uptake and cytotoxicity. In this regard, a cytotoxicity model was proposed, which describes a hydrophobic pocket of set dimensions adjacent to the putative PAT polyamine-binding site.

Animals↗

PubMed1989

Regulation of polyamine biosynthesis in rat hepatoma (HTC) cells by a bisbenzyl polyamine analogue.

A bisbenzyl polyamine analogue, MDL 27695, rapidly repressed ornithine decarboxylase (ODC) and S-adenosyl-L-methionine decarboxylase (AdoMet DC) activity and depleted polyamines in rat hepatoma (HTC) cells. The suppression of ODC and AdoMet DC activity was temporally related to metabolism of MDL 27695 by intracellular polyamine oxidase to a free-amine analogue, MDL 26752, which, when added directly to HTC cells, suppressed ODC activity and polyamine biosynthesis more rapidly and to a greater extent than did the bisbenzyl analogue. The ODC suppression caused by MDL 27695 was completely blocked by the addition of a polyamine oxidase inhibitor to the HTC-cell cultures along with MDL 27695. These data suggested that MDL 27695 acted as a prodrug, with metabolism to an active analogue being necessary for ODC repression to occur. MDL 27695 and MDL 26752 completely abolished division of HTC cells when added to cultures at 1 microM. This established them as being among the most potent antiproliferative polyamine analogues yet described. MDL 27695 has also been shown to possess significant antimalarial effects both in vitro and in vivo, and it is possible that the marked suppression of polyamine biosynthesis described herein may contribute to its anti-malarial effects as well as its antiproliferative effects in mammalian cells.

Adenosylmethionine Decarboxylase↗

PubMed2000

Effects of conditional overexpression of spermidine/spermine N1-acetyltransferase on polyamine pool dynamics, cell growth, and sensitivity to polyamine analogs.

Acetylation of polyamines by spermidine/spermine N(1)-acetyltransferase (SSAT) has been implicated in their degradation and/or export out of the cell. The relationship of SSAT to polyamine pool dynamics and cell growth is not yet clearly understood. MCF-7 human breast carcinoma cells were transfected with tetracycline-regulated (Tet-off) SSAT human cDNA or murine gene. Doxycycline removal for >2 days caused a approximately 20-fold increase in SSAT RNA and a approximately 10-fold increase in enzyme activity. After 4 days, intracellular putrescine and spermidine pools were markedly lowered, and cell growth was inhibited. Growth inhibition could not be prevented with exogenous polyamines due to a previously unrecognized ability of SSAT to rapidly acetylate influxing polyamines and thereby prevent restoration of the endogenous pools. Instead, cells accumulated high levels of N(1)-acetylspermidine, N(1)-acetylspermine, and N(1), N(12)-diacetylspermine, a metabolite not previously reported in mammalian cells. Doxycycline deprivation before treatment with N(1), N(11)-diethylnorspermine markedly increased analog induction of SSAT mRNA and activity and enhanced growth sensitivity to the analog by approximately 100-fold. Overall, the findings demonstrate that conditional overexpression of SSAT lowers polyamine pools, inhibits cell growth, and markedly enhances growth sensitivity to certain analogs. The enzyme also plays a remarkably efficient role in maintaining polyamine pool homeostasis during challenges with exogenous polyamines.

Acetylation↗

PubMed1998

Effects of polyamine synthesis inhibition on polyamines, growth and mechanical properties in hypertrophic rat urinary bladder.

The polyamines putrescine, spermidine and spermine, are ubiquitous intracellular metabolites associated with growth and protein synthesis. In this study effects of polyamine synthesis inhibition on bladder growth, polyamine levels and mechanical properties were investigated in rat urinary bladder subjected to partial outflow obstruction that causes bladder hypertrophy. The S-adenosyl methionine decarboxylase inhibitor CGP-48664 (5 and 20 mg kg-1) was administered alone or in combination with the ornithine decarboxylase inhibitor DFMO (500 mg kg-1), starting one day before creation of partial outflow obstruction and then daily for 7 days. The bladder muscle level of putrescine was increased 38 times and that of spermine reduced by 4 times while spermidine was unchanged after treatment with CGP-48664 (20 mg kg-1). The increase in putrescine was abolished in animals receiving CGP-48664 in combination with DFMO. Treatment with polyamine synthesis inhibitors could not prevent or reduce the hypertrophy of the bladder as judged by bladder wet weight and protein contents. The effects on polyamine quantities were not associated with changes in Ca(2+)-force relationship or in agonist and electrically stimulated force. In summary, treatment of rats with polyamine synthesis inhibitors resulted in changes in polyamine levels in the growing urinary bladder but did not affect growth or mechanical properties.

