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 47,337 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The hematologic and transfusion data of a multicenter randomized trial investigating the effect of blood transfusions on the 5-year survival were used to study the feasibility of an autologous blood donation program in colorectal cancer patients. Three hundred and ten patients were randomized for autologous blood transfusions (predeposition of 2 units) or homologous blood transfusions, and transfusion rules were standardized. The Hb level in the patients who donated blood decreased by 20.1 +/- 1.3 g/l (mean +/- SEM) preoperatively and 4.5 +/- 1.8 g/l postoperatively, and in controls 3.7 +/- 1.1 g/l and 16.5 +/- 1.9 g/l (significantly different between the two groups, both pre- and postoperatively: p less than 0.01). Because blood loss and number of transfusions were similar in both groups, this indicated that either preoperative or postoperative erythropoiesis is stronger in patients who had donated blood. Twenty-three percent of the autologous patients and 61% of the homologous patients were exposed to homologous blood. The effectiveness of the procedure differed per tumor localization. In patients with a right-sided colon carcinoma, 22% of the control patients needed homologous blood, compared to 10% of the autologous patients. In patients with other colon carcinomas, this was 52 and 16%, respectively, and in patients with a rectal carcinoma 85 and 41%. We conclude that predeposition of 2 units of blood for colorectal cancer surgery is feasible and useful to prevent homologous blood usage in a significant number of patients with left colon carcinoma or rectal carcinoma.
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PMID:Feasibility of a predeposit autologous blood donation program in colorectal cancer patients: results from a randomized clinical study. 151 64

Using a murine monoclonal antibody MAb 1A3, which binds to a lipid antigen found enriched in human colon cancer, and MOPC-21 antibody, as a non-specific control, we examined the effect of increasing doses of 125I-labelled MAbs (5 micrograms to 2,000 micrograms) on tumor localization. Biodistribution studies in hamsters with small GW-39 human colon carcinoma tumors [0.44 g +/- 0.014 (SEM)] demonstrated functional saturation of antigen binding sites in tumors when large doses of MAb 1A3 were used. The percentage injected dose bound per gram of tumor (ID/g tumor) remained constant for doses of intact MAb 1A3 less than or equal to 100 micrograms but decreased with doses greater than 100 micrograms, suggesting that a population of antigen binding sites had been saturated. While the percentage ID/g tumor decreased for doses of MAb 1A3 greater than 100 micrograms, the absolute amount specifically bound/g turnover increased (up to the 1,000 micrograms dose), suggesting that another population of less accessible 1A3 antigen could continue to bind MAb 1A3. In contrast, MOPC demonstrated a relatively constant percentage ID/g of tumor (2.26% +/- 0.11) throughout the dose range which was 2-3 times lower than MAb 1A3 (6.8% +/- 0.14) at plateau doses (5-100 micrograms). These data suggest that specific saturation of tumor binding sites was a biphasic phenomenon. Blood and normal tissues did not show binding kinetics suggesting saturation. Results of dose response experiments using MAb 1A3 F(ab')2 fragments (5 micrograms to 1,000 micrograms) closely paralleled those obtained with intact MAb 1A3, but with lower percentages of ID/g tumor, blood and non-tumor tissues as in previous studies with MAb 1A3 and other MAb F(ab')2 fragments. Histological examinations demonstrated that non-specific binding of MOPC or MAb 1A3 to tumor or normal tissues was of such low affinity as to be largely undetected after histological procedures. In contrast, MAb 1A3 (but not MOPC) showed specific cell-binding patterns to tumor but not normal tissues at all doses.
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PMID:Biodistribution and histological localization of anti-human colon cancer monoclonal antibody (MAb) 1A3: the influence of administered MAb dose on tumor uptake. 269 5

