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

An analogue of 1,25-dihydroxyvitamin D3, 22(S)-24-homo-26,26,26,27,27,27-hexafluoro-1 alpha,22,25-trihydroxyvitamin D3 (DD-003), showed 10-fold greater inhibiting effect than 1,25-dihydroxyvitamin D3 on the growth of HT-29 human colonic adenocarcinoma cells in culture. To examine the anticancer activity of DD-003 in vivo, a fibrin clot of HT-29 cells was prepared with fibrinogen and thrombin and implanted under the renal capsule of the severe combined immunodeficient mouse. Starting 7 days after implantation of HT-29 tumor, mice were given 3 micrograms/kg body weight of DD-003 or the vehicle i.p. every other day for 5 times. The HT-29 tumor grew rapidly in control mice; malignant growth was clearly observed with mitosis, massive tumor angiogenesis, and invasion into normal kidney tissue. Tumors in DD-003 treated mice were smaller with less invasion compared to the control. Administration of DD-003 inhibited growth of HT-29 tumor by 63%. Serum calcium concentrations and body weights of the treated mice were similar to those of the control. DD-003 inhibited growth of HT-29 tumor in a dose-dependent manner over the range of 0.1-10 micrograms/kg body weight, with no increase of serum calcium concentration observed at any dose level. When DD-003 was withdrawn after 2 weeks of treatment, tumor growth resumed. Since chemosensitivity tested by the subrenal capsule assay correlates well with clinical response, DD-003 may be clinically applicable in procedures such as postsurgical chemotherapy of colon cancer.
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PMID:Inhibition of HT-29 human colon cancer growth under the renal capsule of severe combined immunodeficient mice by an analogue of 1,25-dihydroxyvitamin D3, DD-003. 792 32

Nude mice bearing xenografts of HT-29 human colon cancer cell line were treated for 4 weeks with somatostatin analog (RC-160), bombesin/gastrin releasing peptide (GRP) antagonists (RC-3095 and RC-3440). In three separate experiments somatostatin analog RC-160 (50 micrograms/day) released from microgranules significantly reduced tumor growth. Bombesin/GRP antagonists, RC-3095 and RC-3440 injected subcutaneously (s.c.) twice daily at a dose of 10 micrograms had the greatest and consistently significant inhibitory effect on tumor growth. RC-3095 given once daily s.c. at a dose of 20 micrograms was less effective. RC-3095 also inhibited metastatic tumor growth after intrasplenic injection of HT-29 cells in nude mice. Specific binding sites of somatostatin, bombesin and epidermal growth factor (EGF) were detected on intact HT-29 cells or on the membranes from HT-29 tumor xenografts. The inhibitory effects of bombesin antagonists on tumor growth were consistently linked with a significant down-regulation of EGF receptors. Bombesin/GRP antagonists and somatostatin analogs could be considered for the development of new hormonal therapies for colon cancer.
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PMID:Inhibitory effects of antagonists of bombesin/gastrin releasing peptide (GRP) and somatostatin analog (RC-160) on growth of HT-29 human colon cancers in nude mice. 794 50