Adenosylmethionine Decarboxylase↗

PubMed1990

Regulation of growth and polyamine biosynthesis of the ciliated protozoan Tetrahymena thermophila. Effects of L-arginine metabolites and polyamines.

Growth of Tetrahymena thermophila in a synthetic nutrient medium with or without the essential amino acid L-arginine was studied in the presence or absence of the arginine metabolites L-citrulline and L-ornithine and the polyamines putrescine, spermidine, and spermine. The effects of the growth conditions on the stimulations of the enzymes of the arginine metabolic and polyamine biosynthetic pathway, arginine deiminase (ADI), citrulline hydrolase (CH), ornithine decarboxylase (ODC), and ornithine-oxo-acid aminotransferase were determined. Tetrahymena cells were unable to grow in the absence of L-arginine and the amino-acid utilization was greatly impaired. None of the metabolites or polyamines was able to substitute for arginine. In the presence of arginine, Tetrahymena cultures grew well and citrulline and ornithine did not alter the growth behaviour in any way. In the presence of putrescine, the lag period was decreased from 3 h to 2 h. Spermidine and spermine acted similar to putrescine but less pronounced. The stimulation of the activity of ADI, the key enzyme of arginine degradation, was absolutely dependent upon the presence of arginine in the medium: in the absence of arginine, the low ADI activity which was present in the cells before inoculation was decreased to zero levels within 30 min. In the presence of arginine, the stimulation of ADI was not altered by citrulline and ornithine but putrescine, spermidine, and spermine decreased ADI-stimulation to half of the control values. The stimulation of CH activity in the presence of arginine was not altered by any added metabolite or polyamine. In the media without arginine, stimulation of CH was greatly reduced, in the presence of ornithine more than in its absence, and even more in the presence of putrescine and spermidine. Stimulation of ODC activity in the presence of arginine was not affected by citrulline and ornithine but in the presence of polyamines it was rapidly decreased to unstimulated levels after an initial ca. 10-fold increase. The "hyperstimulation" of ODC in the absence of free arginine was reduced to normal in the presence of citrulline, the stimulation was decreased even below normal levels in the presence of ornithine and polyamines decreased ODC activity to zero levels. O delta T activity was stimulated more in the presence of arginine than in its absence. In both cases the stimulation was enhanced in the presence of polyamines and only in the absence of arginine--by ornithine.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMedDate not supplied

[Polyamines as biochemical markers of the antiproliferative effect of inhibitors of polyamine and putrescine biosynthesis enzymes in L-cell tissue cultures].

Effects of inhibitors of enzymes involved in biosynthesis of putrescine and polyamines on growth of mice C3H strain transformed fibroblasts as well as on the intracellular content of putrescine and polyamines were studied. Putrescine and polyamines were estimated as dansyl derivatives using HPLC. DL-alpha-difluoromethyl ornithine (F2MeOrn) and methyl glyoxalbis (quanyl hydrazone) (MGBG) were added to cultivation medium at final concentration 10(-4) M daily within 4 days. The cell culture was not treated within the following 3 days of the experiment. Distinct exceeding of spermidine content over concentrations of putrescine and spermine proved to be the specific property of L-cells growth in the culture. Amount of cells correlated strongly with intracellular content of spermidine and spermine (r = 0.964). Treatment of L-cells with F2MeOrn singly or in combination with MGBG led to 4- and 6-fold decrease in their growth rate, respectively. F2MeOrn altered content of polycations 2 days earlier in the cells which exhibited distinct correlation between putrescine and polyamines (r = 0.943). The rate of MGBG inhibition correlated distinctly with content of putrescine and polyamines (r = 0.953) as well as strong correlation between putrescine and polyamines content (r = 0.994) was detected after simultaneous effect of these inhibitors. This suggests that polyamines were involved in the antiproliferative action of the inhibitors studied and may be used as markers of cytostatics chemotherapeutic efficiency.

