Time-dependent Modulation of Liver Lesion Development in Opisthorchis-infected Syrian Hamster by an Antihelminthic Drug, Praziquantel

In the North-east of Thailand, repeated antihelminthic therapy has been introduced for control of the opisthorchiasis known to be a major risk factor for cholangiocellular carcinomas. What influence this may have on tumorigenesis, however, remains unclear. The effects of administration of praziquantel, an antihelminthic drug, at different time points subsequent to infection with Opisthorchis viverrini (OV) on 2,2'-dihydroxy-di- n -propylnitrosamine (DHPN)-initiated lesion development in the liver of female Syrian hamsters were therefore investigated. Praziquantel (250 mg/kg body weight, i.p.) was given 4, 12 or 20 weeks after infection of DHPN-treated animals (two 1000 mg/kg i.p. injections at weeks 0 and 2) with 60 OV metacercariae (at week 4). Survivors at week 38 were killed and examined. It was found that whereas praziquantel administration at the earlier two time points was effective at reducing hepatocellular nodule development, the results for cholangiocellular lesions were less pronounced, significant reduction only being evident in hamsters treated 4 weeks after parasite infestation. The findings thus indicate that enhancement of DHPN-initiated bile duct carcinogenesis by opisthorchiasis is both rapid and to a large degree irreversible. Hepatocellular lesion development in this model, on the other hand, appears to correlate more closely with the duration of parasite-associated proliferative stimulus.     

Lack of modulation effects of praziquantel on DMN-induced lesion development in the Syrian hamster liver.

The effects of repeated praziquantel administration subsequent to dimethylnitrosamine (DMN) treatment of Syrian hamsters were investigated. The antihelminthic drug was given (200 mg/kg body wt. as a suspension in corn oil, by i.g. intubation) 11 times at 2 week intervals starting at week 4 after initial 20 mg/kg DMN i.p. injections at weeks 0 and 2. Sacrifice at week 28 revealed no differences in either hepatocellular or cholangiocellular lesion development between carcinogen-initiated groups with or without antihelminthic treatment. No lesions were observed in the praziquantel alone or untreated groups. The results thus indicate no promotion potential for praziquantel on nitrosamine-induced lesions in the hamster liver.     

Sex-dependent, tissue-specific opposing effects of dehydroepiandrosterone on initiation and modulation stages of liver and lung carcinogenesis induced by dihydroxy-di-n-propylnitrosamine in F344 rats

Administration of the hormone dehydroepiandrosterone(DHEA) (0.6%in the diet) during or subsequent to injections of the carcinogendihydroxy-di-n-propylnitrosamine(DHPN) (2 x 1000 mg/kg bodyweight, i.p.) brought about alteration in the yield of preneoplasticlesions in liver and lung of both male and female F344 rats.Concomitant treatment with DHEA was associated with decreasein the numbers and size of glutathione S-transferase (GST-P)-positivehepatocellular foci while effecting a significant increase indevelopment of lung lesions, especially in females. Long-termtreatment with the hormone subsequent to carcinogen exposurebrought about a reduction in numbers of liver foci in both sexesbut in males was also associated with the development of largeGST-P-negative foci and nodules of amphophilic/tigroid cellcharacter. DHEA itself did not induce any focal lesions in thelungs or livers of either sex. Thus the hormone increased sensitivityto ‘initiation’ in the lung while decreasing thatin the liver and exerted a sex-dependent pronounced modulationof the phenotype of a proportion of hepatocellular lesions.     

Repeated exposure to Opisthorchis viverrini and treatment with the antihelminthic Praziquantel lacks carcinogenic potential.

The effects of repeated Praziquantel administration, subsequent to infection and reinfection with Opisthorchis viverrini (OV), on lesion development in the Syrian hamster liver were investigated. Five applications of the antihelminthic drug were made (300 mg/kg body wt, i.g.), each time approximately 5 weeks after dosing with 60-80 OV metacercariae at weeks 0, 8, 16, 24 and 32. The animals were then maintained until week 40 when they were killed; histopathological investigation revealed no significant development of either hepatocellular of cholangiocellular preneoplastic/neoplastic lesions. The results indicate that repeated exposure to Praziquantel at levels sufficient for successful removal of parasite infestation does not itself carry carcinogenic risk.     

