Oral polyprenoic acid prevents second primary hepatomas after surgical resection of the original tumor or the percutaneous injection of ethanol.

Background: Experimental studies indicate the chemopreventive properties of green tea extract (GTE) on colorectal cancer. Epidemiologically, green tea consumption of >10 cups daily reduced colorectal cancer risk in Japanese. Because colorectal adenomas are the precursors to most sporadic colorectal cancers, we conducted a randomized trial to determine the preventive effect of GTE supplements on metachronous colorectal adenomas by raising green tea consumption in the target population from an average of 6 cups (1.5 g GTE) daily to z10 cups equivalent (2.5 g GTE) by supplemental GTE tablets. Methods: We recruited 136 patients, removed their colorectal adenomas by endoscopic polypectomy, and 1 year later confirmed the clean colon (i.e., no polyp) at the second colonoscopy. The patients were then randomized into two groups while maintaining their

The inhibitory effect of (—)‐epigallocatechin gallate (EGCG), a main constituent of Japanese green tea, on spontaneous hepatoma in C3H/HeNCrj mice was investigated. A total of 72 mice were divided into three groups; the control group without EGCG, and two experimental groups receiving 0.05% (w/w) or 0.1% EGCG in drinking water. EGCG reduced the incidence of hepatoma‐bearing mice from 83.3% (control) to 56.0% (0.05% EGCG) and 52.2% (0.1% EGCG), and also reduced the average number of hepatomas per mouse from 1.83 (control) to 0.72 (0.05% EGCG) and 0.91 (0.1% EGCG) at week 65. Ridit analysis of the distribution of the number of hepatomas in each group revealed that EGCG significantly increased the rate of mice without hepatoma in the two EGCG groups as compared to the control. EGCG did not affect body weight gain, food consumption or any serum biochemical parameter. EGCG inhibited the growth and secretion of α‐fetoprotein by human hepatoma‐derived PLC/PRF/5 cells without decreasing their viability. These results indicate that EGCG may be a practical, nontoxic preventive agent against human hepatoma.

Human liver contains three isoforms (DD1, DD2 and DD4) of dihydrodiol dehydrogenase with 20alpha- or 3alpha-hydroxysteroid dehydrogenase activity; the dehydrogenases belong to the aldo-oxo reductase (AKR) superfamily. cDNA species encoding DD1 and DD4 have been identified. However, four cDNA species with more than 99% sequence identity have been cloned and are compatible with a partial amino acid sequence of DD2. In this study we have isolated a cDNA clone encoding DD2, which was confirmed by comparison of the properties of the recombinant and hepatic enzymes. This cDNA showed differences of one, two, four and five nucleotides from the previously reported four cDNA species for a dehydrogenase of human colon carcinoma HT29 cells, human prostatic 3alpha-hydroxysteroid dehydrogenase, a human liver 3alpha-hydroxysteroid dehydrogenase-like protein and chlordecone reductase-like protein respectively. Expression of mRNA species for the five similar cDNA species in 20 liver samples and 10 other different tissue samples was examined by reverse transcriptase-mediated PCR with specific primers followed by diagnostic restriction with endonucleases. All the tissues expressed only one mRNA species corresponding to the newly identified cDNA for DD2: mRNA transcripts corresponding to the other cDNA species were not detected. We suggest that the new cDNA is derived from the principal gene for DD2, which has been named AKR1C2 by a new nomenclature for the AKR superfamily. It is possible that some of the other cDNA species previously reported are rare allelic variants of this gene.

Acyclic retinoid (polyprenoic acid) has a slightly different structure from retinoic acid. However, acyclic retinoid acts similarly to retinoic acid, because both bind to cellular retinoic acid‐binding protein and cellular retinoid‐binding protein, F‐type, with the same strong binding affinity. We studied the effects of acyclic retinoid, the 7‐hydroxy derivative of acyclic retinoid (7OH‐acyclic retinoid) and retinoic acid on a human hepatoma‐derived cell line PLC/PRF/5 (Alexander cells). Acyclic retinoid inhibited cell growth with an ID50 value of 14 μM, and reduced cell viability with an LD50 value of 86 μM. The ratios of LD50 value to ID50 value were 6.1 for acyclic retinoid, 2.4 for 7OH‐acyclic retinoid and 1.4 for all‐trans‐retinoic acid. Taking this ratio as a parameter of relative cytotoxicity, we concluded that acyclic retinoid is the least toxic compound. Growth inhibition of cells by acyclic retinoid was associated with the incorporation of 3H‐thymidine in the logarithmic phase. Acyclic retinoid reduced secretion of α‐fetoprotein (AFP) and reciprocally increased secretion of albumin in the culture media, suggesting that acyclic retinoid influences gene expression of these proteins. Thus, acyclic retinoid, one of the less toxic retinoids, inhibits cell growth of human cancer cell line PLC/PRF/5 and appears to alter gene expression of AFP and albumin toward a “normal’direction.

These results may help optimizing surveillance strategies for metachronous colon tumors and raising the economic benefit of colonoscopy.

A study was conducted to investigate the inhibitory effects of acidic retinoid (trimethylmethoxyphenyl analog of retinoic acid ethylester or TMMP) and polyprenoic acid (3,7,11,15-tetramethyl-2,4,6,10,14-hexadecapentaenoic acid or E-5166) on the development of hepatoma induced by 3'-methyl-N, N-dimethyl-4-aminoazobenzene (3'-MeDAB) in rats. Morphometric analysis of liver specimens was employed to evaluate the antitumor effects of the compounds in detail, and revealed significant decreases in the number and area of tumors in the TMMP- and E-5166-treated groups. As for adverse effects, retarded growth and marked hypertriglyceridemia were observed only in TMMP-treated rats. During the hepatocarcinogenesis, cellular retinoid-binding protein, F-type or CRBP(F) and cellular retinoic acid-binding protein or CRABP newly appeared in the tumor tissue, particularly in hyperplastic nodules which are the precancerous state of hepatoma. These results suggest that the polyprenoic acid is a good candidate for clinical chemoprevention of hepatoma, targetting its precancerous stage when intracellular receptors for acidic retinoid have emerged.

We examined the efficiency and intracellular fate of oligodeoxy-nucleotides (ODN) in the central nervous system (CNS) after delivery with a hemagglutinating virus of Japan (HVJ)-liposome vector in vivo and in vitro. In primary cultured granular cells of the rat cerebellum, application of fluorescein isothiocyanate (FITC)-labeled ODN complexed with HVJ-liposomes in vitro resulted in strong fluorescence localized in nuclei that persisted for > or = 2 wk, in contrast to 3 days with ODN alone. In vivo ODN transfer was attempted by different approaches: infusions into the paraventricular nuclei of the hypothalamus and the lateral cerebroventricle. Injection of FITC-labeled ODN into the hypothalamus by the HVJ-liposome method produced a higher concentration and more persistent fluorescence than did injection of ODN alone. Administration of ODN into the lateral cerebroventricle with HVJ-liposomes yielded more conspicuous and prolonged fluorescence in the periventricular layer, predominantly in cell nuclei. Furthermore, the distribution of fluorescent cells was broader with the HVJ-liposome method. These results indicate that the HVJ-liposome method prolongs the half-life of ODN and concentrates them in cell nuclei. Thus it is an efficient method for ODN transfer and holds promise as a gene delivery method in the CNS.