Using autoradiography after 1 h of pulsed labeling with tritiated thymidine in endoscopic biopsy specimens from normal-appearing mucosa, cell proliferation was determined at six predetermined sites of the whole colon in patients with neoplastic disease of the large bowel and was compared with that of subjects without macroscopic colonic pathology. The labeling index (the percentage of cells incorporating [3H]thymidine) was 8.6 +/- 0.5 (mean +/- SEM) in 13 patients with colon carcinoma (p less than 0.001 vs. 16 control patients whose labeling index was 4.9 +/- 0.2) and 9.1 +/- 0.4 in 11 patients with a large adenoma in the colon (p less than 0.001 vs. controls). Twenty-one patients with one or more small adenomas (diameter less than 1 cm) had a moderately increased cell proliferation compared with controls (labeling index 6.2 +/- 0.3, p less than 0.02 vs. controls). In patients with neoplastic disease an enlargement of the proliferative compartment was found, whereas 6 patients with Crohn's colitis had values for labeling index and a distribution of labeled cells along the crypt comparable to that of control subjects. An increased cell proliferation was found along the entire colon under each of the neoplastic conditions studied. These findings indicate that although neoplastic lesions develop in a limited area of the colon, the entire large bowel may be at risk for tumor growth.
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PMID:Abnormal pattern of cell proliferation in the entire colonic mucosa of patients with colon adenoma or cancer. 381 91

A phase I clinical trial of N-phosphonacetyl-L-aspartic acid (PALA) and 5-fluorouracil (FUra) was performed on 30 patients. PALA was given as a 15-minute iv infusion once daily for 5 days, and FUra was given as a bolus injection on days 2, 3, 4, and 5. Cycles of treatment were repeated every 3 weeks. Dose-limiting toxicity was manifested by stomatitis and diarrhea. Skin rash was observed also but was not dose limiting. No consistent hematopoietic or renal toxicity was observed. Seventeen patients with disseminated metastatic melanoma and measurable disease were evaluated for response. One partial response was seen; however, the response was associated with significant toxicity, and the treatment could not be repeated. Stable disease was observed in 3 patients with melanoma, 1 patient with colon carcinoma, and 1 patient with ovarian carcinoma. Our findings suggest that the clinical activity of PALA and FUra given according to the above schedule for melanoma is less than 25% (P less than 0.05). Pharmacokinetic studies of FUra revealed no consistent effect of PALA pretreatment on FUra disappearance in plasma. The mean FUra elimination half-line in plasma was 7.11 +/- 0.84 minutes (SEM), which is no different from that reported for FUra alone. The recommended doses on this schedule for phase II studies are 1,000 mg PALA/m2/day iv daily for 5 days and 200 mg FUra/m2/day iv on days 2, 3, 4, and 5.
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PMID:Phase I-phase II trial of N-phosphonacetyl-L-aspartic acid given by intravenous infusion and 5-fluorouracil given by bolus injection. 695 Jan 56

The objective of this study was to provide the first quantitative measurements of the process of vascular growth in the rat peritoneal disseminated tumor model in both arteriolar and venular systems. Male Fischer 344 rats were injected intraperitoneally with 1 x 10(7) cells of colon carcinoma cell line (RCN-9). Three to eleven days after tumor cell inoculation, the rats were subjected to intravital microscopic observation of the mesenteric microcirculation. Accompanying tumor growth, mesenteric windows showed a marked neovascularization. The branching pattern of the vascular network was analyzed based on Horton's law of bifurcation. Arterioles and venules were given an order of branching separately according to the Strahler's nomenclature, and the number of vessel segments (N) having the same order number was counted. A vascular density index (VDI) and a bifurcation ratio (BR) were calculated from a semilogarithmic plot of the vessel density (dividing N by the vascularized area) against vessel order. Values of the VDI in venules (3.1 +/- 0.3 in the tumor-free rats, mean +/- SEM, n = 6) were found to be larger than those in arterioles (1.8 +/- 0.2). These values in both arterioles and venules showed a significant increase with time after the tumor cell inoculation (in venules, 12.3 +/- 1.1 at 9-11 days after the tumor cell inoculation; in arterioles, 5.7 +/- 0.7). Moreover, the rate of increase in the venular VDI was larger than that of the arteriolar VDI. The arteriolar BR remained almost constant (3.8 +/- 0.2 for the tumor-free rats and 4.1 +/- 0.1 for 9-11 days after tumor cell inoculation), whereas the venular BR showed an increase with time (3.0 +/- 0.1 and 3.8 +/- 0.2, respectively). In conclusion, a marked angiogenesis was observed in the mesentery of the rats bearing peritoneal tumors. Neovascularization was found to occur predominantly in the venular system.
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PMID:Angiogenic vascular growth in the rat peritoneal disseminated tumor model. 881 50

