[CANCER RESEARCH 35, 2269-2277, August 1975]

cinoma, which could be of considerable value in theunderstanding of pathogenetic processes of this tumor. Inaddition, an animal model may serve as an effective systemfor various experimental manipulations aimed at preventingor significantly altering the natural progression of thedisease. The lack of experimental work on pancreaticcarcinogenesis may be attributed, in part, to inherentdifficulties in working with pancreas of most laboratoryanimals.

Druckrey et a!. (6) in 1968 reported that prolongedadministration of MNU3 or N-methyl-N-nitrosourethan indrinking water to outbred guinea pigs produced adenocarcinoma of the pancreas and stomach. The average induction time of these tumors with MNU was approximately740 days, and with N-methyl-N-nitrosourethan it wasabout 800 days. In addition to long latency, the overall incidence of pancreatic adenocarcinoma in these studies wasobserved to be about 25% (2). The unusually long inductionperiod and low yield of pancreatic tumors were consideredas serious limitations to the usefulness of this model. Themain objectives of the work currently in progress in ourlaboratory are: (a) to confirm the development of pancreatic carcinoma in guinea pigs treated with MNU andto study the histogenesis of these tumors; (b) to reduce theinduction period of @800days; and (c) to increasethe incidence of pancreatic tumors. As indicated elsewhere (19),a short latency period and a high yield of pancreatic adenocarcinomas, without concomitant development of tumors ofother organs, are 2 major criteria for a satisfactory animalmodel of this tumor. In the present communication, wereport the development within 44 weeks of pancreaticadenocarcinomas in inbred guinea pigs given MNU onceweekly by gavage.

Materials and Methods

Inbred strain 13 guinea pigs, weighing between 250 and300 g, were obtained from Frederick Cancer ResearchCenter, Frederick, Md. These animals were housed 2 to3/cage and were maintained on Purina guinea pig chow(Ralston Purina Company, St. Louis, Mo.). After 1 weekof acclimation to housing conditions, 62 female and 12male guinea pigs were started on once-weekly i.g. administration of MNU (Ash Stevens Inc., Detroit, Mich.), 10mg/kg. Since MNU is rapidly inactivated, it was usuallydissolved in 0.015 M sodium citrate buffer, pH 6.0, as 1%

3 The abbreviations used are: MNU, N-methyl-N-nitrosourea; i.g., in

tragastric.

Summary

Long-term studies of the carcinogenicity of N-methyl-N-nitrosourea (MNU) in inbred guinea pigs were undertakento develop an animal model of pancreatic adenocarcinoma.MNU, freshly dissolved in 0.015 M sodium citrate buffer,pH 6.0, was administered by gavage once weekly at a doseof 10 mg/kg body weight to inbred strain 13 guinea pigs. By27 weeks, 54% of guinea pigs given MNU weekly died,

mostly due to severeatrophy and fatty metamorphosis ofthe exocrine acinar cells of the pancreas. Of 34 guinea pigsthat survived more than 27 weeks of MNU administration,10 (29%) developed pancreatic adenocarcinoma between 28and 44 weeks. Other tumors included adenocarcinoma ofthe stomach (two animals) and of colon (one animal),lymphoma of mesenteric nodes (three animals), and ahepatoma (one animal).

Atypical changes involving acinar cells were observed incertain pancreatic lobules and included ductular or pseudoductular transformation, acinar ectasia, increased mitoticactivity, and periacinar fibrosis. These changes are suggestive of acinar cell dedifferentiation, and their role, if any, inthe histogenesis of pancreatic adenocarcinoma remains tobe elucidated.

These studies suggest the feasibility of using inbredguinea pigs for developing a satisfactory model of pancreatic adenocarcinoma. Additional studies are necessary tominimize the high mortality rate during the first 6 monthsand to enhance the incidence of pancreatic adenocarcinoma.

Introduction

The incidence of pancreatic adenocarcinoma in theUnited States and elsewhere in highly developed countrieshas shown a significant increase in recent years (1, 5, 20,2 1). Cancer of the pancreas ranks as the 4th leading cause of

death from cancer in the United States (I) and, despiteseveral recent epidemiological studies (9, 11, 14, 20, 21), thefactors involved in the causation of pancreatic cancer arenot clearly delineated. However, until recently, very littleattention has been devoted by the experimental oncologistto develop a suitable animal model of pancreatic adenocar

1 Presented at the symposium “Current Progress in Pancreatic

Carcinogenesis Research,― February 4, 1975, Orlando, Fla., as part of theThird Annual Carcinogenesis Conference. Supported by USPHS ContractNIH-NCI-E-72-327l from the National Cancer Institute.

