Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027627 (metastases)
 103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The most common carcinomas metastatic to the ovary that mimic ovarian primaries are colonic adenocarcinomas and endometrial carcinomas. Conventional histochemical staining procedures, even in combination with additional immunohistochemical assays, are of limited value in distinguishing between these metastases and primary ovarian carcinomas. In this study we investigated whether the application of monoclonal antibodies against keratins 7, 8, and 20 could help in differentiating between these categories. The reactivity patterns of 40 carcinomas metastatic to the ovary were compared with those of their primary carcinomas on the one hand and with various primary ovarian carcinomas and mesotheliomas on the other. Colon cancer metastatic to the ovary was keratin 7 negative and keratin 20 positive in 94% of the cases; in contrast, all primary ovarian carcinomas were keratin 7 positive and keratin 20 negative, with the exception of two cases of mucinous cystadenocarcinoma. Ovarian metastases of gastric cancer usually contained keratins 7 and 20. Metastases of endometrial cancer to the ovary and primary ovarian carcinomas usually showed similar keratin expression. We propose that keratin 7 and 20 antibodies may be of help to distinguish between primary ovarian carcinomas and carcinoma metastases in the ovary.
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PMID:Keratins 7 and 20 as diagnostic markers of carcinomas metastatic to the ovary. 754 41

To evaluate the hypothesis that regional delivery of an adenovirus vector containing the Escherichia coli cytosine deaminase gene (AdCMV.CD) together with systemic 5-FC could suppress the growth of metastatic colon cancer in the liver, the AdCMV.CD vector was injected 0.8-1 cm from the site of a human colon cancer tumor in the livers of nude mice. The growth of the human colon cancer cells was quantified by dot blot analysis of genomic DNA extracted from tumor-bearing liver, hybridized with a human-specific Alu probe. The combination of regional AdCMV.CD plus systemic 5-fluorocytosine (5-FC) suppressed the growth of the metastatic tumors over the 21 days of evaluation following vector administration. Histologic evaluation showed necrosis at the site of the tumor in the livers of mice treated with AdCMV.CD/5-FC, but not in control groups. Evaluation of the potential toxicity of AdCMV.CD plus 5-FC on the normal liver showed only mild, self-limited dose-related inflammation, with no deaths. These data suggest that the regional administration of AdCMV.CD together with systemic 5-FC may be a safe and effective strategy to suppress the growth of metastases of colorectal carcinoma in the liver.
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PMID:Regional delivery of an adenovirus vector containing the Escherichia coli cytosine deaminase gene to provide local activation of 5-fluorocytosine to suppress the growth of colon carcinoma metastatic to liver. 886 57

This study demonstrates a novel role for the Fas pathway in the promotion of local tumor growth by inducing apoptotic cell death in normal hepatocytes at the tumor margin in colorectal hepatic metastases. Our results show that >85% of lymphocytes infiltrating colorectal liver cancer express high levels of Fas-ligand (Fas-L) by flow cytometry. Using immunohistochemistry of tumor tissue we showed strong Fas expression in noninvolved hepatocytes, whereas Fas-L expression was restricted to tumor cells and infiltrating lymphocytes at the tumor margin. Apoptosis was observed in 45 +/- 13% of the Fas(high) hepatocytes at the tumor margin whereas only 7 +/- 3% tumor cells were apoptotic (n = 10). In vitro, primary human hepatocytes expressed Fas receptor and crosslinking with anti-Fas antibody induced apoptosis in 44 +/- 5% of the cells compared with 4. 6 +/- 1.0% in untreated controls (P = 0.004). Both tumor-infiltrating lymphocytes (TIL) and human metastatic colon cancer cells cells are able to induce Fas-mediated apoptosis of primary human hepatocytes in coculture cytotoxic assays. TIL induced apoptosis in 47 +/- 9% hepatocytes compared with control 4.3 +/- 1. 0% (P = 0.009) and this effect was reduced by anti-human Fas-L mAb (18.7 +/- 1.3%, P = 0.009). SW620 cells induced apoptosis in 26 +/- 2% hepatocytes compared with control 5.6 +/- 1.7% (P = 0.004) and this was reduced to 11.2 +/- 1.8% (P = 0.004) in the presence of anti-human Fas-L mAb. These data suggest that the inflammatory response at the margin of colorectal liver metastases induces Fas expression in surrounding hepatocytes, allowing them to be killed by Fas-L-bearing TIL or tumor cells and facilitating the invasion of the tumor into surrounding liver tissue.
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PMID:Fas/Fas ligand interaction in human colorectal hepatic metastases: A mechanism of hepatocyte destruction to facilitate local tumor invasion. 1007 47

