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PubMed1991

Secretagogue response of azaserine-induced rat pancreatic acinar tumors in vivo.

This study investigates digestive and lysosomal enzyme secretion of azaserine-induced pancreatic acinar carcinomas in response to cholecystokinin in rats. After 15-20 months of treatment, 95% of the animals developed pancreatic acinar carcinomas encompassing more than 90% of the tissue. In anesthetized rats basal trypsin output was significantly elevated in the tumor group despite diminished fluid secretion. There was a linear correlation between tumor size and basal amylase and trypsin secretion. Intravenous infusion of cholecystokinin (25 IDU.kg-1.h-1) induced a significantly lower secretion of fluid per gram pancreas, as well as decreased amylase and trypsin output, in the tumor group compared with the control group. Plasma amylase and lipase levels were significantly elevated in the tumor group under both basal and stimulated conditions. The output of the lysosomal enzymes beta-D-glucuronidase and alpha-D-glucosidase was significantly increased in the tumor group under background secretin infusion. Additional cholecystokinin infusion caused a sharp increase in glucuronidase output in this group with only minimal increase in controls. Glucosidase output increased similarly in both groups. Amylase, lipase, and trypsin tumor tissue concentrations were markedly reduced by 85%, 90%, and 87%, respectively. It was concluded that the decreased secretory response of digestive enzymes may result from decreased synthesis, lowered storage capabilities, and/or a decreased/increased responsiveness to cholecystokinin. Increased glucuronidase secretion may reflect an augmented cell turnover of malignant tissue.

Adenoma↗
PubMed1984

Recovery of V79 cell clones with different phenotypes in aminopterin- or azaserine-containing media used for the selection of HGPRT revertants.

Three 6-thioguanine (6TG)-resistant mutants were mutagen-treated and selected for clones capable of growing in 2 selective media: HAT medium, containing aminopterin (AP) and HAS medium, containing L-azaserine (AS). Both 6TG-sensitive, wild-type clones and 6TG-resistant mutants were found among colonies growing in HAT medium, while only 6TG-sensitive clones grew in HAS medium. Time for expression was required by 6TG-resistant but not by 6TG-sensitive clones, that were fully expressed immediately after treatment. All HAT-resistant, 6TG-resistant clones which were analyzed proved to be resistant to AP. These data were interpreted as follows: in HAT medium, both HGPRT+ revertants and double mutants (HGPRT-, AP-resistant) were selected, while only HGPRT+ revertants were selected in HAS medium. Not all 6TG-resistant mutants were able to produce both classes of HAT-resistant clones.

Aminopterin↗
PubMed1987

Pancreatic carcinogenesis in azaserine-treated rats: inhibition by a solvent mixture in the diet.

The growth of azaserine-induced foci and nodules in a 4-month experiment and the incidence of carcinomas in a 15-month experiment were greater in LEW/CrlBR inbred rats fed a purified diet (AIN-76A) than in rats fed a natural-ingredient diet (chow). Addition of a mixture of several solvents to either diet reduced the incidence of adenocarcinomas in the pancreas in the long-term study but failed to reduce the number or size of pancreatic atypical acinar cell foci in the experiments of 4 months and 6 months (chow only) duration. Apparently, some component of the solvent mixture inhibits a late stage in the development of pancreatic carcinoma. Glyceryl monooleate and propylene glycol are implicated as the components of the mixture most likely to be responsible for the inhibitory effect, but neither the identity of the critical component nor the mechanism of the inhibition is known. The solvent mixture also contained ethanol and trioctanoin.

Animals↗
PubMed1977

Potentiation of the action of azaserine on the rat pancreas by raw soya bean flour.

Rats were treated with raw soya flour to produce pancreatic hypertrophy and also received azaserine, a pancreatic carcinogen. The combined treatment resulted in the development of large numbers of hyperplastic nodules in the acinar tissue of the rat pancreas. We conclude that the pancreas of the rat stimulated to proliferate by raw soya flour provides a sensitive model for detecting and studying pancreatic carcinogens.

Animals↗
PubMed1979

Transplantation of azaserine-induced carcinomas of pancreas in rats.

