Terence Lawson

Current knowledge of pancreatic carcinogenesis in the hamster and its relevance to the human disease

Syrian hamsters present a unique species for induction of pancreatic tumors that in many aspects resemble human pancreatic cancer. The specific response of Syrian hamsters, in contrast to many other rodents, for development of pancreatic ductal (ductular) tumors is not yet known. All pancreatic carcinogens thus far tested show certain common features. They are all nitrosamines that possess or can be metabolized to compounds with 2‐oxopropyl‐ or 2‐hydroxypropyl substituents. All but one, N‐nitrosomethyl(2‐oxopropyl)amine, occur or metabolize to nitrosamines with the ability to cyclize and form structures resembling glucose. Hence it is suggested that this cyclic structure may be responsible for the pancreatic carcinogenicity of these nitrosamines, as has been proposed for the pancreatotropic effect of streptozotocin. It is also of further interest that one pancreatic ductal (ductular) carcinogen, N‐nitroso‐2‐methoxy‐2,6‐dimethylmorpholine, which possesses a totally cyclic structure, acts, like streptozotocin, as β‐cell cytotoxic and diabetogenic when given in a high single dose. Modification of pancreatic tumor induction has been demonstrated by specific procedures. A high fat diet significantly increases both the incidence and number of induced cancers. Methods for early diagnosis and therapy are being developed and their significance and applicabilities for clinical use will be of major importance. Compared with the other most common types of human cancer, pancreatic cancer has extraordinary characteristics, which make the disease one of the most mysterious of maladies. Consequently, pancreatic cancer represents a serious international problem and requires urgent resolution, especially with regard to its etiology, early diagnosis, prevention, and therapy.

Association of NAT and GST polymorphisms with non-Hodgkin's lymphoma: a population-based case-control study

Several chemicals have been associated with risk of non‐Hodgkins lymphoma (NHL), many of which are substrates for N‐acetyltransferase (NAT) and glutathione S‐transferase (GST) enzymes. We investigated the association between polymorphisms in genes coding for these enzymes and NHL risk in a population‐based study (389 cases and 535 controls). NAT1 slow genotype was associated with a slightly increased risk in women [odds ratios (OR) = 1·4; 95% confidence interval (CI) = 0·9–2·3], but not in men. NAT2 slow genotype was not associated with risk in either sex. The two slow genotypes of NAT1 and NAT2 combined were associated with a minor increase of risk in women (OR = 1·4; 0·8–2·4). There was no association with the GSTM1 or GSTT1 null genotype in either sex, irrespective of histological subtypes. Individuals with GSTP1 Val homozygotes had non‐significant excessive risk of marginal zone lymphoma (OR = 1·8; 0·6–5·1) and ‘other’ B‐cell NHLs (OR = 1·6; 0·7–3·6), but lower risk of diffuse large B‐cell lymphoma (OR = 0·2; 0·1–0·96). Risk did not elevate with an increasing number of high‐risk GST alleles in either sex. In summary, although NAT1, NAT2, GSTM1, GSTT1, or GSTP1 polymorphisms do not appear to be associated with NHL risk overall, there might be gender‐specific and subtype‐specific associations that require confirmation.

The expression of multidrug resistance-associated protein (MRP) in pancreatic adenocarcinoma cell lines

The presence of P-glycoprotein (P-gp) and multiple drug resistance-associated protein (MRP) was examined in four human pancreatic adenocarcinoma cell lines (PANC-1, BxPC-3, AsPC-1, and Capan-1). Cellular accumulation of rhodamine 123 and [3H]vincristine were used to determine functional activity of P-gp and MRP, respectively. None of the cells showed any evidence of P-gp in the rhodamine 123 cellular accumulation assays. In contrast, PANC-1, BxPC-3 and AsPC-1 did display an increased accumulation of [3H]vincristine following treatment with either cyclosporin A or verapamil. Western blot analysis confirmed the expression of MRP, and little, if any, measurable P-gp in the cell lysates. These studies suggest that intrinsic drug resistance in pancreatic duct cancer may be due in part to the presence of MRP.

Effects of oltipraz, BHA, ADT and cabbage on glutathione metabolism, DNA damage and lipid peroxidation in old mice ☆

Eighteen-month-old female mice were fed defined diets for 2 weeks which contained 0.05% or 0.10% oltipraz, 0.10% anethole dithione (ADT), 0.10% butylated hydroxyanisole (BHA) or 20% lyophilized cabbage. All diets resulted in significant increases in hepatic reduced glutathione (GSH) content. Glutathione reductase and glutathione S-transferase activities were also significantly higher than the control values. All diets produced significant decreases in hepatic DNA damage (single strand breaks) and lipid peroxidation (malondialdehyde content). In general, similar effects were produced by the two dithiolthiones, oltipraz and ADT. More pronounced effects were produced by oltipraz and ADT than by BHA or cabbage in the diet. Diets high in antioxidants may be effective in retarding free radical reaction processes associated with aging and cancer.