Inhibitory effect of butylated hydroxyanisole administration on pancreatic carcinogenesis in Syrian hamsters initiated with N-nitrosobis(2-oxopropyl)amine

The modifying potential of butylated bydroxyanisole (BHA) administrationon pancreatic carcinogenesis was evaluated in 70 female Syriangolden hamsters. Groups of animals received saline, 70 mg/kgbody weight of N-nitrosobis(2-oxopropyl)-amine (BOP) or 70 mg/kgplus 20 mg/kg body weight of BOP followed by basal diet or dietcontaining 2% BHA from week 3. Although the body weights ofhamsters receiving the 2% BHA supplement decreased, caloricrestriction was not observed. All hamsters were killed at week18 and histo-pathologically examined for lesion development.The incidences of pancreatic carcinomas in hamsters receiving70 mg/kg plus 20 mg/kg body weight of carcinogen followed by2% BHA was 7.1%, significantly lower than the 64.3% evidentin hamsters given the same doses of BOP followed by basal diet.The total numbers of pancreatic lesions including carcinomas,atypical ductal hyperplasias and ductal hyperplasias and ductularproliferations in the liver were also significantly decreasedin animals receiving BOP followed by 2% BHA. The results thusindicate that both pancreatic and cholangiocellular carcinogenesisinitiated by BOP in Syrian hamsters can be inhibited by 2% BHAtreatment for a relatively short experimental period.     

Early lesions induced by DHPN in Syrian golden hamsters: influence of concomitant Opisthorchisinfestation, dehydroepiandrosterone or butylated hydroxyanisole administration

The effects of concomitant Opisthorchis infestation and dehydroepiandrosterone(DHEA) or butylated hydroxyanisole (BHA) administration on dihydroxy-di-n-propylnitrosamine(DHPN) induction of preneoplastic lesions were investigatedin Syrian golden hamsters. Whereas parasite infection was primarilyassociated with first-order ductular proliferation in the liverand a secondary appearance of cholangiofibrotic lesions, DHEAtreatment brought about increased carcinogen toxicity and enhancedgeneration of glutathione-S-transferase P (GST-P)-positive hepatocellularfoci, liver cysts and focal proliferative changes in the pancreas.BHA also exerted an enhancing influence on pancreatic but notliver carcinogenesis. The results suggest that whereas alterationof DHPN metabolism by DHEA and BHA treatment effected changesat the initiation level, opisthorchiasis principally exertedan enhancing influence subsequent to carcinogen withdrawal.     

Stable phenotypic expression of glutathione S-transferase placental type and unstable phenotypic expression of gamma-glutamyltransferase in rat liver preneoplastic and neoplastic lesions

Using immunohistochemical demonstration of glutathione S-transferase placental type (GST-P) and histochemical demonstration of gamma-glutamyltransferase (gamma-GT), the long-term development of preneoplastic and neoplastic lesions was followed in rats over a 50-week period. Rats were given a single i.p. injection of 200 mg/kg body weight of diethylnitrosamine (DEN), and then 2 weeks later were administered 0.02% 2-acetylaminofluorene (2-AAF) (group 1), 0.05% phenobarbital (PB) (group 2), 2.0% butylated hydroxyanisole (BHA) (group 3) or no supplement (group 4) in their diet for 6 weeks, all rats being subjected to partial hepatectomy at week 3. Hepatocellular proliferated lesions were classified as foci, nodules and hepatocellular carcinomas. Development of foci, nodules and hepatocellular carcinomas was enhanced strongly by 2-AAF and weakly by PB, and inhibited by BHA. Almost all foci and nodules were GST-P positive, although 5-10% of the GST-P-positive foci were gamma-GT negative. The areas of GST-P-positive foci and nodules increased with time in all groups. In contrast, while the areas of gamma-GT-positive lesions also increased with time in groups 2-4, they decreased from week 12 in group 1. As the percentage gamma-GT-positive area in GST-P-positive foci significantly decreased with time in all groups, the rate of phenotypic reversion of gamma-GT in foci in group 1 was revealed to be larger than the focus growing rate, whereas that in groups 2-4 was smaller. Gamma-GT-negative and GST-P-positive micro-nodules of altered morphology appeared within gamma-GT- and GST-P-positive nodules in later stages. All hepatocellular carcinomas found in this experiment consisted of GST-P-positive cells. In contrast, 37% (13/35) of the hepatocellular carcinomas were negative for gamma-GT. The results indicate GST-P to be the most accurate marker enzyme for detection of initiated cells during liver carcinogenesis and gamma-GT to be more appropriate for indicating changes of phenotypic expression in each lesion type.     