The mouse monoclonal antibody, m30.6 (IgG2b), detects an antigenic determinant expressed predominantly on the surface of colorectal adenocarcinoma cells and has been shown previously to be a potentially useful therapeutic and diagnostic reagent for human colon cancer. We report the production and characterization of a mouse/human chimeric antibody, c30.6, with potent in vitro and in vivo antitumor activity. The genes encoding the variable domains for heavy and light chains were amplified by thermal cycling using degenerate oligonucleotide primers complementary to conserved immunoglobulin framework sequences. The gene segments were sequenced, subcloned into eukaryotic expression vectors containing human constant region genes (IgG1 and kappa), and cotransfected into nonsecreting Sp2/0 mouse myeloma cells. There were significant differences in the biological activities of the murine and chimeric antibodies. The i.p. administration of c30.6 but not of m30.6 produced a marked growth inhibition of s.c. 30.6+ COLO 205 tumors in scid/scid mice (approximately 40% reduction in tumor size, measured 21 days after tumor inoculation). Reduced tumor growth was not due to altered binding characteristics of c30.6 because: (a) the chimeric antibody was shown by flow cytometry to bind exclusively to cell lines that expressed the 30.6 determinant; (b) c30.6 was able to completely inhibit the binding of m30.6 on 30.6+ cells; and (c) the affinity of binding of the two antibodies was the same (Ka, approximately 1.50 x 10(8)). Up to 15% of the total injected antibody dose/g tissue was localized in 30.6+ tumors at 24 h, approximately 13% was present in the tumors at 48 h, and approximately 10% was present at 72 h. Furthermore, c30.6 demonstrated a shorter circulating half-life (53 h; m30.6, 72 h) when given i.p. to C57BL6 x BALB/cF1 mice. Unlike m30.6, c30.6 was also strongly active in antibody-dependent cell-mediated cytotoxicity against a range of 30.6+ tumor target cells in vitro. Up to 80% specific 51Cr release was achieved using either freshly isolated human peripheral blood mononuclear cells or 2-day-old interleukin 2-stimulated human peripheral blood mononuclear cells as effectors. The enhanced antitumor activity of c30.6 suggests that it might be a useful immunotherapeutic reagent for colorectal carcinoma.
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PMID:Chimeric (mouse/human) anti-colon cancer antibody c30.6 inhibits the growth of human colorectal cancer xenografts in scid/scid mice. 795 62

Controversy exists about the relationship between hypergastrinemia and colon cancer. Conflicting lines of evidence may be interpreted to support a variety of views regarding the link between the two. Although some experimental and clinical data suggest a strong correlation, other studies refute this. It is likely that the actual situation lies between these two viewpoints; the complex nature of the relationship between carcinogenesis and putative gut hormones makes a definitive answer unlikely. Nevertheless, a critical reading of the recent literature suggests that hypergastrinemia does not play a direct role in colorectal carcinogenesis. Certain subgroups of patients with elevated serum gastrin levels and tumors that possess gastrin receptors may have accelerated tumor growth. Further study of this issue is warranted to elucidate the role of the gastrointestinal hormonal milieu in colorectal neoplasia.
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PMID:Gastrin and colon cancer. Clarifying the controversy. 803 12

Mice with severe combined immunodeficiency reconstituted with human splenic tissue (SCID-sp) taken from 22 patients with advanced gastric cancer and 8 with idiopathic thrombocytopenic purpura (ITP) received subsequent implants of COLO 205 human colon cancer cells. A human immunoglobulin G (IgG) reactive against COLO 205 cells (COLO 205-reactive human IgG) was produced by SCID-sp mice reconstituted with splenic tissue from 8 of the 22 gastric cancer patients, but from none of the ITP patients. Tumor growth in SCID-sp mice which produced the COLO 205-reactive human IgG was greater (tumor weight range, 106-143%) than that in the control SCID mice, while that in SCID-sp mice reconstituted with splenic tissue from 8 ITP patients and that in SCID-sp mice reconstituted with splenic tissue from the other 14 gastric cancer patients which did not produce the COLO 205-reactive IgG were considerably lower and slightly lower, respectively, than those in the control SCID mice (tumor weight range, 56.7-108% and 79.4-119%, respectively). When the COLO 205-reactive human IgG titers in the sera of the SCID-sp mice, expressed as a ratio of the titers in the corresponding patient's serum, were plotted against the tumor weight in each SCID-sp mouse, significant correlations were observed in those that received splenic tissues from 6 of the 8 patients in which the COLO 205-reactive human IgG was produced. Furthermore, the tumor growth rates increased in proportion to the increased COLO 205-reactive human IgG titers in SCID-sp mice. Therefore, the SCID-sp model should be useful to study the paradoxical tumor growth possibly due to impaired immune reaction in patients with advanced gastric cancer.
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PMID:Paradoxical enhancement of tumor growth in mice with severe combined immunodeficiency which produce a human immunoglobulin G reactive against tumor cells. 810 91