2 Presenter. To whom requests for reprints should be addressed.

AUGUST 1975 2269

Pancreatic Adenocarcinoma in Inbred Guinea Pigs Induced byN-Methyl-N-nitrosourea'

Janardan K. Reddy2 and M. Sambasiva Rao

Department of Pathology and Oncology, University of Kansas Medical Center, College of Health Sciences and Hospital, Kansas City, Kansas 66103

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GroupSexNo.

ofanimals

EffecInitial tiveaNo.

ofguinea pigs with tumorsofPan

creasbStom achcIntestinecOtherControl

MNUFemaleMaleFemaleMale6

1262126

1228

67 31 113d l@

J.K.Reddy and M. S. Rao

solution 5 to 10 mm prior to dosing. The half-life of MNUat pH 6.0 in 0.015 M sodium citrate buffer, as determinedin preliminary studies, was approximately 20 hr. Theanimals were starved for 22 hr before i.g. administration ofMNU, in order to ensure an empty stomach. The controlgroup consisted of 12 male and 6 female guinea pigs givenidentical volumes of citrate buffer by gavage once a week.The guinea pigs were allowed accessto food 1 hr afterMNU treatment. Autopsies were done on animals thatdied overnight or were found moribund. For light microscopy, tissues were fixed in formalin and embedded in paraffin. Sections of tumors, pancreas, stomach, and liver wereroutinely stained with hematoxylin and eosin, but when indicated periodic acid-Schiff and mucicarmine stains werealso done.

Results

General. The survival of guinea pigs treated with MNUand tumor incidence are summarized in Table 1. By 27weeks, 54% of guinea pigs receiving MNU died. During theinitial stages of the experiment (1st 4 weeks), deaths weredue to pulmonary hemorrhage or pneumonia. Some animals also died of hemorrhagic necrosis of the gastricmucosa, occasionally complicated by perforation andperitonitis. In guinea pigs that died subsequently, therewas marked atrophy of exocrine pancreas (Figs. 1 and 2).In these animals, pancreatic lobules were greatly reducedin size and the interlobular connective tissue was infiltratedwith fat. The exocrine acinar elements were small andcrowded together. The acinar cell cytoplasm was scantyand displayed a prominent solitary fatty vacuole (Fig. 2),which usually displaced the nucleus to 1 side. The thinrim of acidophilic cytoplasm surrounding the fatty vacuolecontained few zymogen granules. Necrosis of the acinarcells was not observed at any time. There was no significant mitotic activity in acinar cells that showed fattyvacuolation during the 1st 6 months of the experiment.Likewise, mitotic activity in the lining epithelium of thepancreatic ducts was minimal. An occasional duct showeda mild degree of hyperplasia of submucosal or basal

glands. The islets of Langerhans appeared very prominent (Fig. 1) but showed no atypical changes. In essence,the most .significant alteration, in pancreasof guinea pigsthat died within 27 weeks of the experiment, is atrophyand fatty degeneration of the exocrine acinar cells. Theseanimals also had a moderate to severe degree of fattymetamorphosis of the liver parenchyma, possibly resultingfrom functional insufficiency of pancreaticenzymes.

Atypical Acinar Proliferation. In 4 guinea pigs that diedbetween24 and 32 weeks,certain atypical changesin somepancreatic lobules were noted. In Fig. 3, a small focus ofpseudoductular proliferation is shown at the periphery of anatrophic pancreatic lobule. These glandular structures arelined by cuboidal epithelium which each contain a prominent vesicular nucleus. In a guinea pig that died at 30 weeks,2 adjacent pancreatic lobules showed atypical changes (Fig.4). These lobules appeared distinct when compared to otherlobules that were atrophic with fatty vacuolation. In theselobules, the acinar component was irregular and surroundedby periacinar fibrosis. The islets of Langerhans were smallin these lobules. In another guinea pig (Fig. 5), thepancreatic lobule showed marked desmoplastic reaction andhighly atypical acinar component. These acini appeareddilated and tortuous and were irregular in size, closelyresembled proliferating ducts. Destruction of islets ofLangerhans in these lobules was also evident. At 32 weeks,the pancreas of I guinea pig demonstrated severe ectaticchanges of exocrine acini in many lobules (Fig. 6). Theseacini appeared markedly dilated and lined by cuboidal orflat epithelium. Mitotic activity was frequent in the lining

epithelium (Fig. 7). In spite of these severe atypicalalterations, the lobular pattern of the pancreas was maintamed (Fig. 6). These changes suggest that the exocrineacinar cells are capable of dedifferentiation into ductular orpseudoductular structures.