Two pancreatic adenocarcinomas which had been induced in Wistar/Lewis rats by azaserine treatment were transplanted into rats of the same strain by subcutaneous and intraperitoneal injection of minced tumor. Subsequently, we have serially transplanted into non-radiated recipients. Transplanted tumors have maintained evidence of acinar cell differentiation including the presence of zymogen granules in tumors studied by electron microscopy, and of lipase, amylase and trypsin activity in the supernatant of tumor homogenates. Histologically, the tumors vary from poorly differentiated solid carcinomas to well differentiated variants which form acini. Transplanted tumors are locally invasive and have metastasized to lung and liver in some recipients.

Adenocarcinoma↗
PubMed1992

Role of cholecystokinin in dietary fat-promoted azaserine-induced pancreatic carcinogenesis in rats.

The role of cholecystokinin in dietary fat-promoted pancreatic carcinogenesis was investigated in azaserine-treated rats, using lorglumide, a highly specific cholecystokinin-receptor antagonist. The animals were killed 8 months after the start of treatment. Cholecystokinin, but not dietary unsaturated fat, increased pancreatic weight. Rats treated with cholecystokinin developed more acidophilic atypical acinar cell nodules, adenomas and adenocarcinomas than control animals. Rats maintained on the high-fat diet developed significantly more adenomas and adenocarcinomas than controls given a diet low in unsaturated fat. Lorglumide largely inhibited the enhancing effect of cholecystokinin, but not of dietary fat, on pancreatic carcinogenesis indicating that it is unlikely that the promoting effect of dietary unsaturated fat on pancreatic carcinogenesis is mediated via cholecystokinin.

Animals↗
PubMed1996

Epidermal growth factor receptor expression in pancreatic lesions induced in the rat by azaserine.

In the present study, the expression of the epidermal growth factor receptor (EGFR) was investigated in putative preneoplastic and neoplastic acinar cell lesions induced in the rat pancreas by azaserine, using Northern blotting, in situ hybridisation (ISH) and immunohistochemistry. EGFR protein levels were decreased in putative preneoplastic eosinophilic acinar cell lesions (atypical acinar cell nodules, AACN) in comparison with normal acinar cells of the pancreas. However, EGFR mRNA expression correlated positively with the volume of AACN in pancreatic homogenates and ISH showed equal or stronger EGFR mRNA expression in AACN than in the surrounding normal acinar cells. Neither EGFR protein nor EGFR mRNA was detected in more advanced lesions such as acinar adenocarcinomas (in situ). Moreover, EGFR protein expression showed an inverse relationship with the mitotic rate of the acinar cells. These findings suggest that down-regulation of EGFR at the protein level may abrogate negative constraints on cell growth, which may stimulate the development of putative preneoplastic AACN to more advanced lesions and, ultimately, acinar adenocarcinomas.

Animals↗
PubMed1989

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.

Animals↗
PubMed1992

Effects of cholecystokinin and bombesin on development of azaserine-induced pancreatic tumours in rats: modulation by the cholecystokinin receptor antagonist lorglumide.

Cholecystokinin and bombesin have been shown to promote pancreatic growth and development of azaserine-induced acidophilic atypical acinar cell nodules in rat pancreas after treatment for 16 weeks. Lorglumide, a specific cholecystokinin receptor antagonist, inhibited the stimulating effect of cholecystokinin, but not of bombesin. The present study was carried out to determine effects of cholecystokinin and bombesin, alone and in combination with lorglumide, on pancreatic growth and carcinogenesis after chronic treatment. The animals were killed 8 months after the start of treatment. Growth of the pancreas and the development of acidophilic atypical acinar cell nodules in exocrine pancreas was enhanced significantly by both cholecystokinin and bombesin, but the number of carcinomas was increased only by bombesin. Lorglumide inhibited the effects of cholecystokinin on both pancreatic growth and on the development of acidophilic nodules. The effects of bombesin on pancreatic growth and development of pancreatic lesions, except for adenomas, were not inhibited by lorglumide.