The influence of subsequent dehydroepiandrosterone,diaminopropane, phenobarbital,butylated hydroxyanisole and butylated hydroxytoluene treatment on the development of preneoplastic and neoplastic lesions in the rat initiated with di-hydroxy-di-N-propyl nitrosamine

The comparative modifying potential of dehydroepiandrosterone (DHEA), diaminopropane (DAP), phenobarbital (PB), butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT) on the development of lesions initiated by dihydroxy-di-n-propyl nitrosamine (DHPN) in F344 rats were investigated. DHEA, BHA and BHT were all associated with significant reduction in numbers of glutathione-S-transferase P form (GST-P) positive foci in the liver whereas PB brought about their enhanced development. BHT and PB exerted promoting activity on the incidence of thyroid adenomas while DAP similarly increased lung adenoma formation. The results illustrate the advantages to be gained from two stage experiments using broad spectrum carcinogen initiation for comparative analysis of ‘modifiers’ of the neoplastic process and suggest that studies of enzyme alteration within putative preneoplastic lesions may be directly relevant to elucidation of mechanisms underlying such modification.     

Modifying effects of simultaneous treatment with butylated hydroxyanisole (BHA) on rat tumor induction by 3,2'-dimethyl-4-aminobiphenyl, 2,2'-dihydroxy-di-n-propylnitrosamine and N-methylnitrosourea

The modifying effects of concurrent treatment with high or low doses of butylated hydroxyanisole (BHA) on wide-spectrum carcinogen-induced carcinogenesis were studied in male F344 rats. Groups of 20 animals were treated with 2 or 0.04% BHA for 24 weeks. Starting 2 weeks after the commencement of BHA treatment, they were given s.c. injection of 50 mg/kg body weight 3,2'-dimethyl-4-aminobiphenyl (DMAB) once a week, i.g. administrations of 200 mg/kg body weight 2,2'-dihydroxy-di-n-propylnitrosamine (DHPN) once every 2 weeks, or i.p. injection of 15 mg/kg body weight N-methylnitrosourea (MNU) once every 2 weeks for 22 weeks. Further groups of rats were treated with DMAB, DHPN, MNU, or 2 or 0.04% BHA alone. All surviving animals were killed 24 weeks after the beginning of the experiment and the target organs examined histopathologically. The BHA treatment dose-dependently decreased the incidence of DMAB-induced liver preneoplastic lesions but was associated with significant tumor induction in the forestomach (papillomas, 40%, P less than 0.01) and urinary bladder (papillomas, 53%, P less than 0.001; carcinomas, 80%, P less than 0.001), where no lesions were observed in the group given only DMAB. Concurrent administration of 2% BHA also significantly inhibited the development of alveolar hyperplasia (P less than 0.001) of the lung in DHPN-treated animals, while enhancing induction of forestomach papillomas (P less than 0.05) and simple hyperplasia in the urinary bladder. Neither MNU nor 2% BHA alone induced forestomach carcinoma or papillary or nodular hyperplasia (PN hyperplasia) in the urinary bladder. However, these lesions were observed in 100% (P less than 0.001) and 55% (P less than 0.001) of animals respectively, receiving the two compounds in combination. These results demonstrated that concurrent treatment with BHA not only inhibits but can also strongly enhance carcinogenesis depending on the organ, irrespective of whether the carcinogens act directly or require metabolism. The finding that BHA potently modified carcinogenesis at 0.04% in diet, 1/50 of the carcinogenic dose, suggests that actual dietary levels close to the human situation might play a significant role in tumor development in man.     

