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Doctoral Thesis
DOI
10.11606/T.46.2018.tde-18102018-154405
Document
Author
Full name
Jolie Kiemlian Kwee
Institute/School/College
Knowledge Area
Date of Defense
Published
São Paulo, 1998
Supervisor
Committee
Augusto, Ohara (President)
Abdalla, Dulcineia Saes Parra
Armelin, Hugo Aguirre
Ho, Paulo Lee
Hoffmann, Maria Edwiges
Title in Portuguese
Proliferação celular induzida por 8-oxoguanosina e 8-metilguanosina, dois produtos do ataque de radicais livres a ribonucleosídeos e RNA
Keywords in Portuguese
Adutos de ácidos nucleicos
Biologia celular
Citologia
Radical livre
Abstract in Portuguese
Os efeitos de ribonucleosídeos de guanina substituídos na posição C-8 na proliferação de linfócitos B estão bem documentados na literatura. Esses compostos são análogos de adutos formados pela adição de radicais livres a ribonucleosídeos e a RNA. Neste trabalho, verificamos as propriedades proliferativas de dois desses adutos, 8-metilguanosina (8-MeGuo) e 8-oxo-7 ,8-di-hidroguanosina (8-OxoGuo) e comparamos com 8-bromoguanosina (8-BrGuo), o composto mais estudado como indutor da proliferação de linfócitos B. 8-MeGuo e 8-OxoGuo foram sintetisados em rendimentos de 28 e 55%, respectivamente, e foram caracterizados por UV, NMR e CG-massa. Seus efeitos sobre a incorporação de timidina radioativa ([3H] TdR) no DNA de células de baço, fibroblasto 3T3(A31) e melanoma B16F10 foram examinados. Os dois adutos foram mitogênicos para células de baço mas foram seletivos quanto as células imortalizadas. 8-MeGuo atuou sobre células 3T3(A31) e 8-OxoGuo sobre as células de melanoma B16F10. O análogo não fisiológico 8-BrGuo foi efetivo em todas as células testadas. Experimentos de contagem de células, citotoxicidade e citometria de fluxo, indicaram que a síntese de DNA induzida pelas guanosinas substituídas na posição C-8 refletia crescimento celular. Foi proposto que os compostos agem de dentro da célula uma vez que seus efeitos são bloqueados em presença de um inibidor de transporte de nucleosídeo, mas não foram inibidos por um antagonista de receptor purinérgico. Os resultados obtidos, junto com os descritos na literatura, sugerem que no caso dos fibroblastos 3T3(A31) e células de baço de camundongo os efeitos proliferativos dos compostos não são dependentes do metabolismo desses compostos via salvação das purinas. No caso das células de melanoma, entretanto, os compostos parecem fazer parte do "pool" de nucleosídeos. A demonstração de que adutos produzidos por ataques radicalares em ribonucleosídeos e RNA são capazes de induzir proliferação celular, abre novas perspectivas para a compreensão do papel de radicais livres em processos carcinogênicos.
Title in English
Cell proliferation induced by 8-oxoguanosine and 8-methylguanosine, two products of free radical attack to ribonucleosides and RNA
Keywords in English
Cell biology
Cytology
Free radical
Nuclear adducts
Abstract in English
The ability of CS-substituted guanine ribonucleosides to induce B cell proliferation has been well documented in the literature. These compounds are analogues of adducts formed from free radical attack on ribonucleosides and RNA. Here we examined the proliferative properties of two of these radical adducts, 8-methylguanosine (8-MeGuo) and 8-oxo-7 ,8-dihydroguanosine (8-OxoGuo) and compared them with those of the well studied B cell mitogen, 8-bromoguanosine (8-BrGuo). 8-MeGuo and 8-OxoGuo were synthesized in yields of 28 and 55 %, respectively, and were characterized by UV, NMR and CG-MS. Their effects upon [3H] thymidine uptake by Swiss mice splenocytes, mouse embryo 3T3 (A31) fibroblasts and mouse B16F10 melanocytes were examined. Both guanosine radical adducts were shown to increase [3H] thymidine uptake by mice splenocytes but displayed selectivity in regard to continuous cell lines. 8-MeGuo acted upon 3T3(A31) fibroblasts whereas 8-OxoGuo acted upon B16F10 melanocytes. The non physiological analogue 8-BrGuo acted upon all tested cells. Parallel experiments of cell counting, cytotoxicity, and cell sorting indicated that DNA synthesis induced by the C8-substituted guanosines reflected cell growth. It is proposed that the compounds act intracellularly because their proliferative effects were blocked in the presence of a nucleoside transport inhibitor but were not inhibited by an antagonist of the A2 purine receptor. The obtained results, taken together with data from the literature suggest that in the case of 3T3 (A31) fibroblasts and mice splenocytes the proliferative effects of the compounds are not dependent on metabolism through purine salvage pathways. In the case of melanocytes, however, the compounds are likely to become part of the purine nucleoside pool. The demonstration that adducts produced by free radical attack on ribonucleosides and RNA are able to induce cell proliferation opens new perspectives for the understanding of free radical mediated carcinogenesis.
 
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Publishing Date
2018-10-18
 
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