Skip to main content
NCBI home page
Annals of The Royal College of Surgeons of England logoLink to Annals of The Royal College of Surgeons of England
. 1986 Mar;68(2):76–81.

The chemotherapeutic potential of polyamine antimetabolites.

A N Kingsnorth
PMCID: PMC2497796  PMID: 3082276

Abstract

The polyamines, putrescine, spermidine and spermine are small cationic molecules essential for DNA synthesis and cell replication. Because the cytotoxicity of most anti-cancer drugs can be attributed to inhibitory effects on DNA synthesis and cell replication it led to speculation that inhibition of polyamine synthesis could be a useful tool in the control of neoplastic growth. In 1978 alpha-difluoromethylornithine (DFMO), a powerful inhibitor of ornithine decarboxylase, the rate limiting enzyme in polyamine synthesis, was synthesized by Metcalf. Since then numerous investigators have tested the potential of DFMO and other polyamine antimetabolites as chemotherapeutic agents in experimental animals and cell cultures. The accumulated knowledge is now being evaluated in the treatment of human proliferative disorders and cancer.

Full text

PDF
76

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Alhonen-Hongisto L., Deen D. F., Marton L. J. Decreased cytotoxicity of aziridinylbenzoquinone caused by polyamine depletion in 9L rat brain tumor cells in vitro. Cancer Res. 1984 Jan;44(1):39–42. [PubMed] [Google Scholar]
  2. Alhonen-Hongisto L., Kallio A., Sinervirta R., Seppänen P., Kontula K. K., Jänne O. A., Jänne J. Difluoromethylornithine-induced amplification of ornithine decarboxylase genes in Ehrlich ascites carcinoma cells. Biochem Biophys Res Commun. 1985 Jan 31;126(2):734–740. doi: 10.1016/0006-291x(85)90246-3. [DOI] [PubMed] [Google Scholar]
  3. Black O., Jr, Chang B. K. Ornithine decarboxylase enzyme activity in human and hamster pancreatic tumor cell lines. Cancer Lett. 1982 Oct;17(1):87–93. doi: 10.1016/0304-3835(82)90113-6. [DOI] [PubMed] [Google Scholar]
  4. DAMIANI A., LIQUORI A. M., PULITI R., RIPAMONTI A. X-RAY STUDY OF SPERMINE TETRAHYDROCHLORIDE. J Mol Biol. 1965 Feb;11:438–440. doi: 10.1016/s0022-2836(65)80069-9. [DOI] [PubMed] [Google Scholar]
  5. Eversole P., DiGangi J. J., Menees T., Davis R. H. Structural gene for ornithine decarboxylase in Neurospora crassa. Mol Cell Biol. 1985 Jun;5(6):1301–1306. doi: 10.1128/mcb.5.6.1301. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Fozard J. R., Prakash N. J. Effects of DL-alpha-difluoromethylornithine, an irreversible inhibitor of ornithine decarboxylase, on the rat mammary tumour induced by 7,12-dimethylbenz[a]anthracene. Naunyn Schmiedebergs Arch Pharmacol. 1982 Jul;320(1):72–77. doi: 10.1007/BF00499076. [DOI] [PubMed] [Google Scholar]
  7. Grosshans E., Henry M., Tell G., Schechter P. J., Böhlen P., Grove J., Koch-Weser J. Les polyamines dans le psoriasis. Ann Dermatol Venereol. 1980 May;107(5):377–387. [PubMed] [Google Scholar]
  8. Gupta M., Coffino P. Mouse ornithine decarboxylase. Complete amino acid sequence deduced from cDNA. J Biol Chem. 1985 Mar 10;260(5):2941–2944. [PubMed] [Google Scholar]
  9. Harik S. I., Sutton C. H. Putrescine as a biochemical marker of malignant brain tumors. Cancer Res. 1979 Dec;39(12):5010–5015. [PubMed] [Google Scholar]
  10. Hung D. T., Deen D. F., Seidenfeld J., Marton L. J. Sensitization of 9L rat brain gliosarcoma cells to 1,3-bis(2-chloroethyl)-1-nitrosourea by alpha-difluoromethylornithine, an ornithine decarboxylase inhibitor. Cancer Res. 1981 Jul;41(7):2783–2785. [PubMed] [Google Scholar]
  11. Hung D. T., Marton L. J., Deen D. F., Shafer R. H. Depletion of intracellular polyamines may alter DNA conformation in 9L rat brain tumor cells. Science. 1983 Jul 22;221(4608):368–370. doi: 10.1126/science.6408733. [DOI] [PubMed] [Google Scholar]
  12. Izumi K., Hirao Y., Hopp L., Oyasu R. In vitro induction of ornithine decarboxylase in urinary bladder carcinoma cells. Cancer Res. 1981 Feb;41(2):405–409. [PubMed] [Google Scholar]