Pathology of Tumors. Of 34 guinea pigs that survivedmore than 27 weeks ofMNU administration, 12 females (19of 28) and 3 males (5 of 6) developed tumors between 28 and44 weeks after the beginning of the experiment (Table 1).Pancreatic tumors were found in 7 female (7 of 28) and 3male (3 of 6) guinea pigs; this accounted for an incidence of

Table IIncidence of tumors in inbred strain 13 guinea pigs given MNU

Animals were given MNU in a dose of 10 mg/kg body weight by gavage once weekly. Tumorswere discovered in animals dead or killed between 28 and 44 weeks and were determined by grossand microscopic examination of tissues.

a Number of guinea pigs that survived more than 27 weeks.

b Adenocarcinoma of exocrine pancreas.

C Adenocarcinoma.

d Lymphoma of mesenteric nodes.

e Hepatocellular carcinoma of the liver.

2270 CANCER RESEARCH VOL. 35

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Pancreatic Adenocarcinoma in Guinea Pig

29% in animals surviving more than 27 weeks. Among theother tumors were adenocarcinoma of the stomach (2guinea pigs) and colon (1 guinea pig); lymphoma involvingmesentericlymph nodes(3 guinea pigs); and a hepatocellular carcinoma (1 guinea pig).

Grossly, the pancreatic tumors appeared as either irregular or well-circumscribed gray nodules of varying size,measuring 5 to 32 mm in diameter (Figs. 8 and 9). In 9animals, the pancreatic tumors were solitary and in 1 thepancreas contained 2 small tumors. These tumors werelocated either in the duodenal segment (“head―)or in thegastric segment (“body―)of the pancreas. No tumors wereseen in the splenic segment (“tail―)of the pancreas.Histologically, the pancreatic tumors were adenocarcinomas showing varying degrees ofdifferentiation (Figs. 10to 12). The glandular differentiation and marked desmoplastic reaction of the stroma resembled adenocarcinomasof ductal origin, similar to those occurring in the humanpancreas (4, 15). Invasion of the duodenum, regional lymphnodes (Fig. 13), and perineural spaces was occasionallyencountered. Peritoneal dissemination of pancreatic tumorswas not noted.

The adenocarcinomas of the stomach and carcinoma ofcolon were well differentiated. Lymphomas involved themesenteric nodes diffusely and were predominantly lymphocytic in nature. The liver tumor was a highly vascular hepatocellular carcinoma.

Discussion

The studies presented here confirm the earlier report ofDruckrey et a!. (6) that chronic administration of MNU toguinea pigs results in the development of pancreatic adenocarcinomas. However, the promising aspect of this study isthat the pancreatic tumors developed in less than I year,when compared to long latency period of @740daysdescribed by Druckrey et a!. (6). There are 2 possibleexplanations for the reduction in induction period ofpancreatic tumors. First, outbred guinea pigs were used byDruckrey et al. (6) whereas inbred strain 13 guinea pigs wereused in the present investigation, and this may imply relativesusceptibility of this inbred strain to the rapid induction ofpancreatic adenocarcinoma (18). Second, in the presentstudies, the freshly mixed carcinogen was administered bygavage once a week in a dose of 10 mg/kg body weight toanimals starved for approximately 22 hr prior to dosing tominimize degradation of MNU and to ensure rapid absorption from the gut. Druckrey et a!. (6) added the carcinogento drinking water, 5 days a week, in a daily dose of 2.5mg/kg body weight. These differences in the delivery ofcarcinogen may also have accounted for increased mortality(about 54%) of guinea pigs within the 1st 27 weeks of ourexperiment. For prevention of this high mortality rate, itappears necessary to reduce the dose of MNU in futureexperiments.