Atomic force microscopy (AFM) has been used to image a wide variety of cells. Fixed and dried-coated, wet-fixed or living cells were investigated. The major advantage of AFM over SEM is the avoidance of vacuum and electrons, whereas imaging can be done at environmental pressure and in aqueous conditions. Evidence of the successful application of AFM in biological imaging is provided by comparing results of AFM with SEM and/or TEM. In this study, we investigated surface and submembranous structures of living and glutaraldehyde-fixed colon carcinoma cells, skin fibroblasts and liver macrophages by AFM. Special attention was paid to the correct conditions for the acquisition of images of the surface of these cells, because quality SEM examinations have already been abundantly presented. AFM imaging of living cells revealed specific structures, such as the cytoskeleton, which were not observed by SEM. Membrane structures, such as ruffles, lamellipodia, microspikes and microvilli, could only clearly be observed after fixing the cells with 0.1% glutaraldehyde. AFM images of living cells were comparable to SEM images of fixed, dried and coated cells, but contained a number of artefacts due to tip-sample interaction. In addition, AFM imaging allowed the visualization of cytoplasmic submembranous structures without the necessity for further preparative steps, allowing us: (i) to follow cytoskeletal changes in fibroblasts under the influence of the microfilament disrupting agent latrunculin A; (ii) to study particle phagocytosis in macrophages. Therefore, in spite of the slow image acquisition of the AFM, the instrument can be used for high-resolution real-time studies of dynamic changes in submembranous structures.
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PMID:Imaging surface and submembranous structures with the atomic force microscope: a study on living cancer cells, fibroblasts and macrophages. 967 58

The integrin alpha5beta1 seems to be the most relevant receptor of tumor cells for binding to fibronectin. Although numerous studies suggest a role of tumor cell fibronectin interaction in tumor metastasis, differential integrin expression on tumor cells has, however, not been correlated with metastatic capabilities. We addressed this question by transfection of the integrin alpha5beta1 cDNA into HT-29 human colon carcinoma cells which led to de novo expression of functional integrin alpha5beta1. Similar to other reports, expression of the integrin alpha5beta1 in HT-29 tumor cells exerted an inhibitory action on cell proliferation as indicated in our study by formation of fewer colonies in soft agar. The tumor growth inhibitory property of the integrin alpha5beta1 was also shown by reduction of subcutaneous xenograft growth in nude mice to approximately 50% of that of control transfectants. For the first time, we found that several clones of integrin alpha5 subunit transfectants displayed dramatically reduced formation of lung colonies and cutaneous metastasis after intravenous injection into nude mice. While most animals inoculated with control transfectant cells formed macroscopically visible lung colonies ranging from 12.6 +/- 2.6 to 22.0 +/- 6.6 (mean colony number +/- SEM), mice inoculated with HT-29 cell clones expressing the integrin alpha5beta1 were almost completely free of lung colonies (ranging from 0.0 +/- 0 to 0.2 +/- 0.1). Our results imply that integrin alpha5beta1 expression inhibits circulating tumor cells in pursuing late steps of the metastatic process as represented by the artificial metastasis (lung colonisation) model.
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PMID:Integrin alpha5beta1: a potent inhibitor of experimental lung metastasis. 1009 38

To assess the mechanism of action of 5-fluorouracil (5-FU) apoptosis (AI) and proliferation (PI) indices were determined histochemically in colon carcinoma and normal colon tissue of 7 patients treated preoperatively with 5-FU (300 mg/m2/day for 5 days) and 11 controls. 5-Fluorouracil induced apoptosis selectively in malignant colonocytes (AI in 5-FU-group: 0.126 +/- 0.016 [mean +/- SEM] vs. 0.065 +/- 0.012 in controls; P < 0.05), but not in normal colonocytes. 5-Fluorouracil had no effect on the PI of either normal or malignant colonocytes. 5-Fluorouracil-induced apoptosis did not correlate with clinical outcome at 24 months. We conclude that 5-FU: (a) induces apoptosis selectively in colon cancer cells, while it spares the normal colonic mucosa, and (b) has no effect on colonocyte proliferation under the conditions of our protocol. This effect of 5-FU may contribute to its chemotherapeutic activity in human colon cancer.
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PMID:Selective induction of colon cancer cell apoptosis by 5-fluorouracil in humans. 1219 21