  13. Jänne J., Alhonen-Hongisto L., Seppänen P., Siimes M. Use of polyamine antimetabolites in experimental tumours and in human leukemia. Med Biol. 1981 Dec;59(5-6):448–457. [PubMed] [Google Scholar]
  14. Jänne J., Pösö H., Raina A. Polyamines in rapid growth and cancer. Biochim Biophys Acta. 1978 Apr 6;473(3-4):241–293. doi: 10.1016/0304-419x(78)90015-x. [DOI] [PubMed] [Google Scholar]
  15. Kahana C., Nathans D. Nucleotide sequence of murine ornithine decarboxylase mRNA. Proc Natl Acad Sci U S A. 1985 Mar;82(6):1673–1677. doi: 10.1073/pnas.82.6.1673. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Kallio A., Seppänen P., Alhonen-Hongisto L., Jänne J. Modulation of the tissue disposition of methylglyoxal bis(guanylhydrazone) in mice by polyamine depletion and by polyamine administration. Cancer Res. 1983 Jan;43(1):324–327. [PubMed] [Google Scholar]
  17. Kellen J. A., Chan A. W., Mirakian A. Effect of alpha-difluoromethyl ornithine on the transplantable rat hepatoma 5123, 1-1. Res Commun Chem Pathol Pharmacol. 1980 Nov;30(2):377–380. [PubMed] [Google Scholar]
  18. Kingsnorth A. N., King W. W., Diekema K. A., McCann P. P., Ross J. S., Malt R. A. Inhibition of ornithine decarboxylase with 2-difluoromethylornithine: reduced incidence of dimethylhydrazine-induced colon tumors in mice. Cancer Res. 1983 Jun;43(6):2545–2549. [PubMed] [Google Scholar]
  19. Kingsnorth A. N., Lumsden A. B., Wallace H. M. Polyamines in colorectal cancer. Br J Surg. 1984 Oct;71(10):791–794. doi: 10.1002/bjs.1800711019. [DOI] [PubMed] [Google Scholar]
  20. Kingsnorth A. N., McCann P. P., Diekema K. A., Ross J. S., Malt R. A. Effects of alpha-difluoromethylornithine on the growth of experimental Wilms' tumor and renal adenocarcinoma. Cancer Res. 1983 Sep;43(9):4031–4034. [PubMed] [Google Scholar]
  21. Kingsnorth A. N., Russell W. E., McCann P. P., Diekema K. A., Malt R. A. Effects of alpha-difluoromethylornithine and 5-fluorouracil on the proliferation of a human colon adenocarcinoma cell line. Cancer Res. 1983 Sep;43(9):4035–4038. [PubMed] [Google Scholar]
  22. Kingsnorth A. N., Wallace H. M., Bundred N. J., Dixon J. M. Polyamines in breast cancer. Br J Surg. 1984 May;71(5):352–356. doi: 10.1002/bjs.1800710513. [DOI] [PubMed] [Google Scholar]
  23. Levin V. A., Csejtey J., Byrd D. J. Brain, CSF, and tumor pharmacokinetics of alpha-difluoromethylornithine in rats and dogs. Cancer Chemother Pharmacol. 1983;10(3):196–199. doi: 10.1007/BF00255762. [DOI] [PubMed] [Google Scholar]
  24. Luk G. D., Baylin S. B. Ornithine decarboxylase as a biologic marker in familial colonic polyposis. N Engl J Med. 1984 Jul 12;311(2):80–83. doi: 10.1056/NEJM198407123110202. [DOI] [PubMed] [Google Scholar]
  25. Luk G. D., Goodwin G., Marton L. J., Baylin S. B. Polyamines are necessary for the survival of human small-cell lung carcinoma in culture. Proc Natl Acad Sci U S A. 1981 Apr;78(4):2355–2358. doi: 10.1073/pnas.78.4.2355. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Mamont P. S., Duchesne M. C., 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 Mar 15;81(1):58–66. doi: 10.1016/0006-291x(78)91630-3. [DOI] [PubMed] [Google Scholar]
  27. Marton L. J., Levin V. A., Hervatin S. J., Koch-Weser J., McCann P. P., Sjoerdsma A. Potentiation of the antitumor therapeutic effects of 1,3-bis(2-chloroethyl)-1-nitrosourea by alpha-difluoromethylornithine, an ornithine decarboxylase inhibitor. Cancer Res. 1981 Nov;41(11 Pt 1):4426–4431. [PubMed] [Google Scholar]
  28. Oredsson S. M., Deen D. F., Marton L. J. Decreased cytotoxicity of cis-diamminedichloroplatinum(II) by alpha-difluoromethylornithine depletion of polyamines in 9L rat brain tumor cells in vitro. Cancer Res. 1982 Apr;42(4):1296–1299. [PubMed] [Google Scholar]
  29. Oredsson S., Anehus S., Heby O. Irreversible inhibition of the early increase in ornithine decarboxylase activity following growth stimulation is required to block Ehrlich ascites tumor cell proliferation in culture. Biochem Biophys Res Commun. 1980 May 14;94(1):151–158. doi: 10.1016/s0006-291x(80)80200-2. [DOI] [PubMed] [Google Scholar]