Whatever might be the reason for the reduction in tumorinduction time, this inbred strain of guinea pigs may proveto be of considerable value in ultimately developing asatisfactory animal model of pancreatic carcinoma, because

of the histological resemblance of these tumors to humanpancreatic adenocarinoma (4, 15). Furthermore, theseguinea pigs with pancreatic carcinoma did not developsimultaneous tumors of other organs, which is an importantconsideration in evaluating the suitability of an animalmodel of a specific disease entity. Despite this initialoptimism, there are, however, several deficiencies that mustbe rectified before this can be successfully used as an animalmodel. One of these is high mortality rate among theanimals given MNU and the severe atrophy of exocrinepancreas. It is anticipated that a substantial reduction in theamount of carcinogen administered weekly, parenteraladministration of selected fat-soluble vitamins, and/orsupplementing the diet with lipotrope factors and pancreaticenzymes may prevent excessive mortality during the 1st 6months of the experiment. Another drawback appears to bethe low incidence of pancreatic tumors (about 29%) inguinea pigs that survived more than 27 weeks of MNUtreatment. It may be possible to enhance the incidence ofpancreatic adenocarcinoma in inbred guinea pigs, if MNUis given to these animals: (a) during experimentally inducedpancreatic cell division (3, 7, 12, 17, 19); (b) in associationwith high-fat or low-fat diets; and (c) in combination with aknown carcinogen for pancreas, such as azaserine (13),2,2'-dihydroxydi-N-propylnitrosamine (10, 16), or 4-hydroxyaminoquinoline I-oxide (8). These possibilities arecurrently under investigation in this laboratory in ourattempt to develop an animal model that can simulate thepancreatic cancer in man.

Although the histological appearance of pancreatic tumors in guinea pigs, which was characterized by glandulardifferentiation and desmoplastic stroma, was highly suggestive ofductal origin, it may be premature to speculate on thehistogenesis of these tumors. The atypical changes noted inthe exocrine acinar element of pancreas (Figs. 5 to 7) raisethe possibility that well-differentiated acinar cells arecapable of dedifferentiation into ductular structures. 5everal studies have shown that differentiated acinar cells ofpancreas divide following appropriate stimulation (3, 4, 12,17, 19), and it is plausible to assume that these cells candedifferentiate into ductal epithelium. Additional sequentialmorphological studies may shed some light on the role ofacinar and ductal cells in the histogenesis of pancreaticadenocarcinoma.

Recent attempts to induce carcinoma of the pancreas inexperimental animals have met with considerable success(10, 13, 16, 18). Longnecker and Curphey (13) haveobserved predominantly acinar-cell carcinomas of the exocrine pancreas in rats treated with azaserine. The studies ofKrUger et al. (10) and Pour et a!. (16) have demonstratedthat 2,2'-dihydroxydi-N-propylnitrosamine producedmostly ductal adenocarcinomas of pancreas in the Syriangolden hamster. This hamster model of pancreatic adenocarcinoma appears to be highly promising because of thehigh tumor incidence and short induction period. However,1 obvious disadvantage is that nearly 72 to 100% ofhamsters with pancreatic tumors also had tumors of othersites (16). Hayashi and Hasegawa (8) reported the appearance of exocrine adenomas in pancreas of rats treated with

AUGUST 1975 2271

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J. K. Reddy and M. S. Rao

4-hydroxyaminoquinoline 1-oxide. However, this compound failed to induce tumors in guinea pig pancreas (M. S.Rao, unpublished data), suggesting a need to investigatefurther into the species and strain differences in theinduction of pancreatic tumors with these various carcinogens. In conclusion, although some progress has been madein experimental pancreatic oncogenesis in the last 2 to 3years, a great deal of experimental work has to beundertaken to refine these animal models of pancreaticcarcinoma.

References

I. American Cancer Society. ‘72Cancer Facts and Figures, 72 pp. NewYork: American Cancer Society Inc., 1972.

2. BUcheler, J., and Thomas, C. Experimentell erzeugte Drusenmagentumoren bei Meerschweinchen und Ratte. Beitr. Pathol. Anat. Allgem.Pathol., 142: 194-209, 1971.

3. Cameron, G. R. Regeneration ofthe Pancreas. J. Pathol., 30: 7 13—728,1927.

4. Cubilla, A. L., and Fitzgerald, P. J. Morphological Patterns ofPrimary Nonendocrine Human Pancreas Carcinoma. Cancer Res., 35:2234-2248,1975.

