Carcinoma, small intestine

The enthusiasm for using Caco-2 cells and other epithelial cell cultures in studies of drug transport processes has been explained by the ease with which new information can be derived from these fairly simple in vitro models [7]. For instance, drug transport studies in Caco-2 cells grown on permeable supports are easy to perform under controlled conditions. This makes it possible to extract information about specific transport processes that would be difficult to obtain in more complex models such as those based on whole tissues from experimental animals. Much of our knowledge about active and passive transport mechanisms in epithelia has therefore been obtained from Caco-2 cells and other epithelial cell cultures [10-15]. This has been possible since Caco-2 cells are unusually well differentiated. In many respects they are therefore functionally similar to the human small intestinal enterocyte, despite the fact that they originate from a human colorectal carcinoma [16, 17]. 

In contrast to P-gp and the MRP proteins, the breast cancer resistance protein (BCRP) contains six transmembrane domains and only one ATP-binding domain. It was first cloned from the breast cancer cell line MCF-7 selected in doxombicin, in the presence of the P-gp inhibitor verapamil. It is found in many human tissues, such as the placenta, small intestine, colon, and liver [133], It is localized to the apical membrane of epithelial cells of the small intestine and colon and to the bile canalicular membrane in the liver and is involved in reducing intestinal uptake, increasing hepatobiliary excretion, etc., leading to diminished oral bioavailability. cDNA sequences identical to BCRP and named MXR and ABCP, respectively, were independently isolated from human colon carcinoma cells and human placenta [134], BCRP requires... 

Groups of 28 conventional and 28 genn-free Fischer rats received weekly intrarectal injections of 20 mg/kg bw 1,2-dimethylhydrazine for 20 weeks. The rats were killed 15 weeks after the last 1,2-dimethylhydrazine injection. A much higher incidence of squamous-cell carcinomas of the ear canal, mesenchymal kidney tumours, carcinomas of the small intestine and colon was obsen cd in conventional rats than in genn-free rats (Table 10). (Reddy et al., 1976). 

The best characterized multidrug transporter is P-gp which is a membrane protein encoded by the mdrl gene. The most intriguing feature of P-gp is its ability to interact with a large number of structurally and functionally different amphiphilic compounds. P-gp expression can be acquired during the course of treatment (e.g., in leukemias, lymphomas, ovarian carcinomas) or it is constitutive (e.g., in colorectal and renal cancers). In normal tissues of mammals P-gp is localized on the luminal surface of transporting epithelia in liver, kidney, small intestine, testes, and blood-brain barrier. 

Preliminary pharmacokinetic behavior can be tested through a number of whole cell assays. Most commercially successful drugs are administered orally, meaning the drug must be able to enter the bloodstream by crossing membranes in the intestines. The most common membrane permeability assay is performed by monitoring the absorption and secretion of a compound by colon carcinoma cells (Caco-2). Diffusion across Caco-2 cell membranes is considered to be a valid model for molecular transport in the small intestines.16... 

A major indication for colon-specific drug delivery is in the treatment of local disorders of the colon, such as inflammatory bowel disease (IBD which includes ulcerative colitis and Crohn s disease) and carcinoma of the colon. The colon can also be used as an absorption site for the delivery of drags to the systemic circulation. Although absorption from the colon is generally considerably lower than from the small intestine, systemic drag delivery via the colon is associated with a number of advantages, including ... 

The small intestine is drained by the hepatic portal vein, making the liver the first port of call for orally absorbed drugs. Therefore, high hepatic metabolism will compromise systemic availability. Formulation to enhance lymphatic absorption offers the potential for avoiding such first-pass metabolism. It could also target anticancer agents to lymphatic carcinomas. Table 1 lists various materials and associated therapeutic agents that have been formulated for lymphatic delivery. 

A 53-year-old man had a side-to-side Ueo-descending colostomy for disseminated carcinoma. FlnoronracU was given in doses of 15 mg/kg for 4 days, then 7.5 mg/kg intravenously on days 6 and 8. He developed severe diarrhea and severe ulceration of the bypassed portion of the colon, resulting in necrosis, and death occurred as the result of bronchopneumonia. Autopsy showed ulcers from the ileocecal valve to the ileo-colostomy site. The mucosa of the stomach, small intestine, and colon distal to the colostomy were not involved. 

Impaired absorption has been found in some patients with malignant disease, but this is probably related to active disease close to or actually involving the small intestine (P3, K9). Little information is available on folate metabolism in patients with hepatic carcinoma and its effect on the recycling of folate in bile. 

CYTOKERATIN 20 In the small intestine, CK20 stains only the highly differentiated small bowel villous entero-cytes (cytokeratin 18 stains the more immature basilar, proliferative zone cells). In the colon, CK20 stains only the surface epithelial cell layer. CK20 staining is more extensive and stronger in small bowel neoplasms than colonic carcinomas." ... 

Planck M, Ericson K, Piotrowska Z, et al. Microsatellite instability and expression of MLHl and MSH2 in carcinomas of the small intestine. Cancer. 2003 97 1551-1557. 

Cytokeratin 20 (CK20) is a type I acidic low molecular weight cytokeratin that was initially described in 1992. 1 It is found in normal tissues of the stomach, intestine, urothelium, and in Merkel cells. It is found in most adenocarcinomas of the large and small intestines, in mucinous tumors of the ovary, and in Merkel cell carcinomas, and it is frequently present in urothelial carcinoma and in adenocarcinomas of the stomach, pancreas, and bile ducts. It is a useful marker for primary mucinous tumors of the ovary and for various types of metastases that are found in the ovaries. 

The most widely used ceU line in drug transport studies is the Caco-2 cell line. This is an iimnortal ceU line derived from human colon carcinoma that can be grown to monolayer on porous support. Functionally, this cell line models the colon more than the small intestine. The Caco-2 model allows characterization of both mucosal-to-serosal and serosal-to-mucosal transport and can also be used to study transcellular and paracellular transport, hi addition to expressing small intestinal brush border enzymes, Caco-2 cells also express Phase I and Phase II enzymes and can be used to evaluate metabohsm of compounds during transport across the intestinal barrier. ... 

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