Incidence Of Preneoplastic Lesions Research Articles

Role of proton pump inhibitor on esophageal carcinogenesis and pancreatic acinar cell metaplasia development: an experimental in vivo study.

Chronic gastro-duodenal reflux in the esophagus is a major risk for intestinal metaplasia and Barrett’s adenocarcinoma. A role for chronic use of proton pump inhibitor (PPI) in the increased incidence of esophageal adenocarcinoma in Western countries has been previously suggested. The aim of this work was to study the effect of chronic administration of omeprazole (a proton pump inhibitor) per os in a model of reflux induced esophageal carcinogenesis. One week after esophago-gastro-jejunostomy, 115 Sprague-Dawley rats were randomized to receive 10 mg/Kg per day of omeprazole or placebo, 5 days per week. The esophago-gastric specimens were collected 28±2 weeks after randomization and analyzed in a blinded fashion. Mortality and esophageal metaplasia rates did not differ between the two groups (p = 0.99 for mortality, p = 0.36 for intestinal metaplasia and p = 0.66 for multi-layered epithelium). Gastric pancreatic acinar cell metaplasia (PACM) was more frequently observed in PPI-treated rats (p = 0.003). Severe ulcer lesions significantly prevailed in the placebo group (p = 0.03). Locally invasive esophageal epithelial neoplasia were observed in 23/39 PPI-treated versus 14/42 placebo-animals (p = 0.03). In conclusion, chronic omeprazole treatment improved the healing of esophageal ulcerative lesions. Locally invasive neoplastic lesions and PACM prevailed among PPI-treated animals. However, neither an effect on the overall mortality nor on the incidence of pre-neoplastic lesions was observed in this work.

Multipotential carcinogenicity of the fried food mutagen 2-amino-3-methylimidazo[4,5-f]quinoline in rats.

The carcinogenicity of the mutagenic compound 2-amino-3-methylimidazo[4,5-f]-quinoline (IQ), identified in fried and broiled foods, was investigated in female Sprague-Dawley rats. Administration by gavage of IQ (0.4 mmol/kg body weight) on a weekly regimen for 31 weeks starting with 6-week-old animals induced a high yield of multiple mammary gland carcinomas in a limited bioassay lasting a total of 52 weeks. In a positive control group receiving 4-aminobiphenyl (4-AB), the expected carcinomas in the mammary gland developed. IQ, but not 4-AB, also yielded neoplasms in the ear duct and to a lesser degree, in the liver, pancreas, and urinary bladder. In addition, with IQ, a high incidence of preneoplastic lesions in the pancreas was observed. Vehicle and untreated controls did not have any lesions. These findings demonstrate that IQ is a powerful multipotent carcinogen in the rat.

Tea Preparations Protect Against DMBA-Induced Oral Carcinogenesis in Hamsters

The preventive effects of green tea, tea pigments, and mixed tea (a composite of whole water extract of green tea, tea polyphenols, and tea pigments) on 7,12-dimethylbenz[a]anthracene (DMBA)-induced oral carcinogenesis in golden Syrian hamsters were studied. The right buccal pouches of animals were topically treated with 0.5% DMBA three times per week for 15 weeks. Animals were killed separately after 6, 10, and 15 weeks of DMBA treatment. Oral tumors were counted and measured, and mean tumor burden was calculated. The incidence of preneoplastic lesions and micronucleated cells, the number and volume of silver-stained nucleolar organizer regions (AgNOR), the labeling index of proliferating cell nuclear antigen, and the level of epidermal growth factor receptor expression were studied. The results showed that oral administration of 1.5% green tea, 0.1% tea pigments, and 0.5% mixed tea as the sole source of drinking water for two weeks before initiation of the DMBA treatment and until the end of the experiment significantly reduced the mean tumor burden and the incidence of dysplasia and oral carcinoma (p < 0.01). The frequency of micronucleated cells, the number of AgNOR, the total volume of AgNORs, the labeling index of proliferating cell nuclear antigen, and the level of epidermal growth factor receptor expression in the oral mucosal cells were also significantly reduced (p < 0.01). These results clearly indicated that tea preparations could effectively inhibit DMBA-induced oral carcinogenesis in hamsters. Protection from DNA damage and suppression of cell proliferation could be important mechanisms of the anticarcinogenic effects of the tea preparations.

Medium-term bioassay for the hepatocarcinogenicity of hexachlorobenzene.

Hexachlorobenzene (HCB) is an important environmental contaminant derived mainly from industrial and agricultural sources. It is carcinogenic in mice, rats and hamsters. It has now been studied in a medium-term bioassay for carcinogenicity based on the induction of preneoplastic lesions in the liver. We report here that the bioassay can rapidly detect carcinogenic doses of HCB and that there is a clear dose-response relationship. At the lowest dose of HCB administered, the incidence of preneoplastic lesions in the liver was no different from that in controls.