Induction of malignant vascular tumors of the liver in guinea pigs treated with 2,2'-dihydroxy-di-n-propylnitrosamine.

The effect of chronic administration of 2,2'-dihydroxy-di-n-propylnitrosamine (DHPN) was studied in randombred guinea pigs. DHPN, dissolved in olive oil, was injected sc into 40 animals at a dose of 250 mg/kg body weight/week for 30 weeks, and the animals were observed until their death or termination of the experiment at the end of 40 weeks. Of the 32 guinea pigs that survived more than 20 weeks of DHPN treatment, 23 developed angiosarcoma of the liver between 22 and 40 weeks. Metastases to lungs, spleen, and peripancreatic lymph nodes were observed in 8 animals. Other tumors included hepatocellular carcinoma (1 animal), cholangiocarcinoma (1 animal), chronic myeloid leukemia (1 animal), acinar cell adenoma of pancreas (1 animal), and acinar cell carcinoma of pancreas (1 animal). In addition, megalocytic change of hepatic cells with intranuclear inclusions, pelliosis hepatis, and cholangiomatous lesions were also encountered frequently in the livers.     

Modifying effects of butylated hydroxyanisole, di(2-ethylhexyl)phthalate or indomethacin on mouse hepatocarcinogenesis initiated by N-nitrosodiethylamine

Preneoplastic and neoplastic liver and lung lesions were studied in male B6C3F1 mice given a single injection (80 mg/kg) of N-nitrosodiethylamine (DEN) intraperitoneally at 4 weeks of age, followed 1 week later by oral exposure to di(2-ethylhexyl)-phthalate (DEHP; at 6000 ppm in the diet), butylated hydroxyanisole (BHA; 7500 ppm in the diet) or indomethacin (10 ppm in the drinking water) alone or in combination (DEHP and BHA or DEHP and indomethacin), and continued for 29 weeks. DEHP or BHA alone and the combination of DEHP and BHA increased the incidence of DEN-initiated focal hepatocellular proliferative lesions (FHPL), including both microscopic hyperplastic foci and hepatocellular adenomas. Mice that received BHA alone or DEHP plus BHA had FHPL that were composed predominantly of eosinophilic hepatocytes, while FHPL in DEHP-exposed mice were basophilic. Indomethacin showed neither promotional or antipromotional effects, except for lung tumors. Mice receiving DEHP and indomethacin after DEN had significantly fewer lung lesions. A high incidence of renal papillary necrosis and nephropathy was observed in the indomethacin-DEHP exposed mice, while these lesions were not found in mice treated with indomethacin alone or DEHP alone. These findings suggest that BHA, an antioxidant, promoted pre-neoplastic liver lesions while indomethacin, a known inhibitor of prostaglandin synthesis and a chemopreventive agent for colon and mammary tumors in other studies, had no effect on liver tumor promotion by DEHP.     

Enhancement of DHPN induced hepatocellular, cholangiocellular and pancreatic carcinogenesis by Opisthorchis viverrini infestation in Syrian golden hamsters

Infection with 100 Opirthorchis viverrini (OP) metacercariaeprior to two injections of dihydroxy-di-n-propyl nitrosamine(DHPN) (1000 mg/kg body weight) brought about significant enhancementof resultant preneoplastic lesion development in Syrian hamsterliver and pancreas tissue. Thus combined treatment with carcinogenand parasite was associated with pancreatic atypical (dysplastic)foci, hepatocellular nodules, cholangiofibrosis and cholangiocarcinomas.No such lesions were observed in carcinogen alone, parasitealone or untreated control groups. In addition, parasite inducedhyperplastic gall bladder epithelium was found to include areasof putative preneoplastic cells only in the DHPN-OP combinedgroup. The results strongly suggest that pancreatitis and biliarycirrhosis associated with liver fluke infestation are responsiblefor the observed enhancement of carcinogenesis, and that theresultant increased proliferation plays a major role in tumorigenesis.     