  30. Pegg A. E., McCann P. P. Polyamine metabolism and function. Am J Physiol. 1982 Nov;243(5):C212–C221. doi: 10.1152/ajpcell.1982.243.5.C212. [DOI] [PubMed] [Google Scholar]
  31. Pegg A. E., Seely J. E., Pösö H., della Ragione F., Zagon I. A. Polyamine biosynthesis and interconversion in rodent tissues. Fed Proc. 1982 Dec;41(14):3065–3072. [PubMed] [Google Scholar]
  32. Pohjanpelto P., Hölttä E., Jänne O. A. Mutant strain of Chinese hamster ovary cells with no detectable ornithine decarboxylase activity. Mol Cell Biol. 1985 Jun;5(6):1385–1390. doi: 10.1128/mcb.5.6.1385. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Pösö H., Karvonen E., Suomalainen H., Andersson L. C. A human neuroblastoma cell line with an altered ornithine decarboxylase. J Biol Chem. 1984 Oct 25;259(20):12307–12310. [PubMed] [Google Scholar]
  34. Rosenheim O. The Isolation of Spermine Phosphate from Semen and Testis. Biochem J. 1924;18(6):1253–1262.1. doi: 10.1042/bj0181253. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Russell D. H., Snyder S. H. Amine synthesis in regenerating rat liver: extremely rapid turnover of ornithine decarboxylase. Mol Pharmacol. 1969 May;5(3):253–262. [PubMed] [Google Scholar]
  36. Siimes M., Seppänen P., Alhonen-Hongisto L., Jänne J. Synergistic action of two polyamine antimetabolites leads to a rapid therapeutic response in childhood leukemia. Int J Cancer. 1981 Nov 15;28(5):567–570. doi: 10.1002/ijc.2910280506. [DOI] [PubMed] [Google Scholar]
  37. Sunkara P. S., Fowler S. K., Nishioka K., Rao P. N. Inhibition of polyamine biosynthesis by alpha-difluoromethyl ornithine potentiates the cytotoxic effects of arabinosyl cytosine in HeLa cells. Biochem Biophys Res Commun. 1980 Jul 16;95(1):423–430. doi: 10.1016/0006-291x(80)90755-x. [DOI] [PubMed] [Google Scholar]
  38. Sunkara P. S., Prakash N. J., Mayer G. D., Sjoerdsma A. Tumor suppression with a combination of alpha-difluoromethyl ornithine and interferon. Science. 1983 Feb 18;219(4586):851–853. doi: 10.1126/science.6186025. [DOI] [PubMed] [Google Scholar]
  39. Sunkara P. S., Prakash N. J., Rosenberger A. L. An essential role for polyamines in tumor metastases. FEBS Lett. 1982 Dec 27;150(2):397–399. doi: 10.1016/0014-5793(82)80775-8. [DOI] [PubMed] [Google Scholar]
  40. Tabor C. W., Tabor H. Polyamines. Annu Rev Biochem. 1984;53:749–790. doi: 10.1146/annurev.bi.53.070184.003533. [DOI] [PubMed] [Google Scholar]
  41. Takenoshita S., Matsuzaki S., Nakano G., Kimura H., Hoshi H., Shoda H., Nakamura T. Selective elevation of the N1-acetylspermidine level in human colorectal adenocarcinomas. Cancer Res. 1984 Feb;44(2):845–847. [PubMed] [Google Scholar]
  42. Tofilon P. J., Deen D. F., Marton L. J. alpha-Difluoromethylornithine-induced polyamine depletion of 9L tumor cells modifies drug-induced DNA cross-link formation. Science. 1983 Dec 9;222(4628):1132–1135. doi: 10.1126/science.6417790. [DOI] [PubMed] [Google Scholar]
  43. Tofilon P. J., Oredsson S. M., Deen D. F., Marton L. J. Polyamine depletion influences drug-induced chromosomal damage. Science. 1982 Sep 10;217(4564):1044–1046. doi: 10.1126/science.6810463. [DOI] [PubMed] [Google Scholar]
  44. Veldhuis J. D., Hammond J. M. Role of ornithine decarboxylase in granulosa-cell replication and steroidogenesis in vitro. Biochem Biophys Res Commun. 1979 Dec 14;91(3):770–777. doi: 10.1016/0006-291x(79)91946-6. [DOI] [PubMed] [Google Scholar]
  45. Weeks C. E., Herrmann A. L., Nelson F. R., Slaga T. J. alpha-Difluoromethylornithine, an irreversible inhibitor of ornithine decarboxylase, inhibits tumor promoter-induced polyamine accumulation and carcinogenesis in mouse skin. Proc Natl Acad Sci U S A. 1982 Oct;79(19):6028–6032. doi: 10.1073/pnas.79.19.6028. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Whitney P. A., Morris D. R. Polyamine auxotrophs of Saccharomyces cerevisiae. J Bacteriol. 1978 Apr;134(1):214–220. doi: 10.1128/jb.134.1.214-220.1978. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Annals of The Royal College of Surgeons of England are provided here courtesy of The Royal College of Surgeons of England

RESOURCES