In summary, it would appear that the two different growth signals, the induction of growth of a tumour and the PHA-induced hyperplasia of the gut, compete with one another for important exogenous nutrients such as polyamines. The data demonstrate that tumour proliferation is initially slowed by the gut hyperplasia, though growth, however, is not completely arrested. Since it has been established that extraneous polyamines from the diet are required to sustain tumour growth, and the hyperplastic growth of the gut which occurs in response to ingesting the lectin is a polyamine dependent process, then it is evident that this latter growth signal can be used to effectively compete with tumour growth. Results obtained so far have clearly shown that inclusion of the plant lectin PHA in the diet causes an initial low rate of proliferation of NHL tumours in mice, growing either as solid, subcutaneous tumours or as ascites tumours in the peritoneal cavity. The results concerning changes in the weight and polyamine content of tissues indicate that inter-organ competition between the tumour and vital organs can be used to manipulate the metabolism of tumour-bearing mice. The promising results obtained hitherto with PHA indicate that lectins which exhibit such growth-promoting properties may be of extreme value concerning the development of new directions in anti-cancer strategy.
This work forms part of the COST 917 Programme of the European Commission. The Norwegian Cancer Society is thanked for financial support. SB received support from SOAFD.
• Of special interest
•• Of outstanding interest
1. Tabor CW, Tabor H. Polyamines
. Ann Rev Biochem 1984; 53: 749–790.
2. Pegg AE. Recent advances in the biochemistry of polyamines
in eukaryotes. Biochem J 1986; 234: 249–262.
3. Marton L, Morris D. Molecular and cellular functions of the polyamines
. In:Inhibition of Polyamine Metabolism
. McCann PP, Pegg A, Sjoerdsma A (editors). San Diego: Academic Press; 1987. pp. 79–105.
4. Bachrach U, Heimer YM. The Physiology of Polyamines
, Vols 1 and 2. Boca Raton, Florida: CRC Press; 1988.
5. Heby O, Persson L. Molecular genetics of polyamine synthesis in eukaryotic cells. TIBS 1990; 15: 153–158.
6. •Seiler N, Delgros JG, Moulinoux JP. Polyamine transport in mammalian cells. An update. Int J Biochem Cell Biol 1996; 28: 843–861. A useful review on polyamine transport and release. Covers polyamine uptake by cells of the gastrointestinal tract.
7. ••Pryme IF, Pusztai A, Bardocz S, Ewen SWB. The induction of gut hyperplasia
in the diet and limitation of tumour growth
. Histol Histopathol 1998; 13: 575–583. Important background information on dietary phytohaemagglutinin
, tumour growth
and the role of polyamines
8. Takami H, Nishioka K. Determination of erythrocytic polyamines
by reverse-phase liquid chromatography. Br J Cancer 1980; 41: 751–756.
9. Gerbaut L. Determination of erythrocyte polyamines
by reversed-phase liquid chromatography. Clin Chem 1991; 37: 2117–2120.
10. Uehara N, Shirakawa S, Uchino H, Saeki Y, Nozaki M. Elevated polyamine levels in erythrocytes of SLC:ICR mice inoculated with Ehrlich ascites carcinoma cells. Life Sci 1980; 26: 461–467.
11. Uehara N, Kita K, Shirakawa S, Uchino H, Saeki Y. Elevated polyamine content in erythrocytes of malignant lymphoma patients. Gann 1980; 71: 393–397.
12. Uehara N, Shirakawa S, Uchino H, Saeki Y. Elevated contents of spermidine and spermine in the erythrocytes of cancer patients. Cancer 1980; 45: 108–111.
13. Chatel M, Darcel F, Quemener V, Hercouet H, Moulinoux J. Red blood cell polyamines
as biological markers of supratentorial malignant gliomas. Anticancer Res 1987; 7: 33–38.
14. O’Brien T, Simsiman R, Boutwell R. Induction of the polyamine-biosynthetic enzymes in mouse epidermis by tumor-promoting agents. Cancer Res 1975; 35: 1662–1670.
15. Gilmour SK, Verma AK, Madara T, O’Brien TG. Regulation of ornithine decarboxylase gene expression in mouse epidermis and epidermal tumours during two-stage tumorigenesis. Cancer Res 1987; 47: 1221–1225.
16. LaMuraglia GM, Lacaine F, Malt RA. High ornithine decarboxylase activity and polyamine levels in human colorectal neoplasia Ann Surg 1986; 204: 89–93.
