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immunodeficiency) mice, which have a combined T and B-cell deficiency, and beige nude mice, which are triple-deficient in T-cells, B-cells and natural killer cells, have been studied as the host for human pancreatic cancer 25, 36 . It appears that the grade of immunodeficiency does not substantially influence the tumor take and growth. The metastatic potential in different hosts, for example, was found to be cell line dependent and does not increase as the host becomes more immunodeficient 37 . The xenograft models can basically be divided into orthotopic versus ectopic transplantation, and the use of tumor cell suspension versus whole tumor fragments. The pros and cons of each model are discussed elsewhere. Injection sites of pancreatic tumor cells include tissues like the pancreas, liver, spleen, skin and muscle, or injection into the vascular system, for example via the dorsal vein of the tail, the portal vein, intra-arterially or intracardially 36 . Whole tumor fragments are usually implanted subcutaneously or orthotopically 36 . Hotz et al. introduced a less traumatic induction procedure by using micro surgically prepared tissue pockets within the pancreatic parenchyma 25 . 2d. Transgenic Mice The introduction of genes into the germ lines of mammals opened up new possibilities for generating pancreatic cancer models. Different methods are used to introduce foreign genes, including the direct micro-injection of recombinant DNA into the pronucleus of a fertilized egg, the transfection of embryos with retroviruses, or the introduction of DNA by viral transduction or transfection into embryonic stem cells established in vitro from explanted blastocysts 38, 39 . Transgenic mice bearing the elastase promoter SV40 early antigen construct (Ela-1-SV40 T) develop focal acinar cell proliferative lesions that develop into carcinomas with a high incidence after three to six months. This antigen is a potent oncoprotein that exerts its oncogenic effect by inactivating the tumor suppressor genes p53 and Rb 40 . Beside the acinar cell carcinomas, diverse 4 histological types of cancer, including undifferentiated and islet cell tumors occurred 12 . The RIP1-Tag model is a variation in which the antigen construct is directed against the β-cells in the islets of Langerhans 41 . Most of the islets became hyper plastic and only very few developed invasive carcinomas 40 . Another strain bearing the elastase promoter-myc construct (Ela-1-myc) developed acinar cell carcinomas with areas of ductal differentiation, but no pure ductal carcinomas appeared. However, none of the tumors contained the K-ras mutation 25, 38 . Another transgenic model was based on an activated human ras oncogene under the control of rat elastase I regulating elements 38,42 . This construct led to the formation of aggressive acinar cell type adenocarcinomas in the fetal pancreas 38 . By targeting the expression of transforming growth factor-α (TGF-α), Sandgren et al. reported the development of ductal transformation and tubular complexes composed of acinar cells 43 . Older animals in this model showed, in some instances, papillary or cystic carcinoma with ductal markers, but lacked the K-ras mutation 25 . Other groups cross-bred TGF-α with Ela-1-myc mice 44 or p53 knockout mice 45 , which increased the susceptibility and shortened the latency of pancreatic tumors, all of which showed an acinar cell phenotype. The role of islet cells in pancreatic carcinogenesis was highlighted in this model by the observation that isolated islets of juvenile mice infected with the T-oncogene produced a mixed endocrine-ductal cell line, the inoculation of which produced welldifferentiated adenocarcinomas in mice 46 . Recently, genetically engineered mouse (GEM) models of pancreatic exocrine cancer have been developed and used to elucidate mechanisms of pancreatic carcinogenesis, although the pathology is somewhat different from human cases 47 . Mouse models with pancreas-specific expression of mutant K-ras frequently develop acinar-to-ductal metaplasia and pancreatic intra-ductal neoplasms (PanINs), but few pancreatic cancers under normal conditions 48-50 . Additional alterations in tumor suppressor genes, such as p16 51 , p53 50 , dpc4 52 ,
and TGF-β receptor II 53 , or pancreatitis 54 in the GEM models have been shown to cause quite high incidences of pancreatic cancers. Transgenic rats which express a mutated Ha- or K-ras oncogene regulated by the Cre/lox system have also been demonstrated to develop pancreatic ductal carcinomas upon injection of a Cre-carrying adenovirus into the pancreatic ducts and acini via the common bile duct 55, 56 . Ela-myc transgenic mice with a mixed C57BL/6, SJL and FVB genetic background developed pancreatic tumors at two to seven months of age, and half of the tumors were ductal adenocarcinomas. The tumors metastasized to the liver in 20% of the mice. MT100/Ela-myc and MTtgfα-ES/Ela-myc double transgenic mice developed not only acinar carcinomas and mixed carcinomas as previously reported but also various ductal-originated lesions, including multi-locular cystic neoplasms and ductal adenocarcinomas. The double transgenic tumors were more malignant and metastasized to the liver at a higher frequency (33%) compared with the Ela-myc tumors. Sequencing of the coding region of p16ink4, K-ras and Rb cDNA in small numbers of pancreatic tumors did not identify mutations 57 . 