5. Doll, R., Muir, C. S., and Waterhouse, J. A. H. Cancer Incidence inFive Continents. UICC Monograph No. 2. Geneva: Union Internationale Contre Ic Cancer, 1970.

6. Druckrey, H., lvankovic, S., Bucheler, J., Preussmann, R., andThomas, C. Erzeugung von Magen-und pankreas-krebs beim meerschweinchen durch methyl-nitroso-harnstoff und -urethan. Z. Krebsforsch.,71:167-182,1968.

7. Fitzgerald, P. J., Herman, L., Carol, B., Roque, A., Marsh, W. H.,Rosenstock, L., Richardson, C., and Perl, D. Pancreatic Acinar CellRegeneration. I. Cytologic, Cytochemical and Pancreatic WeightChanges.Am. J.Pathol.,52:983-1011,1968.

8. Hayashi, Y., and Hasegawa, T. Experimental Pancreatic Tumor inRats after Intravenous Injection of 4-Hydroxyaminoquinoline- 1-

oxide.Gann, 62:329-330,1971.

9. Krain, L. S. Cancer Incidence. The Crossing of the Curves forStomach and Pancreatic Cancer. Digestion, 6: 356—366, 1972.

10. Kruger, F. W., Pour, P., and Althoff, J. Induction of Pancreas Tumorsby Diisopropanolnitrosamine. Naturwissenschaften, 6/: 328, 1974.

11. Levin, D. L., and Connelly, R. R. Cancer of the Pancreas. AvailableEpidemiologic Information and Its Implications. Cancer, 3!:1231-1236,1973.

12. Longnecker, D. S., Crawford, B. G., and Nadler, D. J. Recovery ofPancreas from Mild Puromycin-induced Injury. A Histologic andUltrastructure Study in Rats. Arch. Pathol., 99: 5—10,1975.

13. Longnecker, D. S., and Curphey, T. J. Carcinoma of the Pancreas inAzaserine-treated Rats. Cancer Res., 35. 2249-2258, 1975.

14. Mainz, D., and Webster, P. D., III. Pancreatic Carcinoma. A Reviewof Etiologic Considerations. Am. J. Digest. Diseases, 19: 459—464,1974.

15. Miller, J. R., Baggenstoss, A. H., and Comfort, M. W. Carcinoma ofthe Pancreas: Effect of Histological Type and Grade of Malignancy onIts Behaviour. Cancer, 4: 233-241, 1951.

16. Pour, P., KrUger, F. W., Althoff, J., Cardesa, A., and Mohr, U.Cancer ofthe Pancreas Induced in the Syrian Golden Hamster, Am. J.Pathol., 76: 349-358, 1974.

17. Reddy, J. K., Rao, M. S., Svoboda, D. J., and Prasad, J. D. PancreaticNecrosis and Regeneration Induced by 4-H ydroxyaminoquinoline- I-oxide in the Guinea Pig. Lab. Invest., 32: 98- 104, 1975.

18. Reddy, J. K., Svoboda, D. J., and Rao, M. S. Susceptibility of anInbred Strain of Guinea Pigs to the Induction of Pancreatic Adenocarcinoma by N-Methyl-N-Nitrosourea. J. NatI. Cancer Inst., 52:991-993, 1974.

19. Wenk, M. L., Reddy, J. K., and Harris, C. C. Pancreatic RegenerationCaused by Ethionine in the Guinea Pig. J. Nail Cancer Inst., 52:533—538,1974.

20. Wynder, E. L., Mabuchi, K., Maruchi, N., and Fortner, J. G. A CaseControl Study ofCancer ofthe Pancreas. Cancer, 31: 641 -648, 1973.

21. Wynder, E. L., Mabuchi, K., Maruchi, N., and Fortner, J. G.Epidemiology of Cancer of the Pancreas. J. Natl. Cancer Inst., 50:645-667,1973.

Fig. 1. Portion of the pancreas from a guinea pig treated with MNU (10 mg/kg body weight) for 16 weeks shows marked atrophy ofexocrine acinartissue and hypertrophy of islets of Langerhans. H & E, x 45.

Fig. 2. Higher magnification of a portion of pancreas from same guinea pig as in Fig. 1 reveals distortion of acinar pattern and atrophy of cytoplasm.Fatty vacuolation of acinar cell cytoplasm is prominent. H & E, x 312.