17. Porter C, Herrera-Ornelas L, Pera P, Petrelli N, Mittelman A. Polyamine biosynthetic activity in normal and neoplastic human colorectal tissues. Cancer 1987; 60: 1275–1281.
18. •Westin T, Edström S, Lundholm K, Gustafsson B. Evaluation of ornithine decarboxylase activity as a marker for tumor growth rate in malignant tumors. Am J Surg 1991; 162: 288–293. Determination of ODC activity in relation to tumour cell proliferation. Discussion concerning prognostic significance for survival.
19. •Ernestus R, Röhn G, Schröder R, Klug N, Hossmann K, Paschen W. Activity of ornithine decarboxylase (ODC) and polyamine levels as biochemical markers of malignancy in human brain tumors. Acta Histochemica 1992; 42: 159–164. ODC measurements in tissue samples from brain tumour patients. High activity represents a reliable marker of malignancy.
20. Scalabrino G, Modena D, Ferioli ME, Puerari M, Luccarelli G. Degrees of malignancy in human primary central nervous system tumors: ornithine decarboxylase levels as better indicators than adenosylmethionine decarboxylase levels. J Natl Cancer Inst 1982; 68: 751–754.
21. Volkow N, Goldman SS, Flamm ES, Cravioto H, Wolf AP, Brodie JD. Labeled putrescine as a probe in brain tumors. Science 1983; 221: 673–675.
22. Dunzendorfer U, Russell DH. Altered polyamine profiles in prostatic hyperplasia
and in kidney tumors. Cancer Res 1978; 38: 2321–2324.
23. Matsuda M, Osafune M, Kotake T, Sonada T, Sobue K, Nakajima T. Concentrations of polyamines
in renal cell carcinoma. Clin Chim Acta 1978; 87: 93–99.
24. ••Thomas T, Thomas TJ. Regulation of cyclin B1 by estradiol and polyamines
in MCF-7 breast cancer cells. Cancer Res 1994; 54: 1077–1084. Indication of role of polyamines
in oestrogenic control of the cell cycle through cyclin B1 mRNA modulation.
25. Bey P, Danzin C, Jung MJ. Inhibition of basic amino acid decarboxylases involved in polyamine biosynthesis. In:Inhibition of Polyamine Metabolism
. McCann PP, Pegg A, Sjoerdsma A (editors). San Diego: Academic Press; 1987. pp. 1–31.
26. Schechter PJ, Barlow JLR, Sjoerdsma A. Clinical aspects of inhibition of ornithine decarboxylase with emphasis on therapeutic trials of eflornithine (DFMO) in cancer and protozoan diseases. In:Inhibition of Polyamine Metabolism
. McCann PP, Pegg A, Sjoerdsma A (editors). San Diego: Academic Press; 1987. pp. 345–364.
27. Sunkara PS, Baylin SB, Luk GD. Inhibitors of polyamine biosynthesis: cellular and in vivo
effects on tumour proliferation. In:Inhibition of Polyamine Metabolism
. McCann PP, Pegg A, Sjoerdsma A (editors). San Diego: Academic Press; 1987. pp. 121–140.
28. Danzin C, Mamont PS. Polyamine inhibition in vivo
and in organ growth and repair. In:Inhibition of Polyamine Metabolism
. McCann PP, Pegg A, Sjoerdsma A (editors). San Diego: Academic Press; 1987. pp. 141–164.
29. Hirvonen A, Eloranta T, Hyvönen T, Alhonen L, Jänne J. Characterization of difluoromethylornithine-resistant mouse and human tumour cell lines. Biochem J 1989; 258: 709–713.
30. Seiler N, Dezeure F. Polyamine transport in mammalian cells. Int J Biochem 1990; 22: 211–218.
31. ••Bardocz S. The role of dietary polyamines
(a review). Eur J Clin Nutr 1993; 47: 683–690. Important review on polyamines
in mammalian tissues, including adaptive growth of the gut.
32. •Pryme IF, Bardocz S, Pusztai A. A diet containing the lectin phytohaemagglutinin
(PHA) slows down the proliferation of Krebs II cell tumours in mice. Cancer Lett 1994; 76: 133–137. First paper showing that dietary phytohaemagglutinin
can modulate growth of a transplantable murine non-Hodgkin lymphoma
33. Bardocz S, Grant G, Duguid TJ, Brown DS, Sakhri M, Pusztai A. et al
in the diet induces growth of the gut and modifies some organ weights in mice. Med Sci Res 1994; 22: 101–103.
