Michel Goldberg

Ser Asp Lys-Ac, a strong inhibitor of liver cell proliferation

Increases in liver cell proliferation have been investigated mostly by partial hepatectomy. It has been found that this increase is controlled by several factors [1]. One of the first factors described is hepatopoietin, a heatand acid-stable glycoprotein with a MW of approx. 30000 Da [2]. Hepatopoietin is organspecific, but species-unspecific. Regarding these qualities, it is distinctly different from the HGF described in 1987 [3]. Formerly the HGF had also been named Hepatopoietin A. This name, however, has now been abandoned [4]. In the course of our investigations of hepatopoietin [5-8], we discovered that, in vivo as well as in vitro, the tripeptide Ser Asp Lys-Ac (SDK-Ac) inhibits in minimal amounts the proliferation of hepatocytes very intensively [9]. Also, the tetrapeptide SDKP-Ac inhibits proliferation of remnant liver cells after partial hepatectomy [10], however, its effect is much less than that of the tripeptide. After a partial hepatectomy, the increased proliferation of the remnant liver cells stops, if the original number of cells is approximately reached again. Also, this inhibition of further proliferation is caused by several factors [1]. However, to date there is no evidence that one of these factors really terminates proliferation of hepatocytes after a partial hepatectomy. In the following, we discuss the very strong inhibition of liver cell proliferation by the tripeptide SDW-Ac. SDK-Ac corresponds to the N-terminal fragment of thymosine ~10, a peptide accomPanying thymosine [34 in mammalian tissues [11]. This peptide inhibits the formation of rosettes between sheep erythrocytes and human T-lymphocytes [12]; other biological activities have not been observed. It has been synthesized by applying a semiautomatic peptide synthesizer [13]. Its inhibitory activity of liver cell proliferation has been proved in the following two models [9]. 1) Six groups of Wistar rats (100 + 5 g) from the Max-Planck-Institut ftir Biochemie (Martinsried) were subjected to a 2/3 partial hepatectomy. After the operation, the rats received an i.p. injection of 1 ~tg SDK-Ac dissolved in 1 ml saline. The first group received the injection immediately after the operation; the four other groups 1, 3, 6, and 10 h after the operation. The sixth group served as the control. The results are presented in Table 1. In particular the group which received the tripeptide 10 h after the operation exhibited a 52 + 5 % decrease in the proliferation activity of the remnant liver cells compared with the control, as measured via addition of 3Hthymidine [5]. 2) In a previous study we reported that the ascites of Yoshida rat liver tumor cells (AH130) contains hepatopoietin or a hepatopoietin-like substance [14]. As a result, the tumor cells apparently maintain their tumorgenicity autocrinically. We therefore hypothesized that the tripeptide could also inhibit the proliferation of these tumor cells in the infected rats. In fact, the daily injection of 1 ~tg tripeptide/rat from the 7th to the 10th day after the infection was followed by a decrease in the mean amount of ascites as well as in the mean number of Yoshida cells in the ascites to less than 20 % (Table 2). Former studies have shown that the plasma of patients with a primary liver tumor and other liver diseases contains