Inhibition of oral carcinogenesis by the arotinoid mofarotene (Ro 40-8757) in male F344 rats.

The chemopreventive effect of dietary administration of a new arotinoid, mofarotene (Ro 40-8757), which contains a morpholine structure in the polar end group, during the initiation phase of 4-nitroquinoline 1-oxide (4-NQO)-induced oral carcinogenesis was investigated in male F344 rats. Also, modulatory effects of this compound on polyamine levels (biomarkers of proliferation), the 5-bromodeoxyuridine-labeling index and the number of silver stained nucleolar organizer region proteins (AgNORs)/nucleus were assessed in the target epithelium. Rats were fed Ro 40-8757 at concentrations of 250 and 500 p.p.m. for 10 weeks. One week after the commencement of the diets, 4-NQO (20 p.p.m.) was administered in the drinking water for 8 weeks. Feeding of Ro 40-8757 at both doses caused a 78% reduction in the incidence of tongue neoplasms (squamous cell papilloma and carcinoma) by 32 weeks when compared with rats treated with 4-NQO alone (P < 0.05). Similarly, in rats treated with 4-NQO together with Ro 40-8757 the incidence of preneoplastic lesions (hyperplasia and dysplasia) was significantly less than the 4-NQO alone group (P < 0.05). Expression of three biomarkers was also decreased significantly by dietary treatment with Ro 40-8757. Thus a new arotinoid, Ro 40-8757, inhibited the oral carcinogenesis induced by 4-NQO when it was administered concurrently with the carcinogen. These results might suggest the possible application of Ro 40-8757 for cancer chemoprevention in the oral cavity, in addition to the breast.

Effects of weak alternating magnetic fields on nocturnal melatonin production and mammary carcinogenesis in rats.

Since extremely low frequency (i.e., 50- or 60-Hz) magnetic fields (MFs) from overhead power lines and other electromagnetic sources are ubiquitous in modern societies, the possible carcinogenic effect of such fields recently suggested by epidemiological studies has engendered much concern. However, in view of various unknown and uncontrolled variables which may bias epidemiological studies on MF interactions, a causal relationship between MFs and tumorigenesis can only be determined precisely in animal experiments. The goal of the study reported here was to determine if low frequency MFs at the low flux densities which are relevant for human populations induce tumor-promoting or copromoting effects in a model of breast cancer. Furthermore, since reduction in pineal production of melatonin has been implicated as a cause of tumor promotion by electromagnetic fields, determinations of nocturnal melatonin peak levels in serum were performed during MF exposure. Mammary tumors were induced by intragastric administration of 20 mg (5 mg/week) 7,12-dimethylbenz(a)anthracene (DMBA) in female Sprague-Dawley rats. Groups of 36 rats were either sham-exposed or exposed for 91 days at a 50-Hz gradient MF of 0.3-1 microT, which is a relevant range for elevated domestic MF exposure as arising from neighboring power lines. Nocturnal melatonin levels were significantly reduced by exposure to this weak alternating MF. However, histopathological evaluation of mammary lesions did not disclose any significant difference between MF- and sham-exposed animals. Incidence of mammary tumors was 61% in controls versus 67% in MF-exposed rats. The predominant tumor type was the invasive adenocarcinoma, which was found in 21 rats of both groups. Examination of tumor size did not indicate significant differences in tumor burden between both groups. Furthermore, the incidence of preneoplastic lesions was not altered by MF exposure. Thus, the data of this study indicate that alternating MF do not exert significant tumor promoting or copromoting effects at environmentally relevant flux densities in the rat mammary cancer system.

Inhibitory effects of the natural products indole-3-carbinol and sinigrin during initiation and promotion phases of 4-nitroquinoline 1-oxide-induced rat tongue carcinogenesis.

The modifying effects of indole‐3‐carbinol (I3C) and sinigrin (SIN) on the initiation and post‐initiation phases of tongue carcinogenesis induced by 4‐nitroquinoline 1‐oxide (4‐NQO) were investigated in male ACI/N rats. Rats were divided into eight groups: group 1 was given 4‐NQO (10 ppm) in the drinking watar for 12 weeks, starting at 7 weeks of age; groups 2 and 3 were given 4‐NQO and fed the diets containing I3C (1,000 ppm) and SIN (1,200 ppm) for 14 weeks, respectively, starting at 6 weeks of age; groups 4 and 5 were given 4‐NQO and then they were fed I3C and SIN containing diets for 23 weeks, respectively, starting one week after 4‐NQO exposure; groups 6 and 7 were given I3C and SIN alone, respectively, during the experiment; group 8 served as an untreated control. At the termination of the experiment (week 37), the incidence of tongue neoplasms (squamous cell papilloma and carcinoma) in group 2 (1/15,7%), group 3 (1/15, 7%), group 4 (3/15, 20%) or group 5 (2/15, 13%) was significantly smaller than that in group 1 (12/17,71%) (P= 0.0003, P=0.005 or P=0.002). No tongue carcinomas developed in rats of groups 2, 3, and 5. Similarly, the incidence of preneoplastic lesions (hyperplasia and dysplasia) of the tougue in group 2 (11/15, 73%), group 3 (10/15, 67%), group 4 (11/15, 73%) or group 5 (10/15, 67%) was significantly lower than that in group 1 (17/17, 100%) (P=0.04 or P=0.02). There were no tongue neoplasms in rats of groups 6, 7, and 8. Administration of I3C and SIN also caused significant decreases in the number and area of silver‐stained nucleolar organizer regions protein (AgNORs), a new cell proliferation index, of tongue squamous epithelium. Thus, I3C and SIN inhibited rat tongue carcinogenesis in both the initiation and post‐initiation phases, when administered in these respective phases together with, or following treatment with, 4‐NQO.

