Efeito inibidor do crescimento tumoral pela metionina-encefalina

Mascarenhas, Georgia; Quirico-Santos, Thereza

doi:10.1590/S0004-282X1992000100015

Resumos

A metionina-enceflalina (Met-Ehk) é um pentapeptídeo opióide derivado do pró-normônio proencefalina A. presente em células neuroendócrinas e hematopoéticas. Estudos experimentais evidenciam seu papel na indução, ativação e controle de eventos imunomodula-dores, inclusive com potente efeito inibidor do crescimento tumoral. O presente estudo demonstra que o efeito inibidor da Met-Enk no crescimento de um fibro-histiocitoma, em camundongos BALB/cJ, é influenciado pelo protocolo utilizado, via de administração e dose do pentapeptídeo opióide utilizada no tratamento. A administração de Met_Enk por via intracerebral retardou de forma eficiente o processo de tumorigênese, aumentando a sobrevida dos animais e reduzindo de forma significativa a área tumoral final. Dose baixa (0,25 mg/kg) de Met-Enk administrada por via intracerebral foi ainda mais potente no controle da tumorigênese.

histiocitoma; metionina-encefalina; neuroimunomodulação

Methionine-enkephalin (Met-Enk) is an endogenous opioid pentapeptide derived from the prohormone proenkephalin A, present in neuroendocrine and hematopoietic cells. Enkephalins are known to play an important role on the processes of induction, activation and control of immunomodulatory events. Met-Enk has been considered a potent antitumoral agent. The present study shows that Met-Enk exerts an inhibitory effect on the growth of a macrophage derived fibrous histiocytoma (MC-II) inoculated intradermally into BALB/cJ mice. Such effect was mainly influenced by the protocol, route of administration and concentration of Met-Enk used for treatment. Neither higher doses of Met-Enk injected intracerebrally or subcutaneously, nor the use of various protocols of treatment, did modify the process of tumorigenesis. In contrast, low dose (0.25mg/kg) of Met-Enk injected intracerebrally together with tumor inoculation, significantly reduced tumor growth and prolonged survival rate.

histiocytoma; methionine-enkephalin; neuroimmunemodulation

Georgia Mascarenhas; Thereza Quirico-Santos

Laboratório de Imunologia Celular, Departamento de Patologia, Hospital Universitário Antonio Pedro, Universidade Federal Fluminense (UFF)

RESUMO

A metionina-enceflalina (Met-Ehk) é um pentapeptídeo opióide derivado do pró-normônio proencefalina A. presente em células neuroendócrinas e hematopoéticas. Estudos experimentais evidenciam seu papel na indução, ativação e controle de eventos imunomodula-dores, inclusive com potente efeito inibidor do crescimento tumoral. O presente estudo demonstra que o efeito inibidor da Met-Enk no crescimento de um fibro-histiocitoma, em camundongos BALB/cJ, é influenciado pelo protocolo utilizado, via de administração e dose do pentapeptídeo opióide utilizada no tratamento. A administração de Met_Enk por via intracerebral retardou de forma eficiente o processo de tumorigênese, aumentando a sobrevida dos animais e reduzindo de forma significativa a área tumoral final. Dose baixa (0,25 mg/kg) de Met-Enk administrada por via intracerebral foi ainda mais potente no controle da tumorigênese.

Palavras chave: histiocitoma, metionina-encefalina, neuroimunomodulação.

SUMMARY

Methionine-enkephalin (Met-Enk) is an endogenous opioid pentapeptide derived from the prohormone proenkephalin A, present in neuroendocrine and hematopoietic cells. Enkephalins are known to play an important role on the processes of induction, activation and control of immunomodulatory events. Met-Enk has been considered a potent antitumoral agent. The present study shows that Met-Enk exerts an inhibitory effect on the growth of a macrophage derived fibrous histiocytoma (MC-II) inoculated intradermally into BALB/cJ mice. Such effect was mainly influenced by the protocol, route of administration and concentration of Met-Enk used for treatment. Neither higher doses of Met-Enk injected intracerebrally or subcutaneously, nor the use of various protocols of treatment, did modify the process of tumorigenesis. In contrast, low dose (0.25mg/kg) of Met-Enk injected intracerebrally together with tumor inoculation, significantly reduced tumor growth and prolonged survival rate.

