Pharmacological Properties of the Ornithine Decarboxylase Inhibitor 3-aminooxy-1-propanamine and Several Structural Analogues

Overview

Journal Cancer Chemother Pharmacol

Specialty Oncology

Date 1993 Jan 1

PMID 8462122

Citations 7

Authors

H Mett

J Stanek

J Janne

L Alhonen

R Sinervirta

J Frei

U Regenass

Affiliations

Soon will be listed here.

Abstract

Analogues of 3-aminooxy-1-propanamine proved to be highly potent and selective inhibitors of ornithine decarboxylase (ODC). The compounds competed with ornithine for the substrate binding site of ODC, but resulted in progressive and apparently irreversible inactivation of the enzyme. Diamine oxidase was inhibited by these compounds to a lesser extent than ODC; the compounds were not metabolized by this enzyme. Several derivatives were growth-inhibitory for human T24 cells and for other mammalian cells, the most active compound being 3-aminooxy-2-fluoro-1-propanamine (AFPA). Growth-arrested cells were largely depleted of putrescine and spermidine. Cellular growth arrest could be antagonized by supplementation with spermidine. Selection for resistance against AFPA led to cells with amplified ODC genes and overexpression of the message. Some of the derivatives were tumoristatic at well-tolerated doses in mice bearing solid T24 tumours. The antiproliferative activity of these compounds appears to be mediated by polyamine depletion.

Citing Articles

Structural basis of binding and inhibition of ornithine decarboxylase by 1-amino-oxy-3-aminopropane.

Zhou X, Suino-Powell K, Schultz C, Aleiwi B, Brunzelle J, Lamp J Biochem J. 2021; 478(23):4137-4149.

PMID: 34796899 PMC: 9125680. DOI: 10.1042/BCJ20210647.

Vitamin B6-dependent enzymes in the human malaria parasite Plasmodium falciparum: a druggable target?.

Kronenberger T, Lindner J, Meissner K, Zimbres F, Coronado M, Sauer F Biomed Res Int. 2014; 2014:108516.

PMID: 24524072 PMC: 3912857. DOI: 10.1155/2014/108516.

L-arginine metabolism and its impact on host immunity against Leishmania infection.

Wanasen N, Soong L Immunol Res. 2007; 41(1):15-25.

PMID: 18040886 PMC: 2639710. DOI: 10.1007/s12026-007-8012-y.

A structural insight into the inhibition of human and Leishmania donovani ornithine decarboxylases by 1-amino-oxy-3-aminopropane.

Dufe V, Ingner D, Heby O, Khomutov A, Persson L, Al-Karadaghi S Biochem J. 2007; 405(2):261-8.

PMID: 17407445 PMC: 1904517. DOI: 10.1042/BJ20070188.

Antileishmanial effect of 3-aminooxy-1-aminopropane is due to polyamine depletion.

Singh S, Mukherjee A, Khomutov A, Persson L, Heby O, Chatterjee M Antimicrob Agents Chemother. 2006; 51(2):528-34.

PMID: 17101681 PMC: 1797741. DOI: 10.1128/AAC.01055-06.

References

Bowlin T, Hoeper B, Rosenberger A, Davis G, Sunkara P . Effects of three irreversible inhibitors of ornithine decarboxylase on macrophage-mediated tumoricidal activity and antitumor activity in B16F1 tumor-bearing mice. Cancer Res. 1990; 50(15):4510-4. View

Kopitz J, Adam G, Bohley P . Very fast purification of ornithine decarboxylase with high yield from mouse kidney and generation of a monoclonal antibody. Biol Chem Hoppe Seyler. 1990; 371(4):363-8. DOI: 10.1515/bchm3.1990.371.1.363. View

Leinonen P, Laine R, Janne O, Janne J . Human myeloma cells acquire resistance to difluoromethylornithine by amplification of ornithine decarboxylase gene. Biochem J. 1987; 242(1):199-203. PMC: 1147683. DOI: 10.1042/bj2420199. View

Hyvonen T, Eloranta T . Regulation of S-adenosyl-L-methionine decarboxylase by 1-aminooxy-3-aminopropane: enzyme kinetics and effects on the enzyme activity in cultured cells. J Biochem. 1990; 107(3):339-42. DOI: 10.1093/oxfordjournals.jbchem.a123048. View

Maddox A, Freireich E, Keating M, Haddox M . Alterations in bone marrow and blood mononuclear cell polyamine and methylglyoxal bis(guanylhydrazone) levels: phase I evaluation of alpha-difluoromethylornithine and methylglyoxal bis(guanylhydrazone) treatment of human hematological malignancies. Cancer Res. 1988; 48(5):1367-73. View

