Pancreatic carcinoma in azaserine-treated rats: Induction, classification and dietary modulation of incidence

Longnecker, Daniel S.; Roebuck, Bill D.; Yager, James D.; Lilja, Herman S.; Siegmund, B

doi:10.1002/1097-0142(19810315)47:6+<1562::aid-cncr2820471419>3.0.co;2-z

Cited by 110 publications

(47 citation statements)

References 15 publications

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“…These foci are now well established as the precursors of pancreatic carcinoma in this model, whereas basophilic foci appear to be of little importance. The acidophilic foci show considerable growth potential with a mitotic index (2.75) which greatly exceeds that of basophilic foci (0.125) or normal pancreas (zero) (Scarpelli et al, 1984 (Longnecker et al, 1979), the number and size of acidophilic AACF seem to correlate positively with the incidence of carcinoma (Roebuck & Longnecker, 1977;Longnecker et al, 1981).…”

Section: Discussionmentioning

confidence: 85%

Inhibitory effect of a cholecystokinin antagonist on pancreatic carcinogenesis after pancreatobiliary diversion

Watanapa

Flaks²,

Oztas³

et al. 1993

Br J Cancer

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The role of cholecystokinin (CCK) has been explored in pancreatic carcinogenesis following pancreatobiliary diversion (PBD), using the specific CCK receptor antagonist CR-1409. Male Wistar rats (n = 80) weighing 70-100 g were given weekly i.p. injections of azaserine (30 mg kg-1 week-1) for 3 consecutive weeks. One week later animals were randomised to receive either PBD or sham PBD and thereafter to receive s.c. injections of either saline or CR-1409 (10 mg kg-1 day-1, 5 days a week). Six months after operation surviving rats were killed as follows: sham + saline 20, PBD + saline 19, sham + CR-1409 14, PBD + CR-1409 11. Cardiac blood was taken for CCK assay and the pancreas was excised for wet weight measurement and quantitative estimation of atypical acinar cell foci (AACF), the precursor of carcinoma. PBD reduced median body weight (3-20% less than shams) but trebled the absolute and relative pancreatic weights (P < 0.001). CR-1409 blunted this adaptive response to PBD, reducing absolute pancreatic weight by 35% (P < 0.005). PBD quadrupled circulating CCK concentrations, regardless of the antagonist treatment. Acidophilic AACF occurred only in rats with PBD. CR-1409 markedly reduced the number of observed acidophilic AACF by 90% (P < 0.001) and the number of foci per pancreas by 93% (P < 0.001). Moreover, CR-1409 reduced the mean focal diameter of each lesion by 18% (P < 0.005), the mean focal volume by 58% (P < 0.05) and the percentage of pancreas occupied by acidophilic foci by 95% (P < 0.001). PBD enhances pancreatic carcinogenesis by causing hypercholecystokininaemia, and CR-1409 largely inhibits this enhancement.

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Section: Discussionmentioning

confidence: 85%

Inhibitory effect of a cholecystokinin antagonist on pancreatic carcinogenesis after pancreatobiliary diversion

Watanapa

Flaks²,

Oztas³

et al. 1993

Br J Cancer

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“…The higher number and area of AFB1-induced hepatic foci in rats fed AIN-76A diet compared to PC diet observed in the present study are in accord with previous studies performed with diethylnitrosamine-induced hepatic foci in rats (Russell et al, 1987;Hendrich et al, 1988). Similar dietary modulations of azaserine-induced pancreatic cancer and nitrosamine-induced lung tumors in rodents have been demonstrated with AIN-76A and PC diets (Longnecker et al, 1981;Hecht et al, 1989).…”

Section: ꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏmentioning

confidence: 99%

Effect of diet on aflatoxin B1-DNA binding and aflatoxin B1-induced glutathione S-transferase placental form positive hepatic foci in the rat

Kimura

Lehmann²,

Gopalan-Kriczky³

et al. 2004

Exp Mol Med

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“…Azaserine (O-diazoacetyl-L-serine), a derivative of serine (32) obtained from Streptomyces fragilis, has been shown to produce persistent DNA damage (33), nodule formation and, after administration for a year or more, pancreatic cancer in rats (34). We have shown rapid and marked potentiation between a diet containing raw soya flour and azaserine in as little as 24 weeks (35).…”

Section: Effect Of Additional Carcinogensmentioning

confidence: 99%

Effects of soybean flour on the pancreas of rats.

McGuinness¹,

Morgan²,

Wormsley³

1984

Environ Health Perspect

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We have reviewed the growth-promoting and carcinogenic effects of feeding raw soya flour to rats. If the raw soya flour-containing diets are fed for more than a year, about 10% of the animals develop pancreatic cancer. In addition, feeding raw soya flour markedly potentiates the action of even subthreshold amounts of pancreatic carcinogens. The raw soya flour therefore acts as a potent promoter, as well as a weak carcinogen. In view of this promotion, the rat fed raw soya flour is a sensitive model for screening pancreatic carcinogens.It is not known whether the human pancreas responds to dietary trypsin inhibitors in a manner similar to the rat. However, in view of the use of soya-based products in human nutrition-especially in infant foods-we urge that the effect of all soya-based products intended for human use be tested on the rat pancreas in long-term feeding studies, combined with subthreshold doses of azaserine to highlight any promoting activity of the product. It seems probable that if a product exerts no effect on the rat pancreas, the human pancreas will also be spared from noxious effects. Morphological Aspects Macroscopic FeaturesRaw soya flour-containing diets have been shown to produce enlargement of the rat pancreas after administration for as little as 10 to 20 days (1). The pancreatic enlargement has been shown to reflect both hypertrophy (defined as increase in cellular size and amount of protein per unit of DNA) (2) and also hyperplasia (increase in the amount of DNA and number of cells in the gland) (3). We have shown that the pancreatic growth-promoting effects continue, ifthe administration of raw soya flour is maintained, but becomes progressively more marked in an exponential manner at some time between 30 and 60 weeks of feeding raw soya flour-containing diets (4).During the period of pancreatic enlargement, the gland changes color to become dark red, reflecting increased vascularity and blood flow, as demonstrated by use of microspheres (unpublished results).Some time between 24 and 30 weeks after the start of raw soya flour-containing diets, small greyish patches become visible on the surface of the gland. Subsequently, overt nodules appear and increase in size (6). These changes correlate with the growth of the gland and with the increased secretory response to stimulants of the pancreas of these animals (7).After feeding raw soya flour-containing diets for 16 to 24 weeks, a few microscopic foci can be found scattered throughout the pancreas. The number and size of the nodules increases with the duration of feeding (4) Reversibility of Morphological ChangesThe pancreatic weights, protein content and morphological appearances revert to normal when rats are fed raw soya flour for 5 days (8), 4 weeks (9) and 6 months (unpublished observations) and then receive non-soyacontaining diets.If rats are fed raw soya flour for as long as 6 months and the diet is then changed to non-soya-containing chow, nodules are not found at death a year or more later, so that histologically the pancreas o...

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Pancreatic carcinoma in azaserine-treated rats: Induction, classification and dietary modulation of incidence

Cited by 110 publications

References 15 publications

Inhibitory effect of a cholecystokinin antagonist on pancreatic carcinogenesis after pancreatobiliary diversion

Inhibitory effect of a cholecystokinin antagonist on pancreatic carcinogenesis after pancreatobiliary diversion

Effect of diet on aflatoxin B1-DNA binding and aflatoxin B1-induced glutathione S-transferase placental form positive hepatic foci in the rat

Effects of soybean flour on the pancreas of rats.

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