Key words: histiocytoma, methionine-enkephalin, neuroimmunemodulation.

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Dra. Theresa Quirico-Santos Hospital Universitário Antonio Pedro, Departamento de Patologia - Rua Marquês do Paraná 303 - 24230 Niterói RJ - Brasil.

1. Bernton E, Frondoza C, Grzanna R, Holaday J. Effects of naloxone on the growth of LPPC-1 plasmacytoma in mice. Proc First Internat Workshop on Neuroimmunomodulation. International Working Group on Neuroimmunomodulation (IWGN), Bethesda, 1985, p 245-248 (abstr).
2. Carr DJJ, De Costa BR, Kim C-H, Jacobson AE, Guarcello V, Rice KC, Blalock JE. Opioid receptors on cells of the immune system: evidence for delta and kappa-classes. J Endocrinol 1989, 122:161-186.
3. Deitch EA, Dazhong X, Bridges RMCI. Opioids modulate human neutrophil and lymphocyte function: thermal injury alters plasma beta-endorphin levels. Sugery 1988, 104: 41-48.
4. Jankovic B, Maric D. Enkephalins and immunity. II: In vivo modulation of cell-mediated immunity. Ann NY Acad Sci 1987, 496:126-136.
5. Jankovic B, Maric D. Enkephalins modulate in vivo immune reactions through delta and mu opioid receptors. Ann NY Sci 1988, 540:691-693.
6. Lopker A, Abood LG, Hoss W, Lionetti F. Stereoselective muscarinic acetylcholine opiate receptors in human phagocytic leukocytes. Biochem Pharmacol 1980, 29:1361-1365.
7. Mehrishi JN, Mills IH. Opioid receptors on lymphocytes and platelets in man. Clin Immunol Immunopathol 1983, 27:240-249.
8. Morcos R, Seidah NG, Lazure C, Chretien M. Endorphines 1989: aspects neuroendocriniens. Rev Neurol (Paris) 1989, 145:747-753.
9. Ovadia H, Nitsan P, Abramsky O. Characterization of opioid binding sites on membranes of rat lymphocyte. J Neuroimmunol 1989, 21:193-202.
10. Plotnikoff NP, Faith RE, Murgo AJ, Miller GC. Enkephalins: immunomodulators and «antitumoral activities». Proc First Internat Workshop on Neuroimmunomodulation. International Working Group on Neuroimmunomodulation (IWGN), Bethesda, 1985, p 240-242 (abstr).
11. Plotnikoff NP. Opioids: immunomodulators. A proposed role in cancer and aging. Ann NY Acad Sci 1988. 521:312-322.
12. Schweigerer L, Bhakdi S, Teschemacher H. Specific non-opioid binding sites for human beta-endorphin on the terminal complex of human complement. Nature 1982, 296:572-574.
13. Sibinge NES, Goldstein A. Opioid peptides and opioid receptors in cell of the immune system. Ann Rev Immunol 1988, 6:219-249.
14. Zagon IS, Goodman SR, McLaughlin PJ. Characterization of zeta: a new opioid receptor involved in growth. Brain Res 1989, 482:297-305.
15. Zagon IS, McLaughlin PJ. Modulation of murine neuroblastoma in nude mice by opioid antagonists. J Natl Cancer Inst 1987, 78:141-147.
16. Zagon IS, McLaughlin P. Endogenous opioids and the growth regulation of a neural tumor. Life Sci 1988, 43:1313-1318.
17. Zagon IS, McLaughlin PJ. Endogenous opioid systems regulate growth of neural tumor cells in culture. Brain Res 1989, 490:14-25.
18. Zagon IS, McLaughlin PJ, Goodman SR, Rhodes RE. Opioid receptors and endogenous opioids are present in diverse human animal cancers. J Natl Cancer Inst 1987, 79:1059-1065.