Radiation induced liver injury detected by a particulate reticuloendothelial MR contrast agent is described in a patient with metastatic colon cancer. The irradiated hepatic parenchyma failed to darken after ferumoxide administration. This finding suggests that detection of metastatic disease after ferumoxide contrast agents may be impaired in patients who have previously received upper abdominal radiation treatment.
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PMID:Radiation induced liver injury detected by particulate reticuloendothelial contrast agent. 1021 Oct 72

Colorectal cancer is one of the most frequent malignancies and one of the greatest causes of cancer death in the Western world. The prognosis is determined by the stage at diagnosis. Patients with metastatic colon cancer have a bad prognosis. Chemotherapeutic treatment with 5-Fluorouracil (5-FU) and folinic acid is actually considered as the standard treatment in patients with metastatic disease. Although the survival benefit is relatively small, many patients can benefit from this treatment in terms of tumor regression or symptom improvement. Several new drugs are actually in development and create hope for improved tumor or symptom control and longer survival. Thymidylate synthase inhibitors (raltitrexed), topoisomerase I inhibitors (irinotecan), the oral 5-FU prodrugs (capecitabine, UFT), ethynyluracil, and oxaliplatin are promising new drugs. The challenge will be to determine the best combination of these new drugs and the exact sequence in which these drugs will be used. Adjuvant post-operative chemotherapy in colon cancer is one of the most important advances in oncology that has been introduced into the clinic during the last years. For rectal cancer, an adjuvant treatment should consist of a combined chemo-radiotherapy. The search for better prognostic factors for recurrence should help to focus on a better adjuvant treatment for patients with the highest risk for recurrence.
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PMID:The medical treatment of colorectal cancer: actual status and new developments. 1037 May 99

Cancer chemotherapy celebrated its fiftieth anniversary last year. It was in 1945 that wartime research on the nitrogen mustards, which uncovered their potential use in the treatment of leukaemias and other cancers, was first made public. Fifty years later, more than sixty drugs have been registered in the USA for the treatment of cancer, but there are still lessons to be learnt. One problem, paradoxically, is that many anticancer agents produce a response in several different classes of the disease. This means that once a new agent has been shown to be effective in one cancer, much effort is devoted to further investigations of the same drug in various combinations for different disorders. While this approach has led to advances in the treatment of many childhood cancers and some rare diseases, a plethora of studies on metastatic colon cancer, for example, has yielded little benefit. 5-fluorouracil continues to be used in trials, yet there is no evidence for an increase in survival. The lesson to be learnt is that many common cancers are not adequately treated by present-day chemotherapy, and most trials of this sort are a waste of time. Significant increases in survival will only occur if the selectivity of present-day anticancer agents can be increased or new classes of more selective agents can be discovered. There are two fundamental problems in drug development: a lack of suitable laboratory tests and the difficulty of conducting early clinical trials. Firstly, no existing laboratory method can accurately predict which chemical will be effective against a particular class of human cancer. At best, tests can demonstrate a general 'anticancer' property. This is well exemplified by the discovery of cisplatin. The fact that cisplatin caused regression in a number of transplanted rodent tumours created no great excitement amongst chemotherapists. It was only later when it was tested clinically against ovarian cancer that results were sufficiently positive to encourage others to investigate. Only then was it discovered that metastatic teratoma was extraordinarily sensitive to the drug. This finding was made as a result of phase II trials and no laboratory model could have predicted it. The lesson to be learnt is that new drugs should be tested extensively in phase II trials before they are discarded. The second problem concerns early clinical trials. Because new drugs can only be tested against advanced and usually heavily pretreated disease, it is unlikely that dramatic responses will occur. The methods used to detect responses in solid tumours and metastases are crude, and it is likely that many useful drugs are missed. New techniques are needed to detect small but important responses. In addition to these technical problems, clinical trials are expensive and the time required for preclinical pharmacology and toxicology is lengthy. In the early days, drugs could enter clinical trials after fairly simple toxicological studies. The thalidomide disaster in the 1960s, however, led to the setting up of regulatory bodies to scrutinize drugs before clinical trials. This proved detrimental for cancer drug development because a series of fairly long-term tests is now required. These must be carried out in both rodents and one other species, usually the dog. This approach was probably a good thing for most medicines where a large margin of safety is required between the therapeutic dose and the dose which causes side effects, but was inappropriate for anticancer agents which are tested at the maximum possible dose which gives manageable side effects. These new regulations meant that the cost of one clinical trial after the 1970s was equivalent to the cost of ten before that time. Solutions to these problems are available, although to put them into practice would require the cooperation of government regulatory authorities, the pharmaceutical industry and other organisations such as the US National Cancer Institute (NCI), the UK Cancer Research Campaign (CRC) and the European Organisation for Research and Treatment of Cancer (EORTC). Firstly, it is important to switch from clinical trials of analogues and combinations of standard drugs to trials of new classes of anticancer agents. Further, an international effort should be launched whereby these new agents can be rapidly tested in phase II trials against common solid cancers using new techniques to detect small but significant tumour responses. Lead chemicals discovered in this way could then be taken back to the laboratory for further development. There is no shortage of new drugs which act by mechanisms quite different from present-day agents, and new approaches can greatly increase the amount of cytotoxic agents delivered to solid tumours. As long ago as 1980, the CRC introduced protocols which enabled early clinical trials to be carried out rapidly and with minimal cost. These procedures used short-term tests only in rodents to determine a safe starting dose. The test can be completed within six months and around fifty clinical trials using this protocol have been successfully carried out in collaboration with the EORTC. Despite this, the American Food and Drug Administration (FDA), regulatory authorities in many other countries and many drug companies still insist on using a second animal species before a phase I clinical trial is permitted instead of using the money spent to develop several agents with minimal toxicology testing. The EORTC and CRC also plan to introduce positron emission tomographic scanning into early clinical trials as a highly sensitive method of measuring tumour response. Cancer mortality has changed little over the past forty years, mainly because of our failure to develop curative chemotherapy for the common solid cancers. The way forward is to carry out extensive phase I and II clinical trials of the many new types of anticancer agent that have become available as a result of increased knowledge about cancer cells and how they differ from normal tissues. In order to do this, the regulatory authorities must recognize that minimal toxicology protocols are adequate, and drug companies must be persuaded to give more emphasis to the search for new chemotherapeutic agents. A coordinated effort to achieve these aims would be a wonderful way to mark the fiftieth anniversary of modern chemotherapy. Unfortunately the regulatory authorities find it less risky to stick with extensive safety testing rather than to use shortcuts, however well-validated clinically. Many but not all drug companies, mindful of profits, prefer the easy way out and concentrate on analogues, while most clinicians opt for trials of combinations of known agents, being aware that they are worth a publication or two. Reprinted with permission from Helix, Volume V, Issue 1, 1996, pp. 20-21.
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PMID:Anticancer Drug Development: The Way Forward. 1038 85