Animals↗
PubMed1993

Overexpression of messenger RNA for cholecystokinin-A receptor and novel expression of messenger RNA for gastrin (cholecystokinin-B) receptor in azaserine-induced rat pancreatic carcinoma.

Using receptor binding assays, we have previously demonstrated the overexpression of the high-affinity cholecystokinin (CCK) receptor and the novel expression of the gastrin (CCK-B) receptor in the azaserine-induced rat pancreatic carcinoma DSL-6. Since cDNA of both the CCK-A receptor (classical pancreatic CCK receptor) coding region and the CCK-B receptor coding region have recently been cloned and sequenced, we investigated the expression of messenger RNA of these receptors in DSL-6 pancreatic carcinoma. Our results showed that the 32P-labelled cDNA probe of the CCK-A receptor coding region hybridized with an approximately 2.7 kb mRNA from both DSL-6 pancreatic carcinoma and normal rat pancreas. However, the relative expression of the CCK-A receptor mRNA in DSL-6 pancreatic carcinoma was approximately 8-fold of that in normal rat pancreas. The 32P-labelled cDNA probe of the CCK-B receptor coding region hybridized with an approximately 2.7 kb mRNA from DSL-6 pancreatic carcinoma; no hybridizing mRNA could be identified from normal rat pancreas. In summary, the CCK-A receptor mRNA is overexpressed approximately 8-fold and the gastrin (CCK-B) receptor mRNA is novelly expressed in DSL-6 pancreatic carcinoma as compared to normal rat pancreas. These results further confirm our previous findings based on receptor binding assays. The gene overexpression of the CCK-A receptor and the novel gene expression of the gastrin (CCK-B) receptor may be generated by alterations in gene regulation during carcinogenesis, and may play an important role in promoting tumor growth.

Animals↗
PubMed1986

Adenosine triphosphatase, a new marker for the differentiation of putative precancerous foci induced in rat pancreas by azaserine.

Enzyme-histochemical investigation of pancreatic carcinogenesis in male Wistar rats treated at the age of 19 days by a single dose of 30 mg azaserine/kg body wt led to the detection of a new 'marker' for the recognition of foci of atypical acinar cells: the Mg2+-dependent ATPase. The two well-known populations of pancreatic atypical acinar cell foci, classified histologically as basophilic and acidophilic foci, showed a decreased and strongly increased ATPase reaction, respectively. The enhanced enzyme activity of the acidophilic foci has been characterized as unspecific nucleoside polyphosphatase. To validate the new marker, comparative quantitative evaluation was performed on haematoxylin and eosin-stained paraffin sections and ATPase-stained cryostat sections of the same pancreata of 25 azaserine-treated rats. Evaluation of basophilic ATPase-deficient foci of small diameter was more reproducible in haematoxylin and eosin-stained sections, while small acidophilic strongly ATPase-positive foci could be detected more reliably by the ATPase staining technique. The number of foci/cm3 pancreas was similar for both staining techniques above a focus diameter of about 100 microns for basophilic foci and 200 micronfor acidophilic foci. There were more acidophilic than basophilic foci/cm3 pancreas, and the acidophilic foci had significantly larger mean focal diameters than the basophilic foci. Together with the strong acidophilic staining of the latter emerging adenoma, this suggests that the acidophilic foci represent a neoplastic cell population progressing eventually to pancreatic carcinoma. The new 'marker' enzyme ATPase may greatly facilitate further investigations into the role of these putative preneoplastic lesions in pancreatic carcinogenesis.

Adenosine Triphosphatases↗
PubMed1988

The production and repair of DNA damage by N-nitrosobis(2-oxopropyl)amine and azaserine in hamster and rat pancreas acinar and duct cells.