Rodent bladder tumors do not always predict for humans

Dr. David Clayson, 20 years ago, suggested that chemicals which lead to the formation of calculi in rodents might pose an artifact with respect to extrapolation to potential carcinogenic risk to humans. We reviewed what has been learned about the role of calculi in urinary bladder carcinogenesis in the ensuing 20 years, along with several examples. Formation of microcrystalluria and amorphous precipitate also poses problems in interpretation and examples are described. The chemicals producing these solid urinary materials are non-genotoxic, with marked increase in cell proliferation being the mode of action by which they are able to produce cancer in long-term rodent bioassays.

The mutagenicity of capsaicin and dihydrocapsaicin in V79 cells

A crude mixture of capsaicinoids (CAPs) from Capsicum frutrescens, capsaicin (C) and dihydrocapsaicin (DC) but not 4-methyl-dihydrocapsaicin (MC), a synthetic homolog of DC, were mutagenic in the V79 assay. Oxidative metabolism of C and DC by microsomes or ferricyanide yielded a dimer of C or DC. Based on the lack of mutagenicity of MC, the mutagenicities of C and DC and the supporting chemical data, a mechanism of action involving an intermediate phenoxy radical is proposed.

Induction of hepatic DNA singlestrand breaks in rats by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)

Previous studies have demonstrated that 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) induces lipid peroxidation in hepatic and extrahepatic tissues. DNA single strand breaks as well as other forms of DNA damage are believed to occur in conjunction with lipid peroxidation. We have therefore examined the effect of TCDD on hepatic DNA single strand breaks. Ten days after the administration of 100 micrograms TCDD/kg to female rats, a 7.5-fold increase in the DNA elution constant (single strand breaks) occurred. Similar changes were observed in the content of thiobarbituric acid reactive substances (TBARS) in the nuclei as well as the NADPH-dependent production of TBARS. The accumulation of TBARS appeared to precede the accumulation of DNA single strand breaks. The tumor promoting effects of TCDD may be associated with the enhanced formation of DNA single strand breaks.

The mechanism of inhibition of cytochrome P450IIE1 by dihydrocapsaicin

Abstract Dihydrocapsaicin ( 2 ) is a noncompetitive inhibitor of cytochrome P450IIE1. This was demonstrated by studying the inhibition of p -nitrophenol oxidation. The covalent binding of 2 to cytochrome P450IIE1 was examined by incubating tritiated 2 with rat liver microsomes and gel electrophoresis of the resulting bound cytochrome P450 isozymes. Autoradiograms of these gels displayed a single band at approximately 48 kDa. The mechanism whereby 2 became covalently bonded to cytochrome P450IIE1 was explored by studying the oxidation of 2 by electrochemical, chemical, and enzymatic methods. Oxidation of 2 by all methods generally resulted in the formation of the 5,5′-dimer of 2, 4 , which likely forms by dimerization of the phenoxy radical 7 . It is suggested that 2 is oxidized to 7 by cytochrome P450IIE1 and 7 then covalently bonds to cytochrome P450IIE1 thereby inactivating it.

Methylation of hamster DNA by the carcinogen N-nitroso-bis (2-oxopropyl)amine

The alkylation of hamster liver, lung and pancreas DNA by [1-14C]- and [2,3-14C]N-nitrosobis (2-oxopropyl) amine (BOP) has been examined. The specific activity of pancreas DNA after [2,3-14C]BOP administration was only 2% of that when [1-14C]BOP was given. 7-Methylguanine, but not O-6-methylguanine, was found in hydrolysates of liver and pancreas DNA. Nearly equal amount of alkylation were produced in the liver when [1-14C]- and [2,3-14C]BOP were given. At least one-half of the radioactivity in the liver was associated with N-alkylated purines, whereas only 20% was in this form in the pancreas.

Enhancement of BOP-induced pancreatic carcinogenesis in selenium-fed Syrian golden hamsters under specific dietary conditions

We measured the effects of dietary selenium (Se) on pancreatic cancer induced in Syrian golden hamsters by N-nitrosobis(2-oxopropyl)amine (BOP). The animals were fed six experimental diets that contained different combinations of the following: 0.1, 2.5, or 5.0 ppm Se from sodium selenite or 2.5 ppm Se from D,L-selenomethionine in either a low (6.0%)- or high (24.4%)-fat diet. Se treatment was begun four weeks before BOP treatment, and the high-fat diet was fed from one week after the last BOP treatment. No evidence for inhibition of pancreatic cancer by Se was observed; in fact, with some experimental conditions, high-Se diets increased the pancreatic carcinoma yield. However, the dietary conditions needed for enhancement differed between the sexes. The male hamsters that received the high-fat diet containing 2.5 ppm Se had more carcinomas than did males given the 0.1 ppm Se level. Carcinoma yields in females did not differ between these diets. Females that received 2.5 ppm Se from D,L-selenomethionine had a greater pancreatic carcinoma yield that did those given 0.1 ppm Se diet. However, carcinoma yields did not differ in males fed these diets. Acinar cell nodule yields were generally reduced in hamsters given the high-Se diets, especially when Se levels in the high-fat diets were compared. Prefeeding 0.1 or 2.5 ppm Se did not influence the elution constants of pancreatic DNA from ductal cells, indicating no effect of Se on the repair of BOP-induced, single-strand breaks in DNA from these cells. Measurements in acinar cells suggested a more rapid repair of single-strand breaks in hamsters prefed 2.5 ppm Se than in those prefed 0.1 ppm Se.