Fig. 3. Pancreas ofguinea pig treated with MNU for 24 weeks. A small focus ofpseudoductular tissue shown here may be acinar in origin (arrows). H& E,x 120.

Fig. 4. Pancreas of guinea pig treated with MNU for 30 weeks. Note 2 areas (A and B) of atypical proliferation of acinar elements. Acini areirregular. Periacinar fibrosis is also seen in these nodules. The remaining pancreatic lobules (arrows) are atrophic. H & E, x 25.

Fig. 5. Irregular proliferation of acinar elements and periacinar dense connective tissue are seen in another pancreatic nodule from a guinea pigtreated with MNU. H & E, x 45.

Fig. 6. Guinea pig treated with MNU for 32 weeks. Note advanced pseudoductular transformation of exocrine acini although the lobular pattern isstill maintained in this pancreas. H & E, x 90.

Fig. 7. Higher magnification of a portion of a pancreatic lobule from same guinea pig as in Fig. 6 reveals markedly irregular and dilated glands.Occasional mitotic figures (arrows) are present in the lining epithelium. H & E, x 225.

Fig. 8 to 9. Guinea pigs dead at 32 (Fig. 8) and 40 weeks (Fig. 9) of MNU treatment reveal tumors in the proximal segment (close to duodenum) ofpancreas (arrows).

Fig. 10. Adenocarcinoma, well-differentiated, of pancreas from a guinea pig treated with MNU for 33 weeks. The stroma is markedly desmoplastic.Arrow, portion of a noruial pancreati@ lobule. H & E, x I 15.

Fig. I I . Adenocarcinoma of pancreas from a guinea pig given MNU for 38 weeks. Lower left (arrow), few normal-appearing pancreatic acini.H & E, x 85.

Fig. 12. Adenocarcinoma of pancreas, poorly differentiated, from a guinea pig treated with MNU for 36 weeks. H & E, x 120.Fig. 13. Metastasis in a pancreatic lymph node ofpancreatic adenocarcinoma from same guinea pig as in Fig. 14. Top, aggregates oflymphocytes and

a portion of normal pancreas. H & E, x 120.

2272 CANCER RESEARCH VOL. 35

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Dr. Fitzgerald: I think we have2 models now that simulatethe pancreas cancers seen in the human. I would have asmall caveat with Dr. Reddy because, where he showsacinar cells in the dilated ductule areas, he implies that ductcells arise from acinar cells. I don't believe this, because theidentical picture is seen if you tied off splenic pancreassegment duct as we did some years before. Did you doelectron microscopy in these suspected areas?

Dr. Reddy: No, we have not done ultrastructural studiesofthese areas.

Dr. Fitzgerald: I think oneof the big problems in pathologyarises when you begin to “see―transition cell types.Propinquity is unreliable in this area. Admittedly, it wouldbe scientific cuckoldry to ignore the juxtaposition of celltypes, but it is extremely difficult to interpret these anatomical relationships in precursor or transitional terms. I doubtthat acinar cells transform into duct cells. I believe thatacinar and islet cells are pretty much the end of the trail interms of differentiation. So far, “dedifferentiation,― if itexists, is a rare event in animals (if dedifferentiation means

that the cells are starting out at the end of differentiationand going back to the primitive cell of origin). I wouldsuspect that the duct cells might be able to differentiate intoislet and acinar cells but the reverse, acinar cells to ductcells, I rather doubt. I've never seen an example of it inexperimental pancreas studies. Otherwise, I think this avery fine model and one which will have considerable value.

Dr. Reddy: Thank you for your comments. I do realize thatthe question of dedifferentiation, particularly in pancreas, isa very difficult problem to prove. However, the illustrationsshown here (see Figs. 5 to 7 of the preceding paper) stronglysuggestthat acini are capableof transforming into, at least,pseudoductules.

Dr. Preussmann: I would like to comment on the highmortality in your experiments. You also indicated that apossible explanation for low tumor incidence in our experiments in Germany was that the compound was administeredin the drinking water and that decomposition of thecarcinogen could have occurred. I think that this is not true.Our animals were housedovernight without water, and the

2276 CANCER RESEARCH VOL. 35

Informal Discussion following the Paper by Reddy and Rao

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1975;35:2269-2276. Cancer Res   Janardan K. Reddy and M. Sambasiva Rao 

-nitrosoureaN-Methyl-NPancreatic Adenocarcinoma in Inbred Guinea Pigs Induced by

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