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

Kolb, Michael; Danzin, Charles; Barth, Jacqueline; Claverie, Nicole

doi:10.1021/jm00347a014

Cited by 71 publications

(53 citation statements)

References 8 publications

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“…Lower doses and longer-term randomized trials will be necessary to determine whether lower doses also produce these effects because the effect on tissue polyamines takes time and, except for one agent [topical trans-retinoic acid (69)], evaluation of chemoprevention agents in the Phase III setting has not borne out promising Phase II results in cervical intraepithelial neoplasia (70 -73). We have also measured the effect of 1 month of oral DFMO on polyamines in the prostate in patients undergoing a definitive surgical procedure, and we have demonstrated a marked lowering of polyamines; 6 (R. Love of Wisconsin has also obtained similar results. 7 ) Although DFMO has been highly effective as a chemoprevention agent in combination in preclinical models, to date only one clinical study has been reported using DFMO in combination (61).…”

Section: Clinical Studies Of Dfmo In Malignant and Precancerous Condimentioning

confidence: 76%

“…The administration of DFMO to men who are scheduled for surgical interventions to treat some form of prostate hyperplasia or neoplasia causes a suppression in all prostate polyamine pools, including the spermine pool. 6 Supplying cells or animals with sufficient amounts of exogenous polyamines to restore normal intracellular pools can reverse most of the effects of DFMO (8,10,41). Several groups reported that polyamine metabolism was an integral component of the mechanism of carcinogenesis, especially in epithelial tissues.…”

Section: Effects Of Dfmo On Cell and Tissue Polyamine Contentsmentioning

confidence: 99%

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Development of difluoromethylornithine as a chemoprevention agent for the management of colon cancer

1995

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D,L-␣-difluoromethylornithine (DFMO) was synthesized over 20 years ago. It was hoped that this enzymeactivated, irreversible inhibitor of ornithine decarboxylase, the first enzyme in polyamine synthesis, would be effective as a chemotherapy for hyperproliferative diseases, including cancer and/or infectious processes. DFMO was generally found to exert cytostatic effects on mammalian cells and tissues, and its effectiveness as a therapeutic agent has been modest. DFMO was also found to cause treatment-limiting (but reversible) ototoxicity at high doses. This side effect, along with its minimal therapeutic activity, contributed to the loss of interest by many clinicians in further developing DFMO as a cancer therapeutic agent. However, DFMO was subsequently shown to inhibit carcinogen-induced cancer development in a number of rodent models, and interest in developing this compound as a preventive agent has increased. The rationale for the inhibition of ornithine decarboxylase as a cancer chemopreventive agent has been strengthened in recent years because this enzyme has been shown to be transactivated by the c-myc oncogene in certain cell/tissue types and to cooperate with the ras oncogene in malignant transformation of epithelial tissues. Recent clinical cancer chemoprevention trials, using dose de-escalation designs, indicate that DFMO can be given over long periods of time at low doses that suppress polyamine contents in gastrointestinal and other epithelial tissues but cause no detectable hearing loss or other side effects. Current clinical chemoprevention trials are investigating the efficacy of DFMO to suppress surrogate end point biomarkers (e.g., colon polyp recurrence) of carcinogenesis in patient populations at elevated risk for the development of specific epithelial cancers, including colon, esophageal, breast, cutaneous, and prostate malignancies. Early Rationale for the Development of Inhibitors of Polyamine MetabolismStudies on the diamine putrescine and its polyamine products spermidine and spermine date to the 17 th century with the observation by Leeuwenhoek of spermine phosphate crystals in human semen (1). The strong association between high levels of the polyamines and rapid proliferation in prokaryotes and eukaryotes was recognized more than 25 years ago (2-4). These investigations led scientists at the Merrell Research Institute in Strasbourg to synthesize specific inhibitors of ODC 3 (5), the first enzyme in mammalian polyamine synthesis, and of other enzymes involved in polyamine metabolism (6 -7). It was hoped that the inhibition of polyamine metabolism would be a successful strategy for chemotherapy for cancer and/or other hyperproliferative diseases or infectious diseases such as protozoal parasiticism (8).Subsequent studies by the Merrell group and others, using specific ODC inhibitors (9 -14) or genetic approaches (15, 16) to manipulate levels of endogenous polyamines, confirmed that amines derived from ornithine are essential for mammalian cell viability, and high levels are n...

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Section: Clinical Studies Of Dfmo In Malignant and Precancerous Condimentioning

confidence: 76%

Section: Effects Of Dfmo On Cell and Tissue Polyamine Contentsmentioning

confidence: 99%

Development of difluoromethylornithine as a chemoprevention agent for the management of colon cancer

1995

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“…More recently, the concept of 'multisubstrate adduct' inhibition has been successfully applied to the aminopropyltransferases [27]. Along these lines, S-methyl-5'-methylthioadenosine, a known inhibitor of AdoMet decarboxylase [13] and S-adenosyl-1,12-diamino-3-thio-9-azaadenosine have been shown to be potent inhibitors of spermine synthase both in vitro and in cultured cells [26,271. When used alone, these inhibitors cause marked decrease of sperrnine concentration in cultured mammalian cells and, therefore, are useful in the search for some specific biological functions of spermine.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of mammalian spermine synthase by N‐alkylated‐1,3‐diaminopropane derivatives in vitro and in cultured rat hepatoma cells

