A double-blind, multicentre comparison of intravenous dolasetron mesilate and metoclopramide in the prevention of nausea and vomiting in cancer patients receiving high-dose cisplatin chemotherapy.

The potent serotonin receptor (5-HT3) antagonists are new highly selective agents for the prevention and control of chemotherapy-induced nausea and vomiting that have been shown to be comparable to or more effective than traditional metoclopramide regimens. This study was designed to compare the antiemetic efficacy of dolasetron and metoclopramide in chemotherapy-naive and non-naive cancer patients receiving high-dose cisplatin-containing chemotherapy. This multicentre, double-blind, randomized trial compared the efficacy and safety of single i.v. doses of dolasetron mesilate salt (1.2 or 1.8 mg/kg) and metoclopramide (7 mg/kg) in 226 patients for the prevention of acute emesis and nausea associated with the administration of high-dose (> or = 80 mg/m2) cisplatin. Efficacy and safety were evaluated for 24 h. Complete responses were achieved by 57%, 48%, and 35% of patients given dolasetron mesilate 1.8 mg/kg (P = 0.0009 vs metoclopramide), dolasetron mesilate 1.2 mg/kg (P = 0.0058 vs metoclopramide), and metoclopramide, respectively. Overall, dolasetron was significantly more effective than metoclopramide for time to first emetic episode, nausea, patient satisfaction, and investigator global assessment of efficacy. Males, chemotherapy-naive patients, and alcoholics had higher response rates. Dolasetron was well tolerated, with mild-to-moderate headache most commonly reported. Twelve percent of patients receiving metoclopramide reported extrapyramidal symptoms compared with 0% of patients receiving dolasetron. In conclusion, dolasetron mesilate was effective for the prevention of CINV with high-dose cisplatin. Single i.v. doses of dolasetron mesilate were more effective than 7 mg/kg metoclopramide in preventing nausea and vomiting induced by highly emetogenic cisplatin-containing chemotherapy. In addition, 1.8 mg/kg dolasetron mesilate consistently produced the highest response rates and appears to be the most effective dose for further clinical development.

A double-blind, placebo-controlled trial of i.v. dolasetron mesilate in the prevention of radiotherapy-induced nausea and vomiting in cancer patients.

The aim of this work was to measure the safety and efficacy of single i.v. doses of dolasetron mesilate for the control of emesis caused by single high-dose (at least 6 Gy) radiotherapy to the upper abdomen. The double-blind, placebo-controlled, multicenter study stratified patients on the basis of being naive or nonnaive to radiotherapy. Patients with or without a history of previous chemotherapy were enrolled. Patients were randomized to receive placebo or 0.3, 0.6, or 1.2 mg/kg dolasetron mesilate 30 min before radiotherapy, then monitored for 24 h. Antiemetic efficacy was assessed from the time to the first emetic episode or rescue, from whether there was a complete response (0 emetic episodes /no rescue medication) or a complete-plus-major response (0-2 emetic episodes/no rescue medication), from the severity of nausea (rated by patients and the investigator), and from the investigator's assessment of efficacy. Fifty patients completed the study (owing to changing medical practice, enrollment objectives were not met; consequently, no significant linear dose trend was expected). Pooled dolasetron was superior to the placebo in its effect on the time to first emesis or rescue in radiotherapy-nonnaive patients (P = 0.015). Dolasetron was statistically superior to the placebo in the overall population on the basis of a complete plus major response: 54%, 100%, 93%, and 83% for the placebo and 0.3-, 0.6-, and 1.2-mg/kg doses respectively (P = 0.002). The low response in the highest dose group may be due to an imbalance in the number of chemotherapy-nonnaive patients in that group. Dolasetron was superior to the placebo on the basis of nausea assessed by the investigator (P = 0.024) and administration of rescue medication (P = 0.006). Complete response at the 0.3-mg/ kg dose was superior to results with the placebo (P = 0.050). Treatment-related adverse events were rare, mild to moderate in intensity, and evenly distributed across the four groups. Overall, dolasetron mesilate was effective and well-tolerated in the control of single, high-dose radiotherapy-induced emesis.

A double-blind, randomised comparison of the anti-emetic efficacy of two intravenous doses of dolasetron mesilate and granisetron in patients receiving high dose cisplatin chemotherapy.

