Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0699790 (colon cancer)
 28,837 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

5-fluoro-3,4-dihydro-2,4-dioxo-N-[2-2- (dimethylphenylsilyl)ethylthioethyl]-1(2H)-pyrimidinocarb oxamide (SDK-12B-5), a novel antitumor agent, is covalently linked with 5-fluorouracil (5-FU) and 2-[(2-dimethylphenylsilyl)ethylthio] ethylamine(SDK-103) which possesses itself antitumor activity against murine solid tumors. It has a broad antitumor spectrum in experimental tumor systems including murine leukemias. Furthermore, SDK-12B-5 administered p.o. with various treatment schedules inhibited significantly the tumor growth of human breast cancer (MX-1), colon cancer (Co-4) and lung cancer (LX-1 and OAT) cells in BALB/c nu/nu mice and the chemotherapeutic index was about 10 for 4 different human cancer xenografts. In the Lewis lung carcinoma (LLC) metastasis model, SDK-12B-5 in combination with amputation of tumors inhibited significantly both the lymph node metastases and lung metastases of LLC and prolonged the life span (%ILS:91%) of BDF1 mice. We also found that the cell killing effect of SDK-12B-5 was affected by both concentration and exposure time in cultured human lung cancer (OAT) cells using soft-agar colony assay. A significant augmentation of delayed type hypersensitivity (DTH) response induced by SDK-12B-5 in comparison with the mixture of SDK-103 and 5-FU was seen when it was administered p.o. simultaneously with the immunization of sheep red blood cell (SRBC) in retired CD1 mice. From the studies on tissue distribution and pharmaco-kinetics of SDK-12B-5 by HPLC and ICP analysis. the persistence of SDK-12B-5 levels in serum and tumors was correlated with the findings that a maximum chemotherapeutic effect was obtained when SDK-12B-5 was administered p.o. repeatedly with every other day to avoid the cumulative toxicity.
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PMID:[Antitumor effects of 5-fluorouracil-bound organic silicon compound]. 278 16

Treatment of human colonic cancer in early stages when the process is still limited to the colonic wall is primarily surgery. We wished to see if maltose tetrapalmitate (MTP) immunotherapy alone or in combination with radiotherapy (R) and cyclophosphamide (C) chemotherapy would be effective against primary colon cancer in a fashion similar to that reported by us for primary liver cancer (Anticancer Research 6: 245-250, 1986). One hundred female CD1 mice were subjected to dimethylhydrazine (DMH) treatment once a week for 26 weeks, a period one week before which, colon cancer was histologically documented in each animal of a group that was sacrificed. Surprisingly, many of the animals harboured early anal cancer as well. At 28 weeks, 85 of the available animals were divided into 6 groups that received: Gr. 1, no treatment; Gr. 2, MTP alone (M); Gr. 3, radiotherapy alone (R); Gr. 4, cyclosphophamide alone (C); Gr. 5, R + C; Gr. 6, M + R + C. Criteria of treatment efficacy were: number, size and staging of colorectal tumors and the incidence and the size of anal tumors at death. Mean survival time was also determined although it remained a questionable criterium since most animals died due to complication (hepatic toxicity, pyelonephritis, thrombose) elicited by DMH, R and C toxicities and not as a result of colonic tumor size or metastases. As a single therapy, M appeared to be superior to either R or C alone. However, R + C combination was effective and was further improved upon by its association with M. With the triple combination, (M + R + C), lesions of both cancers decreased in size and/or number and the colon cancer histologically eclipsed from 46% of the treated animals.
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PMID:Antitumor efficacies of maltose tetrapalmitate immunotherapy alone and in combinations with radiotherapy and with cyclophosphamide chemotherapy against dimethylhydrazine induced colon and anal cancers in CDI mice. 338 53

This study tested the effect of a new gastrin receptor antagonist, CR2945, on colorectal cancer induced by 1,2-dimethylhydrazine (DMH) in mice. 75 CD1 male mice were divided into 3 groups: group 1 received 1 weekly injection of 20 mg/kg of DMH and 2 daily intraperitoneal injections of 0.5 ml of NaCl 0.9% solution for 5 weeks; groups 2 and 3 received the same weekly dose of DMH and 2 daily injections of CR2945 at the respective doses of 2.5 and 7.5 mg/kg for 5 weeks. The animals were sacrificed 25 and 38 weeks after the first injection. No tumours were found at the 25th week. A lower cancer frequency (4%) was observed in treated animals compared to controls (37.4%) at the 38th week (p = 0.002). These data show that CR2945 could prevent chemically induced colon cancer development in mice.
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PMID:Inhibitory effect of a gastrin receptor antagonist, CR2945, on 1, 2-dimethylhydrazine-induced colorectal cancer in mice. 1052 54