Effect of castration and testosterone replacement on pancreatic carcinogenesis in Syrian hamsters.

Hormonal manipulation has been proposed as a possible new approach to the treatment of pancreatic cancer. We studied the effect of orchiectomy and testosterone replacement on early stage pancreatic carcinogenesis induced by diisopropanolnitrosamine (DIPIN) in Syrian golden hamsters. Eighty-five hamsters (mean body weight, 100 g) were divided into the following treatment groups: 1) DIPN (n = 20); 2) DIPN plus orchiectomy (n = 17); 3) DIPN plus orchiectomy plus testosterone (n = 18); 4) orchiectomy (n = 10); 5) sham operation (n = 10); 6) DIPN plus testosterone (n = 10). DIPN (125 mg/kg/body wt.) was administered s.c. every week and testosterone propionate (10 micrograms/g) was administered s.c. every 3 weeks. Bilateral orchiectomy was performed 1 week after the first injection of DIPN. All animals were killed 15 weeks after starting the treatment. The whole pancreas was removed, weighted and histologically examined. There was no difference in the incidence of preneoplastic lesions among groups 1, 2, 3 and 6 (respectively 87%, 83%, 77% and 80%); 3 animals in each group developed invasive carcinoma. In control groups (4 and 5), no precancerous lesions were recorded. In this experimental model, orchiectomy and testosterone replacement had no effect on nitrosamine-induced pancreatic carcinogenesis.

Modulation by indomethacin of diethylnitrosamine-induced early changes in c-myc and c-ras expression and late incidence of preneoplastic lesions in rat liver

We measured the levels of c-myc and c-ras expression before and after diethylnitrosamine (DENA) treatment in the liver of rats previously submitted to partial hepatectomy (PH), in the presence or absence of indomethacin (IMC), given at a dose that reduced by 75% the incidence of preneoplastic foci of altered hepatocytes scored 8 weeks after application of the carcinogen. The time-course evolution of c-myc response to PH was similar in IMC-treated and untreated rats (with a peak at 3-8 h at least as high in IMC-treated animals as in the hepatectomized reference group), whereas the overall c-ras response was significantly reduced by the IMC treatment, resulting in much lower c-ras expression at 18-24 h posthepatectomy. Treatment with DENA 24 h after PH did not significantly modify c-ras expression compared to partially hepatectomized controls. In contrast, DENA treatment resulted in a marked transient increase in c-myc expression that was at least as pronounced, if not the same, in the IMC-treated animals. These results leave open the possibility that increased c-myc expression under DENA influence might play a role in foci induction but exclude that this might be sufficient. They are consistent with a role for c-ras expression in determining the susceptibility of hepatocytes towards the carcinogenic action of DENA.

Chemopreventive trials with vitamin A and β-carotene: Some unresolved issues

The administration of β-carotene (180 mg/week) plus vitamin A (100,000 IU/week) or vitamin A alone (200,000 IU/week) to chewers of betel quids in Kerala, India led to a reduction in the frequency of micronucleated buccal mucosal cells, a remission of oral leukoplakia, and an inhibition of the development of new leukoplakias. The advantages of this test system include a profound knowledge of exposure levels to tobacco-specific nitrosamines, areca nut-specific nitrosamines, and reactive oxygen species (ROS)-generating polyphenolics; the ease of quantitating micronuclei in exfoliated buccal mucosal cells and oral leukoplakia by noninvasive procedures; and solid information on the incidence of preneoplastic lesions and carcinomas. Some practical issues such as the level of nontoxic β-carotene which could maintain the reduced frequency of micronucleated cells and the remission of oral leukoplakias for prolonged periods of time, the logistics of distributing β-carotene to the many millions of smokeless tobacco users who are at elevated risk for oral cancer, and the possibility of using β-carotene in the form of sweet potatoes or red palm oil, which could contain an economical source of β-carotene for developing countries in which most of the tobacco chewers live, still remain unresolved.