This multicentre, double-blind, double-dummy, randomised trial was designed to compare the efficacy and safety of single intravenous doses of dolasetron mesilate and granisetron in the prevention of acute emesis and nausea due to high-dose (> or = 80 mg/m2) cisplatin. Single intravenous doses of 1.8 or 2.4 mg/kg of dolasetron mesilate or 3 mg of granisetron hydrochloride were administered in a volume of 50 ml over a 5-min period, beginning 30 min prior to cisplatin (> or = 80 mg/m2) administration. The number and timing of emetic episodes, time to administration of escape anti-emetic medication, severity of nausea by visual analogue scale (VAS), and safety were monitored for 24 h after the start of cisplatin-containing chemotherapy. Investigators' evaluations of overall efficacy and patients' satisfaction with therapy were recorded at the end of the 24-h study period. Of the 474 patients evaluable for efficacy, complete responses were achieved by 54, 47 and 48% of patients given dolasetron mesilate 1.8 mg/kg, dolasetron mesilate 2.4 mg/kg and granisetron, respectively. Statistically, treatment groups had comparable complete and complete plus major responses, times to first emesis, and use of escape medication; patient maximum nausea severity and treatment satisfaction ratings; and physician nausea severity and overall efficacy assessments. For the majority of efficacy endpoints, 1.8 mg/kg dolasetron mesilate produced numerically superior responses compared with the 2.4 mg/kg dose. Gender and prior chemotherapy were significant predictors of complete response; males and chemotherapy-naive patients had higher responses. The overall incidences of adverse events were comparable among the treatment groups; headache and diarrhoea were most common. In conclusion, 1.8 and 2.4 mg/kg of dolasetron mesilate and granisetron (3 mg) were equally effective in preventing nausea and vomiting induced by highly emetogenic cisplatin-containing chemotherapy. In addition, because no additional benefit was observed with 2.4 mg/kg of dolasetron mesilate and numerically greater responses were observed with the 1.8 mg/kg dose, the lower dose of 1.8 mg/kg is optimal for further clinical development.

Comparative antitumor properties in rodents of irreversible inhibitors of L-ornithine decarboxylase, used as such or as prodrugs.

The antitumor properties of (E)-2-(fluoromethyl)dehydroornithine methyl ester (delta-MFMO-ME) and of (E)-2-(fluoromethyl)dehydroornithine ethyl ester (delta-MFMO-EE), the prodrugs of delta-MFMO, an irreversible inhibitor of mammalian L-ornithine decarboxylase (ODC) 14 times more potent than alpha-difluoromethylornithine (DFMO) and equipotent to (2R,5R)-6-heptyne-2,5-diamine (MAP) in vitro, have been investigated in L1210 leukemia- and Lewis lung carcinoma-bearing mice. The anticancer properties of these esters have been compared with those of DFMO and MAP as a function of the dose, the route of administration, and the stage of the lewis lung carcinoma development in mice. The two esters, administered i.p. shortly after cell inoculation at one-fifth the dose of DFMO, prolonged the survival of mice-bearing leukemia to the same extent as DFMO and MAP. When administered orally to leukemia-bearing mice the two esters were equipotent at prolonging survival. The methyl ester appears, however, to be slightly, but not significantly, more effective than the ethyl ester against leukemia when given i.p., maximum prolongation of the mice survival (79%) occurring at 0.5 g/kg methyl ester every 12 h. The two esters achieve at one-sixth to one-twelfth the dose, antitumor effects similar to DFMO in the Lewis lung carcinoma model, the ethyl ester being slightly, but not significantly, more effective than the methyl ester when administered orally. Moreover, the ethyl ester causes greater reduction of tumor growth than DFMO (P less than 0.05) and MAP (P less than 0.01) in this model. Inhibition of tumor growth is correlated with spermidine depletion and an increase of decarboxylated-S-adenosylmethionine, the aminopropyl donor in the spermidine and spermine synthase reactions. All ODC inhibitors, however, lose most of their antitumor properties when administered at late stage of Lewis lung carcinoma development. Finally, this study demonstrates the advantage of using prodrugs of delta-MFMO, an inhibitor of ODC, since they possess longer duration of action, higher potency, and in some cases better antitumor efficiency than the parent direct inhibitor of ODC. Moreover, and as already noticed for DFMO or MAP, no sign of overt toxicity is caused by the highest effective antitumor doses of the esters.

