alpha-chymotrypsin and Carcinoma--Intraductal--Noninfiltrating

The possibility that pancreatic secretory abnormalities might precede the appearance of pancreatic neoplasms and thus provide clues to early detection of this malignancy has been investigated in an animal model. Syrian golden hamsters were treated with bis-(2-oxopropyl)-N-nitrosamine on two successive weeks (2 mg/100 g body weight/week). Pancreatic secretions from treated and untreated control animals were studied at approximately monthly intervals. The animals were anesthetized, their pancreatic ducts cannulated, and basal pancreatic juice collected for 30 min. Pancreatic secretion was then stimulated by sequential intravenous injection of secretin (50 ng/100 g) and C-terminal octapeptide of cholecystokinin (4 ng/100 g) 1 hr later. Four consecutive 15-min collections of fluid were made following secretin stimulation and four additional collections after CCK administration. Each collection was examined for volume, total protein, trypsin, chymotrypsin, elastase, arylsulfatase, beta-D-glucuronidase, alpha-D-glucosidase, and leucine naphthylamidase. In addition two trypsinogen variants present in pancreatic secretions were determined. The pancreas and other organs were removed and examined histologically at the end of each experiment. Cytological atypia appeared 3 months, ductal hyperplasia 4 months, and pancreatic neoplasms 6 months after the last injection of carcinogen. Striking decreases in flow rate and output of trypsin and chymotrypsin were observed several months prior to the appearance of histologically recognizable pancreatic tumors. By contrast, output of beta-D-glucuronidase and alpha-D-glucosidase in pancreatic juice increased markedly in the last 2 months preceding the emergence of neoplasms. The diagnostic significance of these premalignant abnormalities is illustrated most dramatically in the form of ratios of lysosomal to digestive enzymes, such as beta-D-glucuronidase-trypsin or alpha-D-glucosidase-chymotrypsin. Highly significant increases in these ratios were observed consistently, not only in hamsters with pancreatic neoplasms, but also in animals with preneoplastic lesions (ductular hyperplasia) which preceded malignancies by about 2 months.

Topics: Age Factors; Animals; Carcinoma, Intraductal, Noninfiltrating; Chymotrypsin; Cricetinae; Male; Mesocricetus; Neoplasms, Experimental; Nitrosamines; Pancreas; Pancreatic Elastase; Pancreatic Juice; Pancreatic Neoplasms; Precancerous Conditions; Trypsin

Malignant and uninvolved human breast tissues were maintained in organ culture for 3 to 6 days. Under these conditions, the three-dimensional glandular architecture is maintained with the least disruption of tissue integrity. The biosynthesis and release of glycoproteins were studied by using the incorporation of [14C]glucosamine and [14C]leucine by the breast surgical specimens. Five major families of labeled glycoproteins were identified from culture supernatants using two-dimensional gel electrophoresis. Quantitative immunoprecipitation established that 16 to 30% of the total of labeled glycoproteins were recognized as normal serum components. Two of these glycoproteins were antigenically related to normal human serum components as demonstrated with crossed immunoelectrophoresis. Evidence was obtained for the active synthesis of alpha 1-antichymotrypsin and alpha 1-acid glycoprotein by human breast epithelial cells. alpha 1-Antichymotrypsin accounted for 0.9 to 7.8% of the biosynthetically labeled glycoproteins from organ culture supernatants. This component was 11.9% of the glycoproteins released by a monolayer culture of the established breast carcinoma cell line, MCF-7. alpha 1-Acid glycoprotein made up 0.7 to 3.1% of the labeled glycoproteins. alpha 1-Antichymotrypsin is a known neutral serine proteinase inhibitor with a particularly strong affinity for cathepsin G. alpha 1-Acid glycoprotein may function primarily as a potent immunomodulator by suppressing lymphoblastogenesis. These glycoproteins may thus have regulatory roles in the proteolytic modification of breast tissue and represent the tissue's own protecting shield against invading leukocytes.

Topics: alpha 1-Antichymotrypsin; Breast; Breast Neoplasms; Carcinoma, Intraductal, Noninfiltrating; Chymotrypsin; Female; Humans; Immunoelectrophoresis, Two-Dimensional; Molecular Weight; Organ Culture Techniques; Orosomucoid