Polyamines in human health

Wallace, Heather M.

doi:10.1079/pns19960039

Cited by 25 publications

(16 citation statements)

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“…Taken together, these findings support the potential for an adaptive tissue response to prolonged ODC suppression, resulting in increased cellular uptake of diet- or bacteria-derived putrescine from the colonic lumen 13,14 . Polyamines are an important factor in colonic mucosa renewal 15 ; thus, prolonged inhibition of ODC with DFMO and increased export by sulindac may lead to compensatory uptake of luminal polyamines in the normal rectal mucosa.…”

Section: Discussionmentioning

confidence: 99%

Levels of Rectal Mucosal Polyamines and Prostaglandin E2 Predict Ability of DFMO and Sulindac to Prevent Colorectal Adenoma

et al. 2010

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Background and Aims The combination of polyamine and prostaglandin E2 (PGE2) synthesis inhibitors reduced the risk of colorectal adenoma (CRA) by 70% in patients that received polypectomies. We studied the effects of the combination of difluoromethylornithine (DFMO) and sulindac on biomarkers and investigated factors that might modify efficacy of these drugs. Methods We analyzed rectal mucosal levels of polyamines (spermidine, spermine, and putrescine) and PGE2, treatment regimens, and risk of CRA in 267 participants of a phase IIb/III trial of DFMO/sulindac for prevention of CRA recurrence. Results In the group that received DFMO/sulindac, the spermidine to spermine ratio (Spd:Spm) in rectal mucosa decreased between baseline and the 12- and 36-month follow-up examinations (0.30, 0.23, and 0.24, respectively; P < 0.001 for both comparisons to baseline). Putrescine levels decreased between baseline and 12 months (0.46 to 0.15 nmol/mg protein; P < 0.001) but rebounded between 12 and 36 months (0.15 to 0.36 nmol/mg protein; P = 0.001). PGE2 levels did not change, though aspirin use was significantly associated with lower baseline levels of PGE2. There were no significant associations between changes in biomarker levels and efficacy. However, drug efficacy was greatest in subjects with low Spd:Spm and high levels of PGE2 at baseline. None of these subjects developed CRA, whereas 39% of the patients that received placebo did develop CRA (P < 0.001). Efficacy was lowest in subjects with high Spd:Spm and low levels of PGE2 at baseline; 28% developed CRA, compared with 36% of the patients given placebo (P = 0.563). Conclusions A combination of DFMO and sulindac significantly suppressed production of rectal mucosal polyamines but not PGE2. There was no relationship between changes in biomarker levels and response. However, baseline biomarker levels modified the effect of DFMO/sulindac for CRA prevention.

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Section: Discussionmentioning

confidence: 99%

Levels of Rectal Mucosal Polyamines and Prostaglandin E2 Predict Ability of DFMO and Sulindac to Prevent Colorectal Adenoma

et al. 2010

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“…Polyamines are organic cations found in every living cell (Wallace, 1996). They are synthesised endogenously from the arginine-derived product ornithine, by the rate-limiting enzyme ornithine decarboxylase (ODC) (Gerner and Meyskens, 2004).…”

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confidence: 99%

Role of dietary polyamines in a phase III clinical trial of difluoromethylornithine (DFMO) and sulindac for prevention of sporadic colorectal adenomas

et al. 2013

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Background:The polyamine-inhibitory regimen difluoromethylornithine (DFMO)+sulindac has marked efficacy in preventing metachronous colorectal adenomas. Polyamines are synthesised endogenously and obtained from dietary sources. Here we investigate dietary polyamine intake and outcomes in the DFMO+sulindac colorectal adenoma prevention trial.Methods:Dietary polyamine data were available for 188 of 267 patients completing the study. Total dietary polyamine content was derived by the sum of dietary putrescine, spermine and spermidine values and categorised into two groups: highest (>75–100%) vs the lower three quartiles (0–25, 25–50 and 50–75%). Baseline tissue polyamine concentration and ODC1 genotype were determined. Logistic regression models were used for risk estimation.Results:A significant interaction was detected between dietary polyamine group and treatment with regard to adenoma recurrence (P=0.012). Significant metachronous adenoma risk reduction was observed after DFMO+sulindac treatment in dietary polyamine quartiles 1–3 (risk ratio (RR) 0.19; 95% confidence interval (CI) 0.08–0.42; P<0.0001) but not in quartile 4 (RR 1.51; 95% CI 0.53–4.29; P=0.44). However, a lower number of events in the placebo group within dietary quartile 4 confound the aforementioned risk estimates.Conclusion:These preliminary findings reveal complex relationships between diet and therapeutic prevention, and they support further clinical trial-based investigations where the dietary intervention itself is controlled.

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“…Thus, MTAP links polyamine biosynthesis and SAM salvage. Polyamine biosynthesis is required for rapid cell proliferation (4). The accumulation of MTA can cause feedback inhibition of polyamine production and recycling of MTA to SAM.…”

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Entropy-Driven Binding of Picomolar Transition State Analogue Inhibitors to Human 5′-Methylthioadenosine Phosphorylase

Guan

Brenowitz

et al. 2011

Biochemistry

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Human 5′-methylthioadenosine phosphorylase (MTAP) links the polyamine biosynthetic and S-adenosyl-L-methionine salvage pathways and is a target for anticancer drugs. p-Cl-PhT-DADMe-ImmA is a 10 pM, slow-onset tight-binding transition state analogue inhibitor of the enzyme. Titration of homotrimeric MTAP with this inhibitor established equivalent binding and independent catalytic function of the three catalytic sites. Thermodynamic analysis of MTAP with tight-binding inhibitors revealed entropic-driven interactions with small enthalpic penalties. A large negative heat capacity change of −600 cal/mol•K upon inhibitor binding to MTAP is consistent with the loss of hydrophobic interactions and release of water. Crystal structures of apo MTAP and MTAP in complex with p-Cl-PhT-DADMe-ImmA were determined at 1.9 A and 2.0 A resolution, respectively. Inhibitor binding caused condensation of the enzyme active site, reorganization at the trimer interfaces, the release of water from the active sites and subunit interfaces, and compaction of the trimeric structure. These structural changes cause the entropy-favored binding of transition state analogues. Homotrimeric human MTAP is contrasted to the structurally related homotrimeric human purine nucleoside phosphorylase. p-Cl-PhT-DADMe- ImmA binding to MTAP involves a favorable entropy term of −17.6 kcal/mol with unfavorable enthalpy of 2.6 kcal/mol. In contrast, binding of an 8.5 pM transition state analogue to human PNP has been shown to exhibit the opposite behavior, with an unfavorable entropy term of 3.5 kcal/mol and a favorable enthalpy of −18.6 kcal/mol. Transition state analogue interactions reflect protein architecture near the transition state and the profound thermodynamic differences for MTAP and PNP suggest dramatic differences in contributions to catalysis from protein architecture.

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Polyamines in human health

Cited by 25 publications

References 50 publications

Levels of Rectal Mucosal Polyamines and Prostaglandin E2 Predict Ability of DFMO and Sulindac to Prevent Colorectal Adenoma

Levels of Rectal Mucosal Polyamines and Prostaglandin E2 Predict Ability of DFMO and Sulindac to Prevent Colorectal Adenoma

Role of dietary polyamines in a phase III clinical trial of difluoromethylornithine (DFMO) and sulindac for prevention of sporadic colorectal adenomas

Entropy-Driven Binding of Picomolar Transition State Analogue Inhibitors to Human 5′-Methylthioadenosine Phosphorylase

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