Immunosuppressive effects of (2R,5R)-6-heptyne-2,5-diamine, an inhibitor of polyamine synthesis: II. Beneficial effects on the development of a lupus-like disease in MRL-lpr/lpr mice.

(2R,5R)-6-heptyne-2,5-diamine (MAP; MDL 72175), a potent irreversible inhibitor of L-ornithine decarboxylase (ODC), possesses immunosuppressive activities in vitro as the result of inhibition of lymphocyte polyamine biosynthesis. The effects of MAP were now studied in vivo in MRL-lpr/lpr female mice, an animal model for human systemic lupus erythematosus (SLE). Administration of MAP (0.2% in drinking water; drug intake: 0.25-0.35 g/kg body weight/day) to female mice for 15 weeks, starting 8 weeks after birth, reduced by 47% the number of spleen cells, retarded development of lymphadenopathy and, at that time, markedly prolonged the survival of the mice. At week 23, MAP reduced plasma IgG concentrations by 50% whereas, in contrast, those of IgM were elevated 1.5-fold. No statistically significant effects of MAP were observed on plasma levels of anti-DNA autoantibodies although serum anti-RNP and anti-Sm titres tended downwards during treatment. Neither glomerular lesions nor proteinuria were improved by MAP administration. Finally chronic administration of MAP for 45 weeks prolonged the median survival time from 29.75 to 35.5 weeks.

Fluorine-containing polyamines: biochemistry and potential applications.

Investigations with the fluorinated spermidine analogues show clearly that these compounds have significant potential for studying the metabolism and functions of the polyamines. However, the biochemical and biological properties of these analogues are dissimilar. This is due to the influence of the fluorine substituent(s) on the basicity of the amine function proximal to the fluoromethylene group, this effect being amplified by geminal disubstitution. The monofluorinated spermidine analogues compare well with the natural amine in their ability to regulate the expression of the decarboxylase enzymes, to be substrates of spermine synthase and to support growth of polyamine-deficient cells. It is also likely that 6-monofluorospermine, formed biochemically in situ, shares with spermine similar functions. These findings raise the possibility of using these spermidine analogues to study the metabolism and pharmacology of polyamines in vivo but also to provide more insight into the regulatory role of spermidine in ODC and SAM-DC expression. Another potential application may be the use of these analogues as probes in tumor imaging and therapy control. This indication has been inferred by studies in tumor-bearing animals, using 19F-NMR spectroscopy determination of tissue fluorospermidine and fluorospermine, formed biochemically from the precursors 2-fluoro or 2,2-difluoroputrescine, and which demonstrate preferential accumulation in tumor versus normal tissue. Finally, these monofluorinated spermidine analogues may exert beneficial effects in pathological states associated with polyamine deficiency. These diseases remain however to be identified. Among the difluorinated spermidine analogues, 7,7-difluorospermidine possesses the most interesting properties. This spermidine analogue still possesses ODC and SAM-DC repressing activities although at much higher concentration than spermidine. More importantly it is a potent inhibitor of spermine synthesis both in cultured cells and in vivo due to its efficient competition with spermidine in the spermine synthase reaction. This compound not only depletes tumor cell of its spermine content but, in addition, appears to exert by itself and/or via 6,6-difluorospermine, the product of its metabolism, polyamine antagonist effects. Combined with MAP but also with DFMO, two potent irreversible inhibitors of ODC which block the synthesis of the natural endogenous polyamines, 7,7-difluorospermidine causes an immediate decrease of viability in cultured HTC cells and promotes tumor regression and stabilization in hepatoma-bearing rats.(ABSTRACT TRUNCATED AT 400 WORDS)

Inhibition of polyamine oxidase improves the antitumoral effect of ornithine decarboxylase inhibitors.

Specific inhibition of ornithine decarboxylase activity prevents the formation of putrescine from ornithine and decreases spermidine levels of slow-growing organs by about 20%. However, spermidine levels of rapidly growing tissues, such as tumors, may under the same conditions be decreased by as much as 60%. Inactivation of polyamine oxidase prevents oxidative splitting of N1-acetylspermidine and N1-acetylspermine and therefore the reutilization of putrescine for de novo polyamine biosynthesis. Prolonged inhibition of ornithine decarboxylase and polyamine oxidase activities leads in all normal tissues studied so far to a decrease of the spermidine concentration by 50% or more, demonstrating the general physiological significance of polyamine reutilization. In this work the role of polyamine reutilization in tumors was studied. Combined treatment with the inhibitors of ornithine decarboxylase, alpha-difluoromethylornithine or (2R, 5R)-6-heptyne-2,5-diamine, and N1, N4-bis-allenylputrescine, an inhibitor of polyamine oxidase, produced a more marked depletion of the polyamine contents of L1210 ascitic cells and of Lewis lung carcinoma, than treatment with either compound alone. Concomitantly, the proliferative activity of these tumors decreased significantly below the value that was observed after treatment with an ornithine decarboxylase inhibitor alone. Our results demonstrate that polyamines which are produced by the interconversion pathway are used by the tumors in order to cover their polyamine requirement.