Pegg A, Jones D, Secrist 3rd J . Effect of inhibitors of S-adenosylmethionine decarboxylase on polyamine content and growth of L1210 cells. Biochemistry. 1988; 27(5):1408-15. DOI: 10.1021/bi00405a003. View

Hyvonen T, Khomutov A, Khomutov R, Lapinjoki S, Eloranta T . Uptake of 3H-labeled 1-aminooxy-3-aminopropane by baby hamster kidney cells. J Biochem. 1990; 107(6):817-20. DOI: 10.1093/oxfordjournals.jbchem.a123131. View

Pegg A . Polyamine metabolism and its importance in neoplastic growth and a target for chemotherapy. Cancer Res. 1988; 48(4):759-74. View

Hyvonen T, Alakuijala L, Andersson L, Khomutov A, Khomutov R, Eloranta T . 1-Aminooxy-3-aminopropane reversibly prevents the proliferation of cultured baby hamster kidney cells by interfering with polyamine synthesis. J Biol Chem. 1988; 263(23):11138-44. View

10.

Khomutov R, Hyvonen T, Karvonen E, Kauppinen L, Paalanen T, Paulin L . 1-Aminooxy-3-aminopropane, a new and potent inhibitor of polyamine biosynthesis that inhibits ornithine decarboxylase, adenosylmethionine decarboxylase and spermidine synthase. Biochem Biophys Res Commun. 1985; 130(2):596-602. DOI: 10.1016/0006-291x(85)90458-9. View

11.

Nicolet T, Scemama J, Pradayrol L, Seva C, Vaysse N . Characterization of putrescine- and spermidine-transport systems of a rat pancreatic acinar tumoral cell line (AR4-2J). Biochem J. 1990; 269(3):629-32. PMC: 1131633. DOI: 10.1042/bj2690629. View

12.

Horn Y, Schechter P, Marton L . Phase I-II clinical trial with alpha-difluoromethylornithine--an inhibitor of polyamine biosynthesis. Eur J Cancer Clin Oncol. 1987; 23(8):1103-7. DOI: 10.1016/0277-5379(87)90141-6. View

13.

Seiler N . Polyamine metabolism. Digestion. 1990; 46 Suppl 2:319-30. DOI: 10.1159/000200405. View

14.

Kabra P, Lee H, Lubich W, Marton L . Solid-phase extraction and determination of dansyl derivatives of unconjugated and acetylated polyamines by reversed-phase liquid chromatography: improved separation systems for polyamines in cerebrospinal fluid, urine and tissue. J Chromatogr. 1986; 380(1):19-32. DOI: 10.1016/s0378-4347(00)83621-x. View

15.

Seppanen P, Kapyaho K, Janne J . Two enzyme inhibition assays for methylglyoxal bis(guanylhydrazone). Methods Enzymol. 1983; 94:247-53. DOI: 10.1016/s0076-6879(83)94043-0. View

16.

Stanek J, Frei J, Mett H, Schneider P, Regenass U . 2-substituted 3-(aminooxy)propanamines as inhibitors of ornithine decarboxylase: synthesis and biological activity. J Med Chem. 1992; 35(8):1339-44. DOI: 10.1021/jm00086a003. View

17.

Kendrick D, Danzin C, Kolb M . 2,2-Difluoro-5-hexyne-1,4-diamine: a potent enzyme-activated inhibitor of ornithine decarboxylase. J Med Chem. 1989; 32(1):170-3. DOI: 10.1021/jm00121a031. View

18.

Meyer T, Regenass U, Fabbro D, Alteri E, Rosel J, Muller M . A derivative of staurosporine (CGP 41 251) shows selectivity for protein kinase C inhibition and in vitro anti-proliferative as well as in vivo anti-tumor activity. Int J Cancer. 1989; 43(5):851-6. DOI: 10.1002/ijc.2910430519. View

19.

Mamont P, Duchesne M, Grove J, Bey P . Anti-proliferative properties of DL-alpha-difluoromethyl ornithine in cultured cells. A consequence of the irreversible inhibition of ornithine decarboxylase. Biochem Biophys Res Commun. 1978; 81(1):58-66. DOI: 10.1016/0006-291x(78)91630-3. View

20.

Pleshkewych A, Kramer D, Kelly E, Porter C . Independence of drug action on mitochondria and polyamines in L1210 leukemia cells treated with methylglyoxal-bis(guanylhydrazone). Cancer Res. 1980; 40(12):4533-40. View