Adoptive immunotherapy with lymphokine-activated killer (LAK) cells has shown some promise in the treatment of certain cancers that are unresponsive to conventional treatment approaches. However, colon adenocarcinomas tend to respond poorly to LAK therapy, possibly as a result of tumor-induced immunosuppression. Recently, in vivo administration of anti-CD3 antibody has been shown to induce mouse T lymphocytes to mediate major-histocompatibility-complex(MHC)-unrestricted tumoricidal activity which is distinct from natural-killer-cell-derived LAK activity. It has therefore been suggested that anti-CD3 therapy may find application in tumor immunotherapy in humans. However, the effectiveness of anti-CD3-activated killer cell induction within the environment found in the vicinity of colon adenocarcinoma cells has not been evaluated. The present report demonstrates that colon cancer cells of human (HT-29) and mouse (MCA-38) origin markedly inhibit the generation of activated killer cells in murine spleen cell cultures. DNA synthesis and interleukin-2 production by spleen cells following stimulation with anti-CD3 antibody are also profoundly depressed in the presence of MCA-38 and HT-29 adenocarcinoma cells. MCA-38- and HT-29-mediated inhibition of activated killer cell development is exerted through the production of a tumor-associated soluble factor that is distinct from transforming growth factor beta or prostaglandins. Local immunosuppression associated with sites of tumor growth may therefore represent a major obstacle to successful anti-CD3 immunotherapy of certain colon adenocarcinomas.
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PMID:Colon adenocarcinoma cells inhibit anti-CD3-activated killer cell induction. 812 89

The search for compounds active against solid tumors has led us to the discovery of a novel sulfonamide, E7010 (N-[2-[(4-hydroxyphenyl)amino]-3-pyridinyl]-4- methoxybenzenesulfonamide), which inhibits tubulin polymerization. When administered orally, E7010 showed good antitumor activity against various rodent tumors and human tumor xenografts. In tests on mouse tumor, E7010, administered in doses of 25-100 mg/kg daily for 8 days, inhibited the growth of colon 38 carcinoma inoculated s.c. in mice by 60-99%. E7010 was active against s.c. inoculated M5076 fibrosarcoma (75% tumor growth inhibition), s.c. inoculated Lewis lung carcinoma (84% increase in life span), and i.p. inoculated P388 leukemia (118% increase in life span). In a test on rat tumor, E7010 inhibited the growth of SST-2 mammary carcinoma inoculated s.c. in rats by 84%. In tests on s.c. inoculated human tumor xenografts, E7010, when administered orally, showed a broad spectrum of activity. E7010 inhibited the growth of: four kinds of gastric cancer, H-81, H-111, SC-2, and SC-6 by 60-78%; three kinds of colon cancer, H-143, COLO320DM, and WiDr by 58-83%; three kinds of lung cancer, LC-376, LC-6, and LX-1 by 63-82%; and two kinds of breast cancer, H-31 and MX-1 by 79-87%. In studies on drug-resistant P388 leukemia, E7010 was effective against vincristine-resistant P388, cisplatin-resistant P388, and 5-fluorouracil-resistant P388 sublines in mice. Because of its good activity against rodent tumors and human tumor xenografts, E7010 is currently undergoing Phase I clinical trials.
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PMID:In vivo tumor growth inhibition produced by a novel sulfonamide, E7010, against rodent and human tumors. 813 85