A sensitive high-performance liquid chromatographic procedure with fluorometric detection for the analysis of decarboxylated S-adenosylmethionine and analogs in urine samples.

A highly sensitive HPLC method for the determination of decarboxylated S-adenosylmethionine (dc-SAM) by fluorometric detection was developed. The reaction of dc-SAM and its analogs with chloroacetaldehyde leads to the corresponding 1,N6-etheno derivatives. These highly fluorescent derivatives were fully characterized through their proton nuclear magnetic resonance spectra and/or mass spectra. This derivatization procedure has been applied to the analysis of dc-SAM in rat and human urine. After a simple cation exchange column prepurification, the urine extracts were derivatized with chloroacetaldehyde and analyzed by reversed-phase HPLC with fluorometric detection. The method allowed the determination of subpicomole amounts of dc-SAM and was shown to be highly reproducible with the use of decarboxylated S-adenosylethionine as internal standard. The application of the method to the analysis of urine of rats treated with MDL 72175, a potent ornithine decarboxylase inhibitor, showed that the dc-SAM levels increased in a dose-related fashion.

N-Acetyl decarboxylated S-adenosylmethionine, a new metabolite of decarboxylated S-adenosylmethionine: isolation and characterization.

Treatment with ornithine decarboxylase inhibitors leads to a marked increase of decarboxylated S-adenosylmethionine (dc-SAM) in various tissues, accompanied by the concomitant formation of a metabolite of dc-SAM. This metabolite has been isolated from rat prostate samples by a combination of chromatographic procedures. The use of IH-NMR and of fast atom bombardment mass spectometry and the synthesis of an authentic sample allowed the unambiguous characterization of this unknown compound as the N-acetyl derivative of dc-SAM. A reverse-phase high performance liquid chromatography procedure was developed for the separation of dc-SAM and its N-acetyl derivative into their diastereomers resulting from the chiral sulfonium group.

A rapid high-performance liquid chromatographic procedure for the simultaneous determination of methionine, ethionine, S-adenosylmethionine, S-adenosylethionine, and the natural polyamines in rat tissues.

A method for the analysis of S-adenosyl-L-methionine (SAM) and S-adenosyl-L-ethionine (SAE) and their major metabolites by high-performance liquid chromatography is described. The procedure allows the simultaneous analysis of the natural polyamines, putrescine, spermidine, and spermine, and some of the major amino acids, methionine, tyrosine, and tryptophan. The uv absorbance at 254 nm is used for the determination of the SAM and SAE analogs, whereas the polyamines and amino acids are analyzed by fluorescence detection after postcolumn derivatization with o-phthalaldehyde. The method allows SAM and polyamine determinations by direct injection of the tissue extracts without prepurification. The procedure is applied to study the effects of DL-ethionine treatment on the SAM, SAE, methionine, and polyamine levels in various tissues of rats.

Stereochemistry of the inactivation of 4-aminobutyrate: 2-oxoglutarate aminotransferase and L-glutamate 1-carboxylase by 4-aminohex-5-ynoic acid enantiomers.

Incubation of rat brain or bacterial 4-aminobutyrate aminotransferase (EC 2.6.1.19) with both (S)-(+)- and (R)-(-)-enantiomers of 4- aminohex -5- ynoic acid results in a time-dependent irreversible loss of enzymatic activity. Rat brain glutamate decarboxylase (EC 4.1.1.15) is inactivated by the (S)-(+)-enantiomer while the bacterial glutamate decarboxylase is inactivated by the (R)-(-)-enantiomer. In addition, we demonstrate that (R)-(-)-4- aminohex -5- ynoic acid is a selective and effective inhibitor of rat brain 4-aminobutyrate aminotransferase in vivo.