Modifying influence of dehydroepiandrosterone or butylated hydroxytoluene treatment on initiation and development stages of azaserine-induced acinar pancreatic preneoplastic lesions in the rat

Dietary administration of dehydroepiandrosterone (DHEA) (0.6%) or butylated hydroxytoluene (BHT) (1%) during or subsequent to two i.p. injections of azaserine (30 mg/kg body wt) resulted in significant alteration of yield of preneoplastic lesions in both pancreas and liver. While concomitant application appeared not to have any effect on subsequent development of glutathione S-transferase P form (GST-P) positive hepatocellular lesions in either case, BHT and to a lesser extent also DHEA reduced initiation of pancreatic acinar carcinogenesis. Both BHT and DHEA were associated with significant increase in GST-A form positive pancreatic foci when administered after cessation of carcinogen treatment while clearly inhibiting liver lesion development. The results point to a marked differential in the response of the liver and pancreas to external stimulus with regard to preneoplastic focal lesions while demonstrating significant second stage promotion of pancreatic acinar carcinogenesis by BHT and DHEA.     

Comparison of lesions induced in the Syrian golden hamster by diethylnitrosamine, dimethylhydrazine, and dibutylnitrosamine: influence of subsequent butylated hydroxyanisole treatment

The target organ specificity of the carcinogens diethylnitrosamine [(DENA) CAS: 55-18-5], dimethylhydrazine [(DMH) CAS: 57-14-7], and dibutylnitrosamine [(DBN) CAS: 924-16-3] was examined in Syrian golden hamsters. Groups of male animals were given 8 weekly injections of one of these carcinogens and then were maintained on a basal diet or a diet supplemented with 1% butylated hydroxyanisole [(BHA) CAS: 25013-16-5], or they were given the respective carcinogens in the drinking water until they were sacrificed at week 34. While DENA specifically induced tracheal polyps and hepatocellular foci and nodules, DMH administration was associated with development of both hepatocellular and hemangiocellular liver lesions as well as forestomach papillomas and adenocarcinomas of the large intestine. DBN induced lesions in the urinary bladder, forestomach, and trachea, in addition to a few preneoplastic foci in the liver and lungs. In all organs studied, preneoplastic and neoplastic populations were essentially similar to those observed in other experimental animals, with colon and tracheal lesions demonstrating alteration in polysaccharide metabolism. While inhibiting the development of hepatocellular lesions, especially in the group initiated with DENA, and while itself inducing extensive papillomatous forestomach hyperplasia, BHA administration did not exert a significant modifying influence on tumorigenesis in other organs. The present results demonstrate the efficacy of Syrian golden hamster studies for investigation of comparative neoplasia. Of particular interest in this respect were differences in the degree of phenotypic instability demonstrated by glutathione S-transferase placental form-positive foci induced by the 3 carcinogens, which indicated a possible qualitative variation in "initiation."     

Inhibition by dehydroepiandrosterone of butylated hydroxyanisole (BHA) promotion of rat-bladder carcinogenesis and enhancement of BHA-induced forestomach hyperplasia