Baillon¹,

Kolb²,

Mamont³

1989

European Journal of Biochemistry

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A number of N-alkylated-l,3-diaminopropane derivatives [H2N-(CH2)3-NH-(CH2),,H, where n = 1 -91 have been tested as potential inhibitors of partially purified rat hepatoma (HTC) cell or pure bovine spleen spermine synthase.Among the compounds described in this paper, the most potent competitive inhibitor of spermine synthase, with respect to spermidine, is N-butyl-l,3-didminopropane with Ki values of 11.9 nM and 10.4 nM for the HTC cell and bovine spleen enzymes respectively. Inhibition of spermine synthase by this alkylated amine is selective since spermidine synthase activity is not affected up to 100 pM N-butyl-1,3-diaminopropane at a range of 5 -200 pM putrescine.Added to the culture medium of growing HTC cells, N-butyl-l,3-diaminopropane causes the expected changes in the polyamine levels with a marked decrease of spermine and an increase of spermidine. Under these conditions cell growth continues unabated.Such N-alkylated-I ,3-diaminopropane derivatives may have considerable potential as tools for studying the role of polyamines and in particular the functions of spermine in cell multiplication and differentiation.The requirement of polyamine synthesis for eukaryotic cell multiplication has been demonstrated mainly by the use of specific irreversible inhibitors of L-ornithine decarboxylase, one of the key enzymes of the polyamine biosynthetic pathway (reviewed in [l]). Inhibition of L-ornithine decarboxylase has been shown to exert beneficial effects in animal models of proliferative diseases [2 -51 and in some protozoan infections in humans [6]. Altogether these studies emphasize the importance of the polyamine metabolic pathway as promising target for the design of new anti-proliferative agents [l, 21.Use of L-ornithine-decarboxylase inhibitors for creating polyamine deficiency in mammalian tissues has however certain limitations. In vivo administration of these compounds causes putrescine and spermidine deficiency but scarcely affects tissue spermine concentrations [7, 81. As hypothesized [9, lo], maintenance of residual cell growth and lack of cytotoxicity of these L-ornithine decarboxylase inhibitors may possibly result from their ineffectiveness in altering initial spermine levels. There is some experimental support for this hypothesis, at least in cultured cells [lo, I I]. However, availability of specific and very effective inhibitors of spermine synthase should provide more direct information on particular biological functions of spermine both in vitro and in vivo.Correspondence to P. S. Marnont, Merrell Dow Research Institute,

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“…A number of structural analogs of decarboxy AdoMet have been synthesized as potential inhibitors of AdoMet DC, and several of these have been shown to inhibit the enzyme from rat liver (16,20) and cultured L1210 cells (21) irreversibly. Two of these compounds were found to inhibit the growth of these cells in culture.…”

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confidence: 99%

Cure of Trypanosoma brucei brucei and Trypanosoma brucei rhodesiense infections in mice with an irreversible inhibitor of S-adenosylmethionine decarboxylase

Bitonti¹,

Byers²,

Bush³

et al. 1990

Antimicrob Agents Chemother

109

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A structural analog, 5'-{[(Z)4-amino-2-butenyl]methylamino}-5'-deoxyadenosine (MDL 73811), of decarboxy S-adenosyl-L-methionine, the product of the reaction catalyzed by S-adenosyl-L-methionine (AdoMet) decarboxylase (DC), was found to inhibit Trypanosoma brucei brucei AdoMet DC. The inhibition was time dependent (T.s, 0.3 min), exhibited pseudo-first-order kinetics (Ki, 1.5 ,uM), and was apparently irreversible.The natural substrate of the reaction, AdoMet, protected the enzyme from inactivation, suggesting that MDL 73811 was directed at the enzyme active site and was probably catalytically activated. Administration of MDL 73811 to T. b. brucei-infected rats resulted in rapid inhibition of AdoMet DC activity, a decrease in spermidine, and an increase in putrescine in the trypanosomes isolated from treated rats. Treatment of T. b. brucei-infected mice with MDL 73811 (20 mg/kg of body weight intraperitoneally twice daily for 4 days) resulted in cures of the trypanosome infections. Additionally, drug-resistant T. brucei rhodesiense infections in mice were cured by either a combination of MDL 73811 (50 mg/kg intraperitoneally three times per day for 5 days) and relatively low oral doses of a-difluoromethylornithine or MDL 73811 (50 mg/kg per day for 7 days) administered alone in implanted miniosmotic pumps. These data suggest that MDL 73811 and, perhaps, other inhibitors of AdoMet DC have potential for therapeutic use in various forms of African trypanosomiasis.

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

Cited by 71 publications

References 8 publications

Development of difluoromethylornithine as a chemoprevention agent for the management of colon cancer

Development of difluoromethylornithine as a chemoprevention agent for the management of colon cancer

Inhibition of mammalian spermine synthase by N‐alkylated‐1,3‐diaminopropane derivatives in vitro and in cultured rat hepatoma cells

Cure of Trypanosoma brucei brucei and Trypanosoma brucei rhodesiense infections in mice with an irreversible inhibitor of S-adenosylmethionine decarboxylase

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