Animals↗

PubMed1991

Selective cellular depletion of mitochondrial DNA by the polyamine analog N1,N12-bis(ethyl)spermine and its relationship to polyamine structure and function.

N1,N8-Bis(ethyl)spermidine (BESPD) and N1,N12-bis(ethyl)spermine (BESPM) are minimally modified analogs of spermidine and spermine that deplete cellular polyamine pools by suppressing key polyamine biosynthetic enzymes. The consequences of polyamine depletion and the concomitant analog replacement of these pools were compared on two cellular DNA targets, mitochondrial DNA (mtDNA) and a defined nuclear DNA episome present in 935.1 mouse fibroblasts. The spermidine analog, BESPD, depleted cellular putrescine and spermidine pools, but not spermine pools, and had no effect on either DNA target. Treatment with the corresponding analog of spermine, BESPM, resulted in a near-total depletion of all three polyamine pools and a greater than 80% reduction in the cellular content of mtDNA, without affecting the levels of the nuclear episome. Topological forms analysis by Southern blotting of mtDNA and episomal DNA from BESPM-treated cells failed to reveal any forms interconversion, indicating the absence of analog-induced single- or double-strand break damage to either DNA target. The growth-dependent loss of mtDNA is consistent with a rapid cessation of mtDNA replication and subsequent dilution of existing mtDNA copies by cell division. Similar decreases in polyamine pools and mtDNA were also observed in L1210 cells treated with BESPM. When a comparable level of polyamine depletion was produced in L1210 cells by specific enzyme inhibitors, there was no effect on the cellular content of mtDNA, and BESPD was not rendered capable of decreasing mtDNA levels. Because the analogs are structurally similar to the naturally occurring polyamines and would be expected to have similar binding properties, the loss in mtDNA may reflect dysfunctional replacement by BESPM at spermine-specific binding sites in the mitochondrion.

Animals↗

PubMedDate not supplied

Polyamine metabolism and polyamine excretion in normal and tumor bearing rodents.

Aminoguanidine sulfate (AG) inhibits in vivo oxidative deaminations of the polyamines and their derivatives. This compound was used to study urinary polyamine excretion by normal, and tumor bearing rodents. Of the total expendable polyamines, 64 percent were catabolized by AG-sensitive oxidases and escaped observation. Tumor bearing animals did not excrete enhanced amounts of polyamines at any stage of tumoral growth. However, treatment with adriamycin caused an increased polyamine excretion. Prolonged administration of a 2% solution of a-difluoromethylornithine (DFMO), reduced urinary polyamine excretion to the same level of about 27%, irrespective whether the animals carried a large tumor or not. Cadaverine excretion was not affected by treatment with DFMO. Based on these animal data, it appears that urinary polyamines are of restricted value in the diagnosis of tumors.

9,10-Dimethyl-1,2-benzanthracene↗

PubMed1994

[Involvement of polyamines in malignant proliferative processes: antineoplastic effects of a polyamine deficiency].

The fact that tumors require polyamines for growth has been repeatedly demonstrated. In vivo polyamines are available both from endogenous (intracellular biosynthesis) and exogenous sources (food and intestinal microflora). We investigated in rats grafted with Mat-Lylu prostatic adenocarcinoma the distribution between tumor and tissues of orally administered [14C]putrescine (Pt). The amount of radioactivity retained by tumors was directly proportional to the tumor volume. In a tumor of 25 cm3 19% of the totally retained radioactivity was found. The accumulation of Pt by intestinal brush-border membrane vesicles prepared from tumor-bearing animals was significantly higher than by vesicles from healthy rats. Our results indicate that the presence of a tumor induces an adaptive response in the small intestine which stimulates the uptake of exogenous polyamines. Our therapeutic strategy was to realise a total blockade of all endogenous and exogenous sources of polyamines by feeding animals with a drug (DFMO, MDL 72527, antibiotics) containing polyamine deficient chow. We observed that polyamine deprivation largely reduced both primary tumor and metastatic development. Natural Killer cell cytotoxic activity and blood formula were restored to normal values after treatment. Furthermore polyamine deprivation enhanced antitumoral efficacy of chemotherapy.