The activation of N-nitrosobis(2-oxopropyl)amine (BOP) by pancreas acinar and duct tissue from Syrian hamsters and MRC-Wistar rats in vitro and in vivo was measured in terms of the production and repair of DNA damage. Hamsters were given BOP (1 X 10 mg/kg, s.c.). DNA single strand breaks (SSB) were measured over 2 weeks. Significantly more SSB were present in duct than in acinar tissue. Their persistence in the duct fragments was due to a slower rate of repair. In a related experiment, duct fragments were isolated from BOP-treated (1 X 10 mg/kg, s.c.) hamsters 24 h after exposure and cultured for 6 days, or were isolated 7 days after exposure. The extent of DNA damage was comparable in the two groups, indicating that the repair process(es) were still operative in cultured cells. Isolated duct fragments were exposed to either BOP or N-nitrosomethyl(2-oxopropyl)amine (MOP) in vitro. MOP produced significantly more DNA damage than BOP even at a 5-fold lower dose. This is consistent with the greater carcinogenicity of MOP in the pancreas. BOP produced significantly less DNA damage in the rat pancreas than in the hamster pancreas. The rate of repair was at least twice as fast in the rat pancreas as in the hamster pancreas. There did not appear to be any preference for acinar or duct tissue in rats as there was in hamsters. This procedure was validated in rats by the use of the rat pancreas carcinogen azaserine, which only produced DNA damage in rat acinar tissue.

Animals↗
PubMed1977

Effect of age on nodule induction by azaserine and DNA synthesis in rat pancreas.

The efficacy of various azaserine treatment durations was evaluated with respect to induction of atypical acinar cell nodules in Wistar rat pancreas and was related to animal age and rate of pancreatic DNA synthesis during growth. The sensitivity to nodule induction was maximal in postnatal rats when the rate of pancreatic DNA synthesis was high, whereas treatment of weanlings was less effective and treatment of mature rats was least effective. When weaned growing rats were given 1, 3, or 5 weekly injections of 30 mg azaserine/kg, the number of nodules induced was proportional to the number of injections. A single dose at this level did not induce detectable pancreatic necrosis or inflammation; therefore, DNA synthesis due to regeneration was probably not a major factor in the initiation of nodules. We concluded that multiple daily injections of [3H]thymidine during the first or second postnatal week provided DNA of sufficiently high specific activity for use in DNA repair and biochemical toxicity studies.

Aging↗
PubMed1985

Dietary intervention during the postdosing phase of L-azaserine-induced preneoplastic lesions.

The effects of intervention by diets with high or low levels of dietary fat on the development of preneoplastic pancreatic lesions were examined. Wistar rats were treated ip at 14 days of age with a 30-mg/kg dose of L-azaserine [CAS: 115-02-6; diazoacetate serine (ester)] and weaned onto the test diets. Animals fed 5% corn oil had fewer preneoplastic lesions compared to animals fed 20% corn oil throughout the 4-month posttreatment period. The strong response observed in rats fed 20% corn oil could be markedly reduced by intervention with a 5% corn oil diet halfway through the posttreatment period. Similarly, the low response in animals fed 5% corn oil could be markedly elevated by intervention with a high-fat diet. These results provide evidence for the hypothesis that tumor development may be modified by dietary means.

Animals↗
PubMed1985

Effect of dietary intake of fish oil and fish protein on the development of L-azaserine-induced preneoplastic lesions in the rat pancreas.

The effect of dietary intake of fish (menhaden) oil and fish (cod) protein on the development of pancreatic preneoplastic lesions was examined in male Wistar rats. Fourteen-day-old animals were given a single ip injection of 30 mg L-azaserine/kg body weight [CAS: 115-02-6; diazoacetate serine (ester)]. At 21 days of age they were weaned and maintained on dietary treatment for 4 months. Fish protein did not appear to produce a significantly different preneoplastic response when compared to casein as a protein source. However, a 20% menhaden oil diet, rich in omega 3 fatty acids, produced a significant decrease in the development of both the size and number of preneoplastic lesions when compared to a 20% corn oil diet rich in omega 6 fatty acids. This study provides evidence that fish oils, rich in omega 3 fatty acids, may have potential as inhibitory agents in cancer development.

Animals↗
PubMed1990

L-azaserine induced preneoplasia in the rat pancreas. A morphometric study of dietary manipulation (lipotrope deficiency) and ultrastructural differentiation.