34. •Bardocz S, Grant G, Duguid TJ, Brown DS, Pusztai A, Pryme IF. Effect of phytohaemagglutinin
on the growth of Krebs II tumour cells, body metabolism and internal organs of mice. Int J Oncol 1994; 5: 1369–1374. Changes in weight of tissues and polyamine content indicate that inter-organ competition occurs between vital organs and a transplantable murine non-Hodgkin lymphoma
35. Bardocz S, Grant G, Brown DS, Ewen SWB, Nevison I, Pusztai A. Polyamine metabolism and uptake during Phaseolus vulgaris lectin
, PHA-induced growth of the rat small intestine. Digestion 1990; 46 (suppl) : 360–366.
36. •Pusztai A, Grant G, Williams LM, Brown DS, Ewen SWB, Bardocz S. Phaseolus vulgaris lectin
induces growth and the uptake of polyamines
by the rat small intestine in vivo
. Med Sci Res 1989; 17: 215–217. Gut hyperplasia
induced by phytohaemagglutinin
(Phaseolus vulgaris lectin
) results in sequestration of polyamines
in the tissue.
37. Pusztai A. Plant Lectins
. Cambridge, UK: Cambridge University Press; 1991.
38. Pryme IF, Pusztai A, Bardocz S. The initial growth rate of Krebs II ascites cell tumours in mice is slowed down by the inclusion of phytohaemagglutinin
in the diet. Int J Oncol 1994; 5: 1105–1107.
39. •Pryme IF, Bardocz S, Grant G, Duguid TJ, Brown DS, Pusztai A. Switching between control and phytohaemagglutinin
-containing diets affects growth of Krebs II ascites cells and produces differences in the levels of putrescine, spermidine and spermine. Cancer Lett 1995; 93: 233–237. Suggestion that phytohaemagglutinin
-induced gut hyperplasia
and a transplantable murine non-Hodgkin lymphoma
tumour compete for available polyamines
40. Pryme IF, Bardocz S, Grant G, Duguid TJ, Brown DS, Pusztai A. The plant lectin
PHA as a tool for reducing the progression of tumour growth
. In:Effects of Antinutrients on the Nutritional Value of Legume Diets
(COST 98). Volume 2. Bardocz S, Pusztai A (editors). Luxembourg: European Commission Publications; 1996. pp. 24–29.
41. Pryme IF, Grant G, Pusztai A, Bardocz S. Limiting the availability of polyamines
for a developing tumour: an alternative approach to reducing tumour growth
. In:Polyamines in Health and Nutrition
. Bardocz S, White A (editors). Dordrecht: Kluwer Academic Publishers; 1999. pp. 283–291.
42. Pryme IF, Pusztai A, Grant G, Bardocz S. Phytohaemagglutinin
-induced gut hyperplasia
and the growth of a mouse lymphosarcoma tumour. J Exp Therap & Oncol 1996; 1: 171–176.
43. Pryme IF, Pusztai A, Grant G, Bardocz S. The effect of switching between phytohaemagglutinin
-containing and a control diet on the growth and lipid content of a Krebs II lymphosarcoma tumour. J Exp Therap & Oncol 1996; 1: 273–277.
44. Pryme IF, Bardocz S, Pusztai A, Ewen SWB. The growth of an established murine non-Hodgkin lymphoma
tumour is limited by switching to a phytohaemagglutinin
-containing diet. Cancer Lett 1999; 146: 87–91.
45. •Bardocz S, Grant G, Duguid TJ, Brown DS, Pusztai A, Pryme IF. Intracellular levels of polyamines
in Krebs II lymphosarcoma cells in mice fed phytohaemagglutinin
-containing diets are coupled with altered tumour growth
. Cancer Lett 1997; 121: 25–29. A three-fold increase in the level of cellular polyamines
was required for tumour cells to enter the S phase.
Pryme IF, Pusztai A, Ewen SWB, Bardocz S. Reduction in growth of a non-Hodgkin lymphoma
tumour in mice fed a polyamine-poor phytohaemagglutinin
-containing diet is reversed by addition of polyamines
. In:Biogenically Active Amines in Food
(COST 917). Volume 4. Morgan DML, White A, Sanchez-Jimenez F, Bardocz S (editors). Luxembourg: European Commission Publications; 2000. pp. 167–172. Dietary polyamines
appear to be important in the stimulation of growth of a transplantable murine non-Hodgkin lymphoma