High-performance liquid chromatographic analysis of S-adenosylmethionine and its metabolites in rat tissues: interrelationship with changes in biogenic catechol levels following treatment with L-dopa.

A method is described for the simultaneous analysis of S-adenosylmethionine (SAM) and its metabolites, S-adenosylhomocysteine (SAH) and decarboxylated S-adenosylmethionine along with the natural polyamines, putrescine, spermidine and spermine. The separation is obtained by a reversed-phase ion-pair liquid chromatographic procedure with gradient elution followed by dual detection. The UV absorbance at 254 nm is used for the analysis of SAM and of the SAM metabolites, whereas the polyamines and some major amino acids, e.g., methionine, tyrosine and tryptophan, are analyzed by fluorescence detection after UV-cell derivatization with o-phthalaldehyde. A separate ion-pair reversed-phase high-performance liquid chromatographic (HPLC) procedure using isocratic elution and electrochemical detection is employed to analyse in the same tissue extracts the catechols and 5-hydroxyindoles, 3,4-dihydroxyphenylalanine (DOPA), dopamine, norepinephrine, 3,4-dihydroxyphenylacetic acid, homovanillic acid, 4-hydroxy-3- methoxyphenylalanine , tryptophan, 5-hydroxytryptophan, serotonin and 5- hydroxyindolacetic acid. The sample preparation for the two HPLC procedures requires only homogenization of the tissues in perchloric acid and centrifugation before injection onto the column. The two chromatographic procedures have been applied to study the interrelationship, in various tissues of rats, between the SAM and SAH levels and the biogenic catechols after different treatments with L-DOPA alone or in combination with alpha- monofluoromethyl -DOPA, a potent enzyme-activated irreversible inhibitor of aromatic L-amino acid decarboxylase.

Comparison of 3-isobutyl-1-methylxanthine-induced accumulation of putrescine in rat pancreas and liver.

3-Isobutylmethylxanthine (IBMX), a potent phosphodiesterase inhibitor, causes accumulation of putrescine of same magnitude in rat pancreas and liver. IBMX produces increases of acetyl CoA: polyamine N'-acetyltransferase (PAT) and of ornithine decarboxylase (ODC) activities in both organs. However ODC activity is 300 times higher in liver than in pancreas. In the latter organ, there is a transient increase of N1-acetylspermidine, followed by a decrease of spermidine, alpha-Difluoromethylornithine (DFMO), a potent ODC inhibitor, impairs the accumulation of putrescine in liver but not in pancreas. These results suggest that in pancreas the accumulated putrescine is essentially formed from spermidine, via N1-acetylation and oxidation, while in liver it is formed from decarboxylation of ornithine. A possible involvement of cAMP in the stimulation of the polyamine interconversion pathway is discussed.

(2R,5R)-6-heptyne-2,5-diamine, an extremely potent inhibitor of mammalian ornithine decarboxylase.

It was previously shown that 5-hexyne-1,4-diamine is a potent enzyme-activated irreversible inhibitor of mammalian ornithine decarboxylase. However this compound has secondary pharmacological effects owing to its in vivo oxidation to 4-aminohex-5-ynoic acid, an irreversible inhibitor of 4-aminobutyrate aminotransferase. The first step of this oxidation is catalysed by mitochondrial monamine oxidase. The monomethyl and dimethyl analogues of 5-hexyne-1,4-diamine, i.e. 6-heptyne-2,5-diamine and 2-methyl-6-heptyne-2,5-diamine, which cannot be substrate of monoamine oxidase, were tested as selective irreversible inhibitors of ornithine decarboxylase. Our results demonstrate that (2R,5R)-6-heptyne-2,5-diamine is greater than 10 times more potent, both in vitro and in vivo, than alpha-difluoromethylornithine, the most widely used irreversible inhibitor of this enzyme.

alpha-Monofluoromethyl and alpha-difluoromethyl putrescine as ornithine decarboxylase inhibitors: in vitro and in vivo biochemical properties.