Animals↗

PubMedDate not supplied

The gastrointestinal polyamine source depletion enhances DFMO induced polyamine depletion in MCF-7 human breast cancer cells in vivo.

Due to the polyamine requirement for cell growth, blockade of polyamine biosynthesis is considered a potential anticancer target. The lack of efficacy of DFMO in vivo, has been attributed to other sources of polyamines, mainly from the gastrointestinal tract (alimentary and bacterial). An experiment was designed to test the role of intestinal polyamine deletion in addition to DFMO (a specific inhibitor of ODC) in established MCF-7 tumors in nude mice. Using DFMO and polyamine-free diet, the tumor putrescine concentrations were more profoundly decreased in comparison to DFMO alone and cellular spermine was also depleted, as has never been observed with DFMO alone. The blockade of the gastrointestinal sources of polyamines enhances the intracellular polyamine depletion induced by DFMO on MCF-7 tumor in nude mice.

Animals↗

PubMed1990

Polyamines and Flower Development in the Male Sterile Stamenless-2 Mutant of Tomato (Lycopersicon esculentum Mill.) : II. Effects of Polyamines and Their Biosynthetic Inhibitors on the Development of Normal and Mutant Floral Buds Cultured in Vitro.

The floral organs of the male sterile stamenless-2 (sl-2/sl-2) mutant of tomato (Lycopersicon esculentum Mill.) contain significantly higher level of polyamines than those of the normal (R Rastogi, VK Sawhney [1990] Plant Physiol 93: 439-445). The effects of putrescine, spermidine and spermine, and three different inhibitors of polyamine biosynthesis on the in vitro development of floral buds of the normal and sl-2/sl-2 mutant were studied. The polyamines were inhibitory to the in vitro growth and development of both the normal and mutant floral buds and they induced abnormal stamen development in normal flowers. The inhibitors of polyamine biosynthesis also inhibited the growth and development of floral organs of the two genotypes, but the normal flowers showed greater sensitivity than the mutant. The inhibitors also promoted the formation of normal-looking pollen in stamens of some mutant flowers. The effect of the inhibitors on polyamine levels was not determined. The polyamine-induced abnormal stamen development in the normal, and the inhibitor-induced production of normal-looking pollen in mutant flowers support the suggestion that the elevated polyamine levels contribute to abnormal stamen development in the sl-2/sl-2 mutant of tomato.

Journal Article↗

PubMedDate not supplied

[The involvement of polyamines in the malignant proliferative process. The anticancer effect of polyamine deprivation].

The fact that tumors require polyamines for growth has been repeatedly demonstrated. In vivo polyamines are available both from endogenous (intracellular biosynthesis) and exogenous sources (food and intestinal microflora). We investigated in rats grafted with Mat-Lylu prostatic adenocarcinoma the distribution between tumor and tissues of orally administered (14C) putrescine (Pt). The amount of radioactivity retained by tumors was directly proportional to the tumor volume. In a tumor of 25 cm3 19% of the totally retained radioactivity was found. The accumulation of Pt by intestinal brush-border membrane vesicles prepared from tumor-bearing animals was significantly higher than by vesicles from healthy rats. Our results indicate that the presence of a tumor induces an adaptive response in the small intestine which stimulates the uptake of exogenous polyamines. Our therapeutic strategy was to realise a total blockade of all endogenous and exogenous sources of polyamines by feeding animals with a drug (DFMO, MDL 72527, antibiotics) containing polyamine deficient chow. We observed that polyamine deprivation largely reduced both primary tumor and metastatic development. Natural Killer cell cytotoxic activity and blood formula were restored to normal values after treatment. Furthermore polyamine deprivation enhanced anti-tumoral efficacy of chemotherapy.

Adenocarcinoma↗