To identify prostate cancer-associated Ags, tumor-reactive T lymphocytes were generated using iterative stimulations of PBMC from a prostate cancer patient with an autologous IFN-gamma-treated carcinoma cell line in the presence of IL-2. A CD8+ T cell line and TCR alphabeta+ T cell clone were isolated that secreted IFN-gamma and TNF-alpha in response to autologous prostate cancer cells but not to autologous fibroblasts or lymphoblastoid cells. However, these T cells recognized several normal and malignant prostate epithelial cell lines without evidence of shared classical HLA molecules. The T cell line and clone also recognized colon cancers, but not melanomas, sarcomas, or lymphomas, suggesting recognition of a shared epithelium-associated Ag presented by nonclassical MHC or MHC-like molecules. Although Ag recognition by T cells was inhibited by mAb against CD8 and the TCR complex (anti-TCR alphabeta, CD3, Vbeta12), it was not inhibited by mAb directed against MHC class Ia or MHC class II molecules. Neither target expression of CD1 molecules nor HLA-G correlated with T cell recognition, but beta2-microglobulin expression was essential. Ag expression was diminished by brefeldin A, lactacystin, and cycloheximide, but not by chloroquine, consistent with an endogenous/cytosolic Ag processed through the classical class I pathway. These results suggest that prostate cancer and colon cancer cells can process and present a shared peptidic Ag to TCR alphabeta+ T cells via a nonclassical MHC I-like molecule yet to be defined.
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PMID:Recognition of a shared human prostate cancer-associated antigen by nonclassical MHC-restricted CD8+ T cells. 1057 Mar 28

Progression of cells through the G1 phase of the cell cycle requires the assembly and activation of specific cyclin:cyclin-dependent kinase (cdk) complexes in a tightly regulated, sequential fashion. To more clearly define the temporal events leading to the G1/S transition, sequential changes in the expression of cyclin E and cdks 2, 4, and 6, as well as the phosphorylation of the retinoblastoma protein (pRb), were assayed in RA28 cells, a variant of human colon cancer RKO cells which were modified by transfection of an ecdysone-inducible antisense (AS) CD1 expression system. Induction of cyclin D1 antisense mRNA by the ecdysteroid, ponasterone A, resulted in a 55% decrease in cyclin D1 mRNA and a 58% decrease in CD1 protein levels. There was a 2.4-fold decrease in the ratio of hyperphosphorylated pRb (ppRb) to hypophosphorylated pRb, as well as a 60-75% decrease in cdk 2- and cdk 4-specific phosphorylated pRb proteins. Of interest, cyclin E-dependent phosphorylation (cdk2) decreased 2.5-fold at 3 h despite only a 30% decrease in cyclin E protein level. Levels of cdk 2, cdk 4, and cdk 6 decreased 40-70%, while levels of cyclin A and B were unaffected by induction of CD1 antisense. Induction of a CD1 antisense gene in a human colon cancer cell line resulted in rapid, concomitant changes in CD1 mRNA and protein, cyclin E, cdk2, cdk4, and cdk6, as well as the ratio of ppRb to pRb. In this system, growth regulatory events are tightly regulated and the perturbed expression of a single protein, CD1, rapidly alters expression of multiple regulatory proteins involved in the G1/S transition phase of cell cycle progression.
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PMID:Downregulation of cyclin D1 alters cdk 4- and cdk 2-specific phosphorylation of retinoblastoma protein. 1103 57

Our previous experimental data demonstrated that a new gastrin receptor antagonist (CR2945) has a chemopreventive effect on dimethylhydrazine-induced colon cancer in mice. The aim of this study is to test the effect of CR2945 on the appearance and distribution of aberrant crypt foci (ACF), proposed as early "preneoplastic" lesions in colon carcinogenesis, in the murine model. 176 CD1 male mice were randomly divided into 4 groups: group 1, sham group received 2 daily intra-peritoneal injections of saline solution; group 2 received 1 weekly intra-peritoneal injection of DMH 20 mg/kg, for 5 weeks, and 2 daily intra-peritoneal injections of equal volume of NaCl 0.9%; group 3 and 4 received the same weekly dose of DMH and 2 daily injections of CR2945 at the respective doses of 2.5 and 7.5 mg/Kg for 5 weeks. The rodents were sacrified 15, 20, 25, and 38 weeks after receiving the first injection. The number of ACF per area (ACF frequency), their multiplicity (number of crypts per focus), ACF frequency according to each colonic site were recorded. No ACF were found in the sham group. No substantial differences were observed in ACF distribution between the remaining groups. Our hypothesis is that CR2945 does not alter the final number of ACF but might induce a regression of some dysplastic ACF.
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PMID:Distribution of 1,2 DMH-induced colonic aberrant crypt foci after administration of a gastrin receptor antagonist (CR2945), in the murine model. 1155 78