Seven isoflavones, biochanin A, daidzein, genistein, genistin, prunectin, puerarin, and pseudobaptigenin were tested for cytostatic and cytotoxic effects on 10 newly established cancer cell lines of the human gastrointestinal origin. Proliferation of HSC-41E6, HSC-45M2, and SH101-P4 stomach cancer cell lines was strongly inhibited by biochanin A and genistein, whereas other stomach, esophageal, and colon cancer lines were moderately suppressed by both compounds. Biochanin A and genistein were cytostatic at low concentrations (< 20 micrograms/ml for biochanin A, < 10 micrograms/ml for genistein) and were cytotoxic at higher concentrations (> 40 micrograms/ml for biochanin A, > 20 micrograms/ml for genistein). DNA fragmentation was observed at cytotoxic doses of both compounds, indicating the apoptotic mode of cell death by the compounds. Chromatin condensation and nuclear fragmentation of each cell line were also observed. The advent of apoptosis was dose dependent for both isoflavones. Biochanin A suppressed tumor growth of HSC-45M2 and HSC-41E6 lines in athymic nude mice. Our results suggest that two of isoflavone derivatives, biochanin A and genistein, inhibit the cell growth of stomach cancer cell lines in vitro through activation of a signal transduction pathway for apoptosis. Moreover, in vivo experiments demonstrate that biochanin A can be used as an anticancer agent.
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PMID:Antiproliferative effects of isoflavones on human cancer cell lines established from the gastrointestinal tract. 824 41

Tumor stroma is a specialized form of tissue that is associated with epithelial neoplasms. Recent evidence indicates that significant changes in proteoglycan content occur in the tumor stroma and that these alterations could support tumor progression and invasion as well as tumor growth. Our main hypothesis is that the generation of tumor stroma is under direct control of the neoplastic cells and that, via a feedback loop, altered proteoglycan gene expression would influence the behavior of tumor cells. In this review, we will focus primarily on the work from our laboratory related to the altered expression of chondroitin sulfate proteoglycan and its role in tumor development and progression. The connective tissue stroma of human colon cancer is enriched in chondroitin sulfate and the stromal cell elements, primarily colon fibroblasts and smooth muscle cells, are responsible for this biosynthetic increase. These changes can be reproduced in vitro by using either tumor metabolites or co-cultures of human colon carcinoma cells and colon mesenchymal cells. The levels of decorin, a leucine-rich proteoglycan involved in the regulation of matrix assembly and cell proliferation, are markedly elevated in the stroma of colon carcinoma. These changes correlate with a marked increase in decorin mRNA levels and a concurrent hypomethylation of decorin gene, a DNA alteration associated with enhanced gene expression. Elucidation of decorin gene structure has revealed an unexpected degree of complexity in the 5' untranslated region of the gene with two leader exons that are alternatively spliced to the second coding exon. Furthermore, a transforming growth factor beta (TGF-beta)-negative element is present in the promotor region of decorin gene.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Altered proteoglycan gene expression and the tumor stroma. 829 47

Human tumors transplanted into nude mice have long been used to assess the effectiveness of antitumor drugs and yet there is still no established standard method in preclinical practice for screening new antitumor drugs in vivo using nude mice. Thus, a cooperative study on the feasibility of a human tumor/nude mouse system for the in vivo screening of drugs was conducted by the Japanese Research Society for Chemosensitivity of Cancer. Two human stomach cancers, H-111 and SC-6-JCK, and one human colon cancer, Co-4, were transplanted serially into nude mice and used as gastrointestinal tract tumors with stable tumor growth. The appropriate dosage of six well-known antitumor drugs [mitomycin C (MMC), cyclophosphamide (CPA), nimustine hydrochloride 1-(4-amino-2-methyl-5-pyrimidinyl) methyl-3-(2-chloroethyl)-3-nitrosourea hydrochloride (ACNU), cis-platinum (II) diaminodichloride (CDDP), adriamycin (ADM) and 5-fluorouracil (5-FU)] in human tumor-bearing nude mice was determined based on the maximum tolerance dose of the drug. The respective dosages were 6 mg/kg of MMC x 1 (i.p.), 120 mg/kg of CPA x 1 (i.p.), 30 mg/kg of ACNU x 1 (i.p.), 8 mg/kg of CDDP x 1 (i.p.), 8 mg/kg of ADM x 1 (i.v.), and 50 mg/kg of 5-FU q4d x 3 (i.p.). Three weeks after treatment, drug effectiveness was judged by the tumor growth inhibition rate. Treatment with these appropriate doses appeared to show the maximum effect of the respective drugs on the tumor-bearing nude mice.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:A standardized method of using nude mice for the in vivo screening of antitumor drugs for human tumors. 832 34


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