This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Garcea, R. Articles by Feo, F. Search for Related Content PubMed PubMed Citation Articles by Garcea, R. Articles by Feo, F.

Inhibition of Promotion and Persistent Nodule Growth by S-Adenosyl-L-methionine in Rat Liver Carcinogenesis: Role of Remodeling and Apoptosis¹

Istituto di Patologia generale dell'Università di Sassari, Via P. Manzella 4, Sassari, 07100 Italy

The resistant hepatocyte model (initiation/selection) and the triphasic model (initiation/selection followed by phenobarbital, for a maximum of 16 weeks) were compared for their ability to generate enzyme-altered foci (EAF) and nodules in the liver of Wistar rats initiated by diethylnitrosamine. The effects of S-adenosyl-L-methionine (SAM) on the development of preneoplastic tissue was tested in these experimental models. In the absence of phenobarbital (PB), EAF and early nodules (EN) went through a phase of rapid growth, between 4 and 9 weeks after initiation, to a phase in which progressive decrease in number and size occurred. By the 26th week only a few remodeling EAF and nodules were found. In PB-treated rats a rapid increase in the percentage of liver occupied by EAF and EN, up to the 9th week after initiation, was followed by a period of slow growth (from the 9th to the 20th week) and then, after PB withdrawal (20th week), by a drop in the number and size of EAF and EN. However, at the 26th week actively growing nodules with a low tendency to spontaneous remodeling (persistent nodules) developed. EAF and EN showed a high DNA synthesis 5 weeks after initiation. Thereafter, progressive decline in DNA synthesis, coupled with remodeling and decrease in number of biochemical markers, was seen both in the absence and, even though to a lesser extent, in the presence of PB, indicating that preneoplastic lesions became increasingly insensitive to PB. Relatively few apoptotic bodies could be observed in EAF and EN during PB treatment. After PB withdrawal, decrease in growth potential was coupled with increase in apoptotic bodies. In contrast, in persistent nodules relatively high apoptosis occurred which partially counterbalanced high DNA synthesis. Administration of SAM for a maximum of 16 weeks, starting at the 4th week after initiation, caused a great decrease in number and size of EAF and EN, associated with inhibition of DNA synthesis, high cell death by apoptosis, high remodeling, and loss of biochemical markers, in preneoplastic lesions of both PB-treated and untreated rats. A 1–8-week SAM treatment, started after the development of persistent nodules, caused a great regression of nodular lesions, coupled with a sharp fall in DNA synthesis and increase in apoptosis. It is suggested that inhibition by SAM of the development of preneoplastic tissue is linked to a shift of the equilibrium between cell production and cell death in favor of cell death. This phenomenon and differentiation of putative preneoplastic cells to normal appearing hepatocytes could accelerate disappearance of preneoplastic lesions and makes phenotype of persistent nodules highly unstable.

¹ This research was supported by grants from the Consiglio Nazionale delle Ricerche, Progetto Finalizzato Oncologia (Grant 87.01281.44), Associazione Italiana Ricerca sul Cancro, and Ministero Pubblica Istruzione (Program 60%).

² To whom requests for reprints should be addressed.

Received 8/15/88. Revised 12/ 7/88. Accepted 12/14/88.

This article has been cited by other articles:

				E. M. de Almeida Vasconcelos Fonseca, C. E. A. Chagas, R. P. Mazzantini, R. Heidor, T. P. Ong, and F. S. Moreno All-trans and 9-cis retinoic acids, retinol and {beta}-carotene chemopreventive activities during the initial phases of hepatocarcinogenesis involve distinct actions on glutathione S-transferase positive preneoplastic lesions remodeling and DNA damage Carcinogenesis, November 1, 2005; 26(11): 1940 - 1946. [Abstract] [Full Text] [PDF]

				M. M. Simile, G. Pagnan, F. Pastorino, C. Brignole, M. R. De Miglio, M. R. Muroni, G. Asara, M. Frau, M. A. Seddaiu, D. F. Calvisi, et al. Chemopreventive N-(4-hydroxyphenyl)retinamide (fenretinide) targets deregulated NF-{kappa}B and Mat1A genes in the early stages of rat liver carcinogenesis Carcinogenesis, February 1, 2005; 26(2): 417 - 427. [Abstract] [Full Text] [PDF]

				M. M. Simile, M. R. De Miglio, M. R. Muroni, M. Frau, G. Asara, S. Serra, M. D. Muntoni, M. A. Seddaiu, L. Daino, F. Feo, et al. Down-regulation of c-myc and Cyclin D1 genes by antisense oligodeoxy nucleotides inhibits the expression of E2F1 and in vitro growth of HepG2 and Morris 5123 liver cancer cells Carcinogenesis, March 1, 2004; 25(3): 333 - 341. [Abstract] [Full Text] [PDF]

				M L. Martinez-Chantar, E. R Garcia-Trevijano, M U. Latasa, I. Perez-Mato, M. M Sanchez del Pino, F. J Corrales, M. A Avila, and J. M Mato Importance of a deficiency in S-adenosyl-L-methionine synthesis in the pathogenesis of liver injury Am. J. Clinical Nutrition, November 1, 2002; 76 (5): 1177S - 1182S. [Abstract] [Full Text] [PDF]

				J. M. MATO, F. J. CORRALES, S. C. LU, and M. A. AVILA S-Adenosylmethionine: a control switch that regulates liver function FASEB J, January 1, 2002; 16(1): 15 - 26. [Abstract] [Full Text] [PDF]

				M. M. Simile, M. R. De Miglio, D. Calvisi, M. R. Muroni, M. Frau, G. Asara, L. Daino, L. Deiana, R. M. Pascale, and F. Feo Long-term dehydroepiandrosterone and 16{{alpha}}-fluoro-5-androsten-17-one administration enhances DNA synthesis and induces expression of c-fos and c-Ha-ras in a selected population of preneoplastic lesions in liver of diethylnitrosamine-initiated rats Carcinogenesis, February 1, 2001; 22(2): 301 - 308. [Abstract] [Full Text] [PDF]

				E. R. GARCÍA-TREVIJANO, M. U. LATASA, M. V. CARRETERO, C. BERASAIN, J. M. MATO, and M. A. AVILA S-Adenosylmethionine regulates MAT1A and MAT2A gene expression in cultured rat hepatocytes: a new role for S-adenosylmethionine in the maintenance of the differentiated status of the liver FASEB J, December 1, 2000; 14(15): 2511 - 2518. [Abstract] [Full Text]

				G. M. Ledda-Columbano, A. Perra, R. Loi, H. Shinozuka, and A. Columbano Cell Proliferation Induced by Triiodothyronine in Rat Liver Is Associated with Nodule Regression and Reduction of Hepatocellular Carcinomas Cancer Res., February 1, 2000; 60(3): 603 - 609. [Abstract] [Full Text]

				G. A. Wood, D. S.R. Sarma, and M. C. Archer Resistance to the promotion of glutathione S-transferase 7-7-positive liver lesions in Copenhagen rats Carcinogenesis, July 1, 1999; 20(7): 1169 - 1175. [Abstract] [Full Text] [PDF]