Evidence has been provided of the anti-proliferative activity of certain antidepressants, mainly the selective serotonin reuptake inhibitors (SSRIs). We tested the effect of different antidepressants on cell viability and proliferation of human colorectal carcinoma cell lines HT29 and the multi-drug resistant (MDR) LS1034. The SSRIs, paroxetine and sertraline, induced a dose-dependent inhibition of cell viability and proliferation in the two cell lines (IC50 8-15 micro M). When compared to cytotoxic agents e.g. doxorubicin, vincristine and 5-fluorouracil, the SSRIs showed comparable activity (HT29) or a superior effect (LS1034). Using flow cytometry analysis, we found that the two SSRIs arrested cells at the G0/G1 stage and stimulated DNA fragmentation in a dose-dependent manner. The SSRIs (10 and 20 microM) increased caspase-3 activation. Western blot analysis showed an increase after 24 h in c-Jun and a decrease in the expression of the anti-apoptotic protein Bcl-2. The results suggest a proapoptotic activity for the active SSRIs accompanied by mitogen-activated protein kinase cascade activation and Bcl-2 inhibition. In vivo, we used CD1 nude mice xenografted subcutaneously with HT29 cells. On day 8, after cell inoculation sertraline or paroxetine (15 mg/kg x3/week i.p.) were administered to animals (6/group), which were monitored weekly (for 5 weeks) for tumor volume and body weight. At 5 weeks, the animals survived, with no significant difference in body weight. Sertraline, though not paroxetine, significantly inhibited tumor growth. Collectively, our results suggest that the widely-used antidepressant, sertraline, possesses a potential anti-tumor activity, which circumvents the MDR mechanism. Since SSRI therapy is frequently indicated in cancer patients, the use of sertraline in colon cancer patients with co-morbidity of depression seems attractive.
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PMID:Evaluation of the potential anti-cancer activity of the antidepressant sertraline in human colon cancer cell lines and in colorectal cancer-xenografted mice. 1863 48

In this report, we describe the synthesis of a panel of disulfide-linked huC242 (anti-CanAg) antibody maytansinoid conjugates (AMCs), which have varying levels of steric hindrance around the disulfide bond, in order to investigate the relationship between stability to reduction of the disulfide linker and antitumor activity of the conjugate in vivo. The conjugates were first tested for stability to reduction by dithiothreitol in vitro and for plasma stability in CD1 mice. It was found that the conjugates having the more sterically hindered disulfide linkages were more stable to reductive cleavage of the maytansinoid in both settings. When the panel of conjugates was tested for in vivo efficacy in two human colon cancer xenograft models in SCID mice, it was found that the conjugate with intermediate disulfide bond stability having two methyl groups on the maytansinoid side of the disulfide bond and no methyl groups on the linker side of the disulfide bond (huC242-SPDB-DM4) displayed the best efficacy. The ranking of in vivo efficacies of the conjugates was not predicted by their in vitro potencies, since all conjugates were highly active in vitro, including a huC242-SMCC-DM1 conjugate with a noncleavable linkage which showed only marginal activity in vivo. These data suggest that factors in addition to intrinsic conjugate potency and conjugate half-life in plasma influence the magnitude of antitumor activity observed for an AMC in vivo. We provide evidence that bystander killing of neighboring nontargeted tumor cells by diffusible cytotoxic metabolites produced from target cell processing of disulfide-linked antibody-maytansinoid conjugates may be one additional factor contributing to the activity of these conjugates in vivo.
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PMID:Disulfide-linked antibody-maytansinoid conjugates: optimization of in vivo activity by varying the steric hindrance at carbon atoms adjacent to the disulfide linkage. 2142 76

Rodent models are invaluable to understanding health and disease in many areas of biomedical research. Unfortunately, many models suffer from lack of phenotype reproducibility. Our laboratory has shown that differences in gut microbiota (GM) can modulate phenotypes of models of colon cancer and inflammatory bowel disease. We and others have also shown that a number of factors associated with rodent research, including vendor, cage system, and bedding can alter GM. The objective of this study was to expand these studies to examine the effect of additional bedding materials and methods of water decontamination on GM diversity and composition. To this end, Crl:CD1 (ICR) mice were housed on corn cob or compressed paper chip bedding and provided water that was decontaminated by four different methods: autoclaving with reverse osmosis, autoclaving with hydrochloric acid, autoclaving with sulfuric acid, and autoclaving alone. Feces was collected at day 0, and at day 28 (endpoint), fecal and cecal samples were collected. DNA was extracted from samples, amplified by PCR using conserved bacterial primer sets and subjected to next generation sequencing. Sequence data were analyzed using Qiime and groups were compared using principal coordinate analysis (PCoA) and permutational multivariate analysis of variance (PERMANOVA). Two factor PERMANOVA of cecal GM data revealed significant changes when comparing bedding and water decontamination methods, while no significant effects were noted in the fecal GM data. Subsequent PERMANOVA and PCoA of cecal data revealed that several combinations of bedding and water decontamination methods resulted in differing GM, highlighting the complexity by which environmental factors interact to modulate GM.
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PMID:Effects of water decontamination methods and bedding material on the gut microbiota. 3035 79