The effects of dehydroepiandrosterone (DHEA) with/without ribonucleoside (RN_s) supplementation on butylated hydroxyanisole (BHA) bladder-tumor promotion and forestomach carcinogenesis were investigated. Male F344 rats were given N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) in their drinking water for 4 weeks and then received basal diet or diet containing BHA, DHEA, a mixture of RN_s, BHA + DHEA or BHA + DHEA + RN_s for 32 weeks. The occurrences of papillomas and carcinomas in the urinary bladder were increased in the groups given BHA or BHA + DHEA + RN_s, as compared with control group values. In comparison with the BHA group, the BHA + DHEA group incidences and numbers of these tumors were decreased. However, the incidence and multiplicity of papillomas in the group given BHA + DHEA + RN_s were again elevated. DNA synthesis levels in normal-appearing bladder epithelium, but not tumor cells, were closely correlated with the observed level of promotion in most groups. The case of DHEA alone proved exceptional in that DNA synthesis was markedly decreased without any significant influence on lesion development. In the forestomach, DHEA, which itself was associated with slight although non-significant hyperplasia, enhanced BHA-induced epithelial lesions, characterized by marked basal-cell proliferation and keratin-cyst formation, independently of additional RN_s administration. Our results suggest that the anti-promoting effects of DHEA in the bladder depend on a deficiency in the pentose phosphates necessary for production of nucleosides. Organ-specific modulation is indicated by the enhancing effects of DHEA on BHA-induced forestomach hyperplasia.     

Selective induction of rat urinary bladder tumors by simultaneous administration of 3,2'-dimethyl-4-aminobiphenyl (DMAB) and butylated hydroxyanisole or butylated hydroxytoluene is associated with increased DMAB-DNA adduct formation

Modification of 3,2'-dimethyl-4-aminobiphenyl (DMAB) multi-organ carcinogenesis by simultaneous treatment with butylated hydroxyanisole (BHA) or butylated hydroxytoluene (BHT) was studied using young and old male F344 rats. Animals, 4 or 54 weeks old, were given DMAB (s.c. injection of 50 mg/kg body wt once a week for 10 weeks) along with BHA (2.0% in diet for 11 weeks) or BHT (1.0% in diet for 11 weeks). The experiments were terminated 55 weeks after the commencement. Combined administration of BHA or BHT with the carcinogen resulted in development of urinary bladder tumors in greater than 90% of both young and old rats thus treated, whereas no tumors were induced in animals given DMAB alone. In contrast, the appearance of preneoplastic lesions in the liver and pancreas was reduced by BHA or BHT treatment. Tumor development (less than 30% incidence) was also evident in the small and large intestines, prostate, preputial glands, skin/subcutis and ear duct, with no modification by BHA or BHT. No ageing effects were evident. The formations of DMAB-DNA adducts, evaluated by the enzyme-linked immunosorbent assay and immunohistochemical staining, correlated well with tumorigenesis in the urinary bladder, liver and pancreas. The selective enhancement of urinary bladder tumor induction by BHA and BHT appeared to be due to both increased DMAB-DNA adduct formation caused by metabolic alteration of DMAB in the liver and increased DNA synthesis in the urothelial cells.     

Lack of hepatocarcinogenic potential of acetaminophen in rats with liver damage associated with a choline-devoid diet

The potential carcinogenic activity of acetaminophen (paracetamol, APAP) was studied in male F344 rats with pre-existing liver damage induced by a choline-devoid (CD) diet. In a short-term experiment, APAP was administered by intragastric intubation as single doses of 0.5-1.5 g/kg body wt after 4 weeks feeding of CD diet had produced fatty livers in rats. Two-thirds partial hepatectomy was performed 4 h subsequent to the initiating treatment step. After a 2 week recovery period, all rats were subjected to the selection procedure of Cayama et al. and killed at week 9 of the experiment. Quantitative analysis of placental form glutathione S-transferase (GST-P)-positive liver lesion development did not reveal any enhancement by APAP, whereas administration of a non-necrogenic dose of diethylnitrosamine (20 mg/kg body wt) in the same protocol demonstrated significant promotion, confirming the utility of the model for detection of weak carcinogenicity of chemicals. In the second long-term experiment, APAP was fed at doses of 0.45 and 0.9% for 25 weeks following 27 weeks administration of CD diet which produced liver cirrhosis in the rats. Despite a slight enhancement of focal liver lesions positive for gamma-glutamyltranspeptidase (GGT), no significant promotion of GST-P-positive altered foci or nodules was observed. In contrast, continuous feeding of CD diet or 0.5% phenobarbital treatment after generation of cirrhosis with CD diet clearly enhanced the induction of both GST-P and GGT-positive liver lesions. Thus, these results indicate that APAP does not possess significant carcinogenic activity in damaged rat liver.     