Dysregulation of the Wnt pathway and altered Beta-catenin expression are central early events in colorectal carcinogenesis. We studied the ortho, meta, and para (o-, m-, and p-) positional isomers of NO-donating aspirin (NO-ASA), a chemopreventive agent against colon cancer, for their effect on Beta-catenin/T cell factor (TCF) signaling. In human SW480 colon carcinoma cells, cell-growth inhibition by NO-ASA [IC50 values for p-, o-, and m- were 48.1 +/- 4.3 (mean +/-SEM), 60.4 +/- 2.1, and 900 +/-50 microM, respectively] was accompanied by significant inhibition of Beta-catenin signaling. We determined Beta-catenin-dependent TCF-4 transcriptional activity by measuring the activity of the luciferase gene placed under the control of TCF-4 regulatory sequences. The IC50 values for Beta-catenin/TCF-4-signaling inhibition by NO-ASA were: o-, 2.6 +/- 0.4; m-, 15 +/- 5; p-, 1.1 +/- 0.1 microM; and for ASA, >5,000 microM. Total or nuclear levels of Beta-catenin and its distribution in the cell were not altered by NO-ASA, as judged by protein expression levels and semiquantitative immunofluorescence analysis. NO-ASA disrupted the association of Beta-catenin and TCF-4 in the nucleus, whereas ASA did not affect it. NO-ASA reduced the expression of cyclin D1, a downstream target gene that plays an important role in colon carcinogenesis. In contrast, a structural analog of NO-ASA lacking the -NO2 moiety did not affect TCF-4 transcriptional activity. Thus, NO-ASA inhibits Beta-catenin-mediated TCF activity by preventing the formation of the Beta-catenin/TCF-4 complex. This effect, occurring at NO-ASA concentrations far below those required to inhibit cell growth, may be a critical early event in the chemopreventive activity of NO-ASA against colon cancer.
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PMID:Nitric oxide-donating aspirin inhibits beta-catenin/T cell factor (TCF) signaling in SW480 colon cancer cells by disrupting the nuclear beta-catenin-TCF association. 1456 53

The hypoxic cytotoxin tirapazamine (TPZ) is currently in phase III clinical trial and appears to have clinical activity. One hypothesis as to why TPZ has been used more successfully in the clinic than most other bioreductive drugs is that its unusual O(2) dependence allows killing of radioresistant cells at "intermediate" O(2) concentrations. We have determined the O(2) dependence of the metabolism of TPZ to its reduction product SR 4317, and its cytotoxicity, in stirred suspensions of HT29 colon carcinoma cells while monitoring O(2) in solution with an Oxylite trade mark probe. The O(2) dependence of the cytotoxicity of TPZ is entirely accounted for by its inhibition of the metabolism of TPZ, with a K(O(2)) value (O(2) concentration for 50% inhibition) of 1.21 +/- 0.09 (SEM) microM. We used this experimental O(2) dependence to extend a recent (Hicks et al., Cancer Res. 63, 5970-5977, 2003) pharmacokinetic/pharmacodynamic model for the cytotoxicity of TPZ in anoxic HT29 multicellular layers to model cell killing in tumors. The model indicates that the O(2) dependence of killing by TPZ complements that of radiation well during fractionated radiotherapy. It predicts that lowering K(O(2)) would decrease killing in radioresistant cells at intermediate O(2) concentrations, while higher K(O(2)) values would exacerbate metabolic consumption of TPZ and thus further impede its penetration into hypoxic regions. Raising K(O(2)) would also increase metabolic activation at physiological O(2) concentrations, thereby compromising hypoxic selectivity. We conclude that the K(O(2)) value of TPZ is indeed close to the optimum for a bioreductive drug of this class (i.e. one that kills only cells in which it is reduced).
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PMID:Oxygen dependence of the metabolic activation and cytotoxicity of tirapazamine: implications for extravascular transport and activity in tumors. 1516 54


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