Prevention of Second Primary Tumors by an Acyclic Retinoid in Patients with Hepatocellular Carcinoma

Abstract

Oral administration with acyclic retinoid, a synthetic vitamin A analog, for a limited period of 12 months (48 weeks) prevented the development of second primary hepatocellular carcinoma (HCC) and also improved the survival of patients who underwent curative treatments of the initial tumor. Following that randomized controlled study reported in 1996 and 1999, we have continued to follow up the patients by medical imaging and blood chemical analyses, and found that the preventive effect of acyclic retinoid lasted up to 199 weeks after randomization (or 151 weeks after completion of retinoid administration). The retinoid’s effect was not mediated by reduction in hepatic necro-inflammation since no significant decrease in serum aminotransferase activity was seen in the retinoid group. Such observation seems quite distinct from the cancer-preventive mechanism of interferon, a potent immunopreventive agent for HCC. We have also shown here the reduction by the retinoid in serum levels of lectin-reactive α-fetoprotein (AFP-L3) and protein induced by vitamin K absence or antagonist-II (PIVKA-II), both of which indicate the presence of latent HCC cells. These results suggest that acyclic retinoid may delete such malignant clones before they expand to clinically detectable tumors and thereby inhibited second primary HCC. Once such latent clones are eradicated, it may well take at least several years for the next cancer clone to arise clinically. This may possibly explain a reason for the long-term effect of the retinoid even after the limited period of administration.

Asian Pacific Association for the Study of the Liver consensus recommendations on hepatocellular carcinoma

“…In 1966, Muto et al [407] reported that administration of polyprenoic acid, an acyclic retinoid, reduced recurrence of HCC in an RCT. Updated, long-term data were subsequently published [408], postulating that the eradication of premalignant or latent malignant clones is the mechanism of action. The effect is, however, yet to be confirmed in a large-scale RCT.…”

Anti-tumor effects of cimetidine on hepatocellular carcinomas in diethylnitrosamine-treated rats

“…YAC-1 cells, kindly provided by the Cell Resource Center for Biochemical Research, Institute of Development, Aging and Cancer, Tohoku University, were used as target cells. YAC-1 cells (2x10 6 ) were labeled with 3.7 MBq of Na 2 51 CrO 5 (MP Biomedicals, Irvine, CA) at 37˚C for 1 h in a shaking water bath. Labeled target cells were washed with PBS and adjusted to 1x10 5 /ml in a complete medium, then seeded at a concentration of 1x10 4 cells/well in micro-well plates.…”

“…Most patients with HCC also suffer from liver cirrhosis, which is the major risk factor for HCC, mainly caused by infection with either the hepatitis B virus (HBV) or the hepatitis C virus (HCV) (2). Ursodeoxycholic acid (3) and glycyrrhizin (4) have been reported to be effective in preventing liver carcinogenesis, while recently the preventive effects of vitamin K2 (5) and acyclic retinoid (6) towards recurrence in patients with HCC have been reported. Nevertheless, HCCs frequently occur in patients with HCV cirrhosis at an annual rate of ~8% in Japan, with recurrence within 5 years seen in 70% of cases (7).…”

CYP4A11 is repressed by retinoic acid in human liver cells

“…In the human hepatoma cell line HepG2, retinoic acid induces growth arrest and differentiation [20]. The survival rate of patients with hepatocarcinoma was significantly prolonged by a 12-months postoperative treatment with retinoids as adjuvant treatment [21].…”