Modification by Analgesics of Lesion Development in the Urinary Tract and Various Other Organs of Rats Pretreated with Dihydroxy-di-N-propylnitrosamine and Uracil

Effects of the analgesics phenacetin, acetaminophen and antipyrine on lesion development in the urinary tract and other organs in male F344 rats were investigated. Animals were concurrently administered with 0.1% dihydroxy-di-N-propylnitrosamine (DHPN) in drinking water and 3.0% uracil in the diet for 4 weeks and then, starting 1 week after the cessation of this treatment, received basal diet or diet containing phenacetin, acetaminophen or antipyrine for 35 weeks. The occurrences of renal cell tumors were increased in the groups given phenacetin or antipyrine, as compared with the DHPN+uracil alone controls. Antipyrine, but not the two other compounds, also enhanced development of hyperplastic lesions in the renal pelvis and ureter. In the urinary bladder, phenacetin and antipyrine treatments were both associated with increased incidence of preneoplastic or neoplastic lesions. Furthermore, phenacetin alone, without the initiating agent pretreatments, induced simple hyperplasias of the urinary bladder at high incidence. Antipyrine enhanced induction of hyperplastic lesions in the ureter and was also found to increase the incidences of preneoplastic and neoplastic lesions in the liver. Although decreased incidences of tumor development of lung and thyroid were observed for the group given phenacetin, this might have been linked to the decreased weight gain. The results confirmed that combination treatment with DHPN+uracil is effective for wide-spectrum initiation of carcinogenesis in the urological tract and demonstrated significant modification potential for both phenacetin and antipyrine.     

Generation of High Yields of Syrian Hamster Cholangiocellular Carcinomas and Hepatocellular Nodules by Combined Nitrite and Aminopyrine Administration and Opisthorchis viverrini Infection

Combined administration of 0.1% nitrite and 0.1% aminopyrine in the drinking water for eight to ten weeks resulted in subsequent development of both hepatocellular nodules and cholangiofibrotic lesions/cholangiocellular carcinomas in Syrian golden hamsters. Additional prior dosing with Opisthorchis viverrini metacercariae (100/animal) induced inflammatory and proliferative changes in the livers of infected hamsters and was associated with a significant increase in yields of hepatocellular and cholangiocellular preneoplastic and neoplastic lesions. Thus, environmental factors thought to be casually related to the high levels of human liver cancer observed in the Northeastern provinces of Thailand were sufficient to bring about development of equivalent tumors in experimental animals. The results indicate that parasite associated liver injury and non-specific compensatory regeneration may play an important role in generation of both hepatocellular and cholangiocellular carcinomas in man.     

Generation of high yields of Syrian hamster cholangiocellular carcinomas and hepatocellular nodules by combined nitrite and aminopyrine administration and Opisthorchis viverrini infection

Combined administration of 0.1% nitrite and 0.1% aminopyrine in the drinking water for eight to ten weeks resulted in subsequent development of both hepatocellular nodules and cholangiofibrotic lesions/cholangiocellular carcinomas in Syrian golden hamsters. Additional prior dosing with Opisthorchis viverrini metacercariae (100/animal) induced inflammatory and proliferative changes in the livers of infected hamsters and was associated with a significant increase in yields of hepatocellular and cholangiocellular preneoplastic and neoplastic lesions. Thus, environmental factors thought to be casually related to the high levels of human liver cancer observed in the Northeastern provinces of Thailand were sufficient to bring about development of equivalent tumors in experimental animals. The results indicate that parasite associated liver injury and non-specific compensatory regeneration may play an important role in generation of both hepatocellular and cholangiocellular carcinomas in man.