Putatively preneoplastic, pancreatic atypical acinar cell foci (AACF) and nodules (AACN), collectively termed atypical acinar cell lesions (AACL), were induced in male Lewis rats by L-azaserine (300 mg/kg body weight [bw] in divided doses). Rats given carcinogen and then fed a lipotrope deficient (LD) diet developed a significantly greater number of larger lesions than animals fed complete diet throughout the experiment. It is suggested that lipotrope deficiency plays a promoting role in this model of pancreatocarcinogenesis. Ultrastructural morphometric studies of AACF, when compared to control tissues, revealed the following significant results: 1) a decrease in surface area of cell cytoplasm with no change in nuclear area, and hence increased nucleus/cytoplasm (N/C) ratio; 2) a reduction in size and uniformity of zymogen granules; and 3) an increase in number of granules per microns 2 of cell. The results suggest that arrested development of the AACF cells is associated with reduced cytoplasm and zymogen production per cell. AACL may be eosinophilic due to an overall increased concentration of zymogen in these hyperplastic lesions and not because individual acinar cells in the AACL contain an increased amount of zymogen or are "zymogen-rich," as has been reported.

Animals↗
PubMed2001

Ubiquitin cytochemical changes during azaserine-initiated pancreatic carcinogenesis.

The ubiquitin (Ub)-proteasome proteolytic system is highly selective, and the specific proteins involved in cell division, growth, activation, signaling and transcription are degraded at different rate depending on the physio-pathological state of the cell. Ubiquitination serves first of all as a signal for protein degradation of short-lived and abnormal proteins under several stressful conditions. The immunocytochemical localization of Ub in some malignant tumours has recently been presented and differences in Ub expression has been observed during malignant transformation. Change in the level of Ub and Ub-conjugated proteins might reflect a higher metabolic-catabolic ratio in neoplastic cells. Most studies have been focused on the malignant stage of tumour progression, and only a few papers have dealt with the change in Ub and Ub-protein conjugates level during the whole progression. To address this problem, we applied an azaserine-induced pancreatic carcinogenesis model, in which premalignant and malignant stages were investigated throughout the progression. The level of Ub immunoreactivity was measured in nucleus and cytoplasm by electron microscopic immunocytochemical and morphometrical methods. We found a significant increase of Ub level in the nucleus and the cytoplasmic area in premalignant atypical acinar cell nodule (AACN) cells and in malignant adenocarcinoma in situ (CIS) cells at month 20 after initiation.

Adenocarcinoma↗
PubMedDate not supplied

Angiogenesis is continuous with two peaks during azaserine-induced rat pancreatic adenocarcinoma progression: an electron microscopic morphometrical study.

Although the indispensable role of neoangiogenesis in tumour growth became generally accepted, quantitative microvascular changes associated to tumour progression have been followed only in a few experimental models. In our study a further experimental system, the azaserine-induced rat pancreatic adenocarcinoma was applied for this purpose. The 15-20 month long progression of this tumour provides us a special opportunity to dissect multistage carcinogenesis in different respects. Tumour samples were taken at months 6, 8 (early lesions), 10, 13, 15 (adenomas), and 20 (differentiated and anaplastic adenocarcinomas) and identified by semithin section histology. We applied reliable and reproducible electron microscopic morphometry for quantification of capillary volume and surface densities in unit tissue volume. Correlation of microvessel volume (MVVD) and surface (MVSD) density data indicated that their changes were the consequence of the changing balance between tumour growth and neoangiogenesis. The significantly decreased but persistent size of the tumour microvasculature during the early slow premalignant growth (months 6-10) is indicative for a slow, but continuous balanced angiogenesis. A dramatic MVVD and MVSD increase at month 13 and the consecutive decrease measured in month 15 adenomas depicted a hitherto unprecedented angiogenic wave within the month 10-15 premalignant growth period. The size of the tumour microvasculature became again stabilized below the control level for the next 5 months of slow growth during which, however, several differentiated adenocarcinomas were transformed to fastly growing angiogenic anaplastic carcinomas, some of which gave rise to invasive tumours. These findings once again verify the angiogenic switch theory.

Adenocarcinoma↗