2e. Other Models Systemic carcinogen administration to guinea pigs by Druckrey et al. in 1968 led to the first successful induction of tumors of questionable ductal (ductular) origin 58 . Other groups used this experimental design later with minor variations 59 , 60 . Methylnitrosourea (MNU) and methylnitrosourethane (MNUT), administrated in drinking water, was used in most of these studies and led to the induction of pancreatic adenocarcinomas with varying degrees of differentiation. The disadvantage of this model was the low tumor incidence (37%), long tumor latency (800 days) and simultaneous tumor development in many other tissues. Reddy and Rao were able to shorten the tumor latency to about 200-300 days 5 by giving freshly dissolved MNU once a week to inbred NIH guinea pigs. The tumor rate in other organs was also reduced, however, the toxic side effects of the carcinogen was quite high 21 . In guinea fowls, pancreatic lesions induced by Pts 56 retrovirus infection display a duct/ductular phenotype resembling hamster and human pancreatic lesions 61 . In this model, a high-fat diet also enhances tumor development (personal communication) and alterations of islets similar to that in hamsters. Dogs and rabbits were used sporadically in experimental pancreatic carcinogenesis. Vesselinovitch et al. 20 induced acinar and ductal cell hyperplasia in dogs by local administration of benzo(a)pyrene. Epithelial hyperplasia was further produced in canine by the perfusion of the main pancreatic duct with deoxycholate 62 or N-ethyl-N’nitro-N-nitrosoguanidine 63 . Kamano et al. 64 and Sato et al. 65 were able to produce ductal adenocarcinoma in a few dogs. The capability of the canine pancreas to metabolize N-nitrosobis(2oxopropyl)amine (BOP) was shown to be ineffective, as neither systemic nor local application of this compound could induce pancreatic carcinomas in dogs 65, 66 . Pancreatic cancer induction in rabbits was attempted by Elkort et al. 67 in 1975 by dimethylhydrazine administration into the main pancreatic duct. The induced alterations were initially described as hyperplasia, dysplasia and metaplasia of duct epithelium, and progressed to periductal adenosis and adenoma formation between 34 and 48 weeks. It is not known whether such lesions represented a pre-neoplastic alteration or merely a severe degenerativeregenerative process. Intra-ductal or retropancreatic injection of virus-induced rabbit papilloma (VX2) cells resulted in the formation of tumors with extensive lymphatic and perineural invasion 68, 69 .
Page 2 and 3: Proof Copy The Hamster as a Pancrea
Page 4 and 5: 11. Etiology of Induced Pancreatic
Page 6 and 7: This book is dedicated to the late
Page 8 and 9: with his researchers and provided h
Page 10 and 11: The first experimental pancreatic t
Page 14 and 15: CHAPTER 3 Hamsters in Toxicological
Page 16 and 17: Figure 1. Comparative data on the a
Page 18 and 19: CHAPTER 4 The Pancreas of the Syria
Page 20 and 21: This designation, although arbitrar
Page 22 and 23: through the common duct into the gu
Page 24 and 25: shape with an almost transparent cy
Page 26 and 27: of the ducts (i.e., the wider the l
Page 28 and 29: Figure 20. Pancreatic islets of Syr
Page 30 and 31: Figure 23. Two cilia in a normal ha
Page 32 and 33: Figure 27. An islet with mostly typ
Page 34 and 35: enclosed in the lymphoreticular tis
Page 36 and 37: females showed no significant diffe
Page 38 and 39: CHAPTER 6 Spontaneous Diseases of t
Page 40 and 41: incidence) and almost regularly inv
Page 42 and 43: Figure 37. Patterns of islet cell t
Page 44 and 45: Figure 39. The molecular structure
Page 46 and 47: mg/kg body wt resulted in pancreati
Page 48 and 49: Lesions were also found in the peri
Page 50 and 51: high protein diet. These findings w
Page 52 and 53: eached 50%, which was a significant
Page 54 and 55: CHAPTER 8 Metabolic Studies on Panc
Page 56 and 57: 450 3A family was involved, directl
Page 58 and 59: The ability of MOP to damage pancre
Page 60 and 61: (along with traces of BHP, but no u
Page 62 and 63:
CHAPTER 9 Drug-Metabolizing Enzymes
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Accordingly, in the rat and possibl
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carcinoma in Group 2 relate to the
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BOP by subcutaneous injection (5 mg
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Figure 52. The patterns of hamster
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experiments, SZ-induced diabetes si
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Figure 55. Presence of endocrine ce
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Figure 56. Homologous islets transp
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The normoglycemia in SZ-treated ham
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CHAPTER 11 Etiology of Induced Panc
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Among 75 adenocarcinomas, 14 (19%)
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egularly show hypertrophy and hyper
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Figure 69. Top: Hyperplastic centro
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Figure 71. Pseudoductular formation
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Figure 73. Ductular complexes showi
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Figure 75. Intra-insular ductular p
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Figure 77. a) A cystic ductule with
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Figure 79. Islet cell neogenesis. T
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Figure 81. Alteration of large and
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aising the question of the possible
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Classification of pancreatic tumors
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include those lesions which consist
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Figure 92. Intra-ductal papillomas.