In vitro, 5-fluoropentane-1,4-diamine and 5,5-difluoropentane-1,4-diamine are potent enzyme-activated inhibitors of rat liver ornithine decarboxylase (EC 4.1.1.17). The two alpha-fluoromethyl derivatives of putrescine activate to different degrees S-adenosyl-L-methionine decarboxylase (EC 4.1.1.50). The difluoromethyl derivative differs from the monofluoromethyl derivative in that it is not a substrate of diamine oxidase (EC 1.4.3.6), but is a better substrate of mitochondrial monoamine oxidase (EC 1.4.3.4) than the monofluoromethyl derivative. In vivo, a single i.p. injection of 200 mg/kg of 5-fluoropentane-1,4-diamine to rats causes a marked decrease of the ornithine decarboxylase activity in the ventral prostate and to a lesser extent in the thymus, whereas 5,5-difluoropentane-1,4-diamine causes only a slight decrease of this enzyme activity in the prostate and does not affect it in the thymus. Both compounds produce a decrease of 4-aminobutyrate: 2-oxoglutarate aminotransferase (EC 2.6.1.19) activity in the brain. The differences observed between the biochemical properties of the two alpha-fluoromethyl derivatives of putrescine are discussed in relation to the pKa value of the alpha-amino group which decreases from 7.75 for 5-fluoropentane-1,4-diamine to 6.4 for 5,5-difluoropentane-1,4-diamine.

Synthesis and biochemical properties of chemically stable product analogues of the reaction catalyzed by S-adenosyl-L-methionine decarboxylase.

Structural analogues of decarboxylated S-adenosyl-L-methionine (dc-SAM), product of the reaction catalyzed by S-adenosyl-L-methionine decarboxylase (SAM-DC), with modifications in the side-chain portion of the molecule have been synthesized, and their ability to inhibit SAM-DC has been investigated. Mainly, compounds with a nitrogen atom in place of the sulfur were investigated. The data from these inhibition studies have resulted in a delineation of the structural features required for binding on SAM-DC. It was concluded that a terminal primary amino group, a terminal carboxyl group, and the sulfonium functionality are not required for binding on SAM-DC. It was also found that analogues of dc-SAM in which replacement of the sulfur by nitrogen was the only modification were still able to form an azomethine with the enzyme. As found for SAM and dc-SAM, these compounds also caused a time-dependent inactivation of SAM-DC.

Accumulation of decarboxylated S-adenosyl-L-methionine in mammalian cells as a consequence of the inhibition of putrescine biosynthesis.

Biological transmethylation reactions and polyamine biosynthesis share the substrate S-adenosyl-L-methionine. Under normal conditions, decarboxylated S-adenosyl-L-methionine, the aminopropyl donor for polyamine biosynthesis, does not accumulate because of its rapid utilization in spermidine and spermine synthesis. Alteration of polyamine synthesis by DL-alpha-difluoromethylornithine, an enzyme-activated irreversible inhibitor of L-ornithine decarboxylase, leads to a striking accumulation of decarboxylated S-adenosyl-L-methionine in rat hepatoma cells cultured in vitro and in rat ventral prostate. This increase is due both to lack of putrescine and spermidine for the aminopropyltransferase reactions and to the elevation of S-adenosyl-L-methionine decarboxylase activity. The biological implications of accumulation of decarboxylated S-adenosyl-L-methionine are discussed with regard to the regulation of S-adenosyl-L-methionine decarboxylase activity and to the antiproliferative effects of DL-alpha-difluoromethylornithine.

Effect on prostatic growth of 2-difluoromethylornithine, an effective inhibitor of ornithine decarboxylase.

2-Difluoromethylornithine (DFMO), an enzyme-activated irreversible inhibitor of ornithine decarboxylase, causes marked changes in the polyamine metabolism of ventral prostate when given to adult rats in drinking water (20 g/l) for 3 consecutive days. A 90% inhibition of ornithine decarboxylase activity is accompanied by approx. 80% decreases of the concentrations of putrescine and spermidine and by a 36% decrease in spermine. Concomitantly, S-adenosylmethionine decarboxylase activity increases 7-fold and the concentration of decarboxylated S-adenosylmethionine 450-fold. When DFMO is given to immature rats for 12 consecutive days the above described changes are accompanied by a marked reduction in the age-dependent increases of the wet weight and RNA and DNA contents of the ventral prostate. In adult rats DFMO decreases the weight and RNA content of the ventral prostate within 4 days by 32% and 24% respectively and maintains them constant for the next 19 days. After 23 days of treatment, the prostatic weight is 46% of that of control animals of the same age, whereas the weights of other organs are only slightly decreased. Cytological studies carried out at this time show that DFMO reduces the size of both prostatic acini and the epithelial cells lining the acini.