Efeito inibidor do crescimento tumoral pela metionina-encefalina

Inhibitory effect of methionine-enkephalin on tumor growth

Datas de Publicação

Publicação nesta coleção
22 Fev 2011
Data do Fascículo
Mar 1992

This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.

[1] 1. Bernton E, Frondoza C, Grzanna R, Holaday J. Effects of naloxone on the growth of LPPC-1 plasmacytoma in mice. Proc First Internat Workshop on Neuroimmunomodulation. International Working Group on Neuroimmunomodulation (IWGN), Bethesda, 1985, p 245-248 (abstr).

[2] 2. Carr DJJ, De Costa BR, Kim C-H, Jacobson AE, Guarcello V, Rice KC, Blalock JE. Opioid receptors on cells of the immune system: evidence for delta and kappa-classes. J Endocrinol 1989, 122:161-186.

[3] 3. Deitch EA, Dazhong X, Bridges RMCI. Opioids modulate human neutrophil and lymphocyte function: thermal injury alters plasma beta-endorphin levels. Sugery 1988, 104: 41-48.

[4] 4. Jankovic B, Maric D. Enkephalins and immunity. II: In vivo modulation of cell-mediated immunity. Ann NY Acad Sci 1987, 496:126-136.

[5] 5. Jankovic B, Maric D. Enkephalins modulate in vivo immune reactions through delta and mu opioid receptors. Ann NY Sci 1988, 540:691-693.

[6] 6. Lopker A, Abood LG, Hoss W, Lionetti F. Stereoselective muscarinic acetylcholine opiate receptors in human phagocytic leukocytes. Biochem Pharmacol 1980, 29:1361-1365.

[7] 7. Mehrishi JN, Mills IH. Opioid receptors on lymphocytes and platelets in man. Clin Immunol Immunopathol 1983, 27:240-249.

[8] 8. Morcos R, Seidah NG, Lazure C, Chretien M. Endorphines 1989: aspects neuroendocriniens. Rev Neurol (Paris) 1989, 145:747-753.

[9] 9. Ovadia H, Nitsan P, Abramsky O. Characterization of opioid binding sites on membranes of rat lymphocyte. J Neuroimmunol 1989, 21:193-202.

[10] 10. Plotnikoff NP, Faith RE, Murgo AJ, Miller GC. Enkephalins: immunomodulators and «antitumoral activities». Proc First Internat Workshop on Neuroimmunomodulation. International Working Group on Neuroimmunomodulation (IWGN), Bethesda, 1985, p 240-242 (abstr).

[11] 11. Plotnikoff NP. Opioids: immunomodulators. A proposed role in cancer and aging. Ann NY Acad Sci 1988. 521:312-322.

[12] 12. Schweigerer L, Bhakdi S, Teschemacher H. Specific non-opioid binding sites for human beta-endorphin on the terminal complex of human complement. Nature 1982, 296:572-574.

[13] 13. Sibinge NES, Goldstein A. Opioid peptides and opioid receptors in cell of the immune system. Ann Rev Immunol 1988, 6:219-249.

[14] 14. Zagon IS, Goodman SR, McLaughlin PJ. Characterization of zeta: a new opioid receptor involved in growth. Brain Res 1989, 482:297-305.

[15] 15. Zagon IS, McLaughlin PJ. Modulation of murine neuroblastoma in nude mice by opioid antagonists. J Natl Cancer Inst 1987, 78:141-147.

[16] 16. Zagon IS, McLaughlin P. Endogenous opioids and the growth regulation of a neural tumor. Life Sci 1988, 43:1313-1318.

[17] 17. Zagon IS, McLaughlin PJ. Endogenous opioid systems regulate growth of neural tumor cells in culture. Brain Res 1989, 490:14-25.

[18] 18. Zagon IS, McLaughlin PJ, Goodman SR, Rhodes RE. Opioid receptors and endogenous opioids are present in diverse human animal cancers. J Natl Cancer Inst 1987, 79:1059-1065.