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Figure 96. a) Intra-ductal carcinom
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Figure 98. Ductular (tubular), well
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Figure 103.a) Tubular mucinous carc
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Squamous cell carcinoma. Pure squam
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Figure 110. poorly differentiated p
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Figure 114. Giant cell carcinomas o
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Mixed Cell Carcinomas. As in humans
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These findings ubiquitously point t
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Figure 125. Top: Under SEM tumors p
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14a. Blood group antigen expression
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Table 2. Expression of Human Tumor
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There seemed to be differences betw
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Figure 137. Gold-labeled anti-A ant
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Table 3. Lectin-binding patterns in
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As part of our comparative studies,
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DCC, and Rb-1 suppressor genes and
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Figure 142. Karyotype of the normal
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present crucial factors. Progress h
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Figure 145. Human islets in culture
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Figure 147. Human islets in culture
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Figure 150. Chromosomal pattern of
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Carbonic anhydrase was demonstrated
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Figure 154. a) KL5N cells grew in r
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Figure 156. Tumor growth in the ham
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Figure 160. Mono nucleated and poly
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formed a large encapsulated mass wi
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1 cm in the first and the second ge
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Consequently, it must be concluded
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e transferred from the M3:5 medium,
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decrease in the HI° histone was fo
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easonably controlled environment of
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Consumption of HF diets after eight
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saturated fat on pancreatic carcino
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suggested that the enhancement of P
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wt at six and seven weeks of age. T
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synthesis and release of large amou
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pancreatic ductular carcinoma incid
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modifying effect of PH on pancreati
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predominant form of DNA alkylation
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the following 37 weeks. Additional
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tritiated thymidine (unpublished),
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or at the time of cellular regenera
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hamsters receiving the 2% BHA suppl
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the inhibition of pancreatic cancer
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diet in comparison with hamsters fe
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diet supplemented with 2% (group 1)
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single subcutaneous injection of BO
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Figure 168. Pancreatography by retr
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Although we have identified insulin
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Figure 169. Perivascular iendocrine
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ducts and in the micro carcinoma (F
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CHAPTER 19 Prevention and Therapy o
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proMMP-2 is highly activated in PC
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plus adenocarcinomas were significa
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and the combination of 5-fluorourac
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duct carcinogenesis. OPB-3206 may b
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thus receive the highest photodynam
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The same applies to hyperplastic an
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Figure 177. Serial sectioning of a
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atypical-to-malignant and were remo
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CHAPTER 21 Conclusions from the Stu
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While these precursor cells may be
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transform the cultured human islet
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Figure 181. After massive degenerat
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27. Caygill CP, Hill MJ, Hall CN, K
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68. Nakase A, Koizumi T, Fujita N,
Page 240 and 241:
116. Pour PM, Kazakoff K, Dulaney K
Page 242 and 243:
162. Pour P, Althoff J, Nagel D. In
Page 244 and 245:
203. Lawson T, Kolar C. Mutation of
Page 246 and 247:
246. Rettie AE, Korzekwa KR, Kunze
Page 248 and 249:
289. Bell RH, Jr., McCullough PJ, P
Page 250 and 251:
335. Pour PM, Uchida E, Burnett DA,
Page 252 and 253:
375. Resau JH, Hudson EA, Jones RT.
Page 254 and 255:
419. Schreiber AB, Winkler ME, Dery
Page 256 and 257:
463. Fitzgerlad P, Sharkey F, Fogh
Page 258 and 259:
507. Herrington MK, Permert J, Kaza
Page 260 and 261:
548. Permert J, Ihse I, Jorfeldt L,
Page 262 and 263:
586. Nishikawa A, Furukawa F, Kasah
Page 264:
627. Rao MS, Scarpelli DG, Reddy JK
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