An ultra-high metastatic model of human colon cancer was developed in order to represent highly malignant patient disease for which there is no current model. Surgical orthotopic implantation (SOI) of a histologically intact liver metastasis fragment derived from a surgical specimen of a patient with metastatic colon cancer was initially implanted in the colon, liver and subcutaneously in nude mice. This tumor did not metastasize for the first 10 passages. At the eleventh passage, the tumor exhibited metastasis from the colon to the liver, spleen, and lymph nodes. At this time, two selective passages were carried out by transplanting resulting liver metastases in the nude mice to the colon of additional nude mice. After these two passages, the tumor became stably ultra-metastatic and was termed AC3488UM. One-hundred percent of mice transplanted with AC3488UM with SOI to the colon exhibited local growth, regional invasion, and spontaneous metastasis to the liver, lymph nodes, and spleen. While the maximum size of the primary tumor was 0.9 g, the metastatic liver was over 9 times the weight of the normal liver with the maximum weight of the metastatic liver over 12 g. Liver metastases were detected by the tenth day after transplantation in all animals. Half the animals died of metastatic tumor 25 days after transplantation. Histological characteristics of AC3488UM tumor were poorly differentiated adenocarcinoma of colon. Mutant p53 is expressed heterogeneously in the primary tumor and more homogeneously in the liver metastasis suggesting a possible role of p53 in the liver metastasis. The human origin of AC3488UM was confirmed by positive fluorescence staining for in situ hybridization of human DNA. The AC3488 human colon-tumor model with its ultra-high metastatic capability in each transplanted animal, short latency and a short median survival period is different from any known human colon cancer model and will be an important tool for the study of and development of new therapy for highly metastatic human colon cancer.
Clin Exp Metastasis 1999 Feb
PMID:An ultra-metastatic model of human colon cancer in nude mice. 1039 Jan 46

The appropriate use of plasma carcinoembryonic antigen (CEA) levels in the management of patients with colorectal cancer has been debated over the last 30 years. It is clear from the very low sensitivity of this test in normal populations that there is no role for CEA assessment as a screening tool for colon cancer. Although in patients receiving chemotherapy for metastatic colon cancer, elevations of CEA generally indicate disease progression, while decreases are indicative of improvement, there is no convincing evidence that CEA monitoring significantly affects either survival or quality of life. The area of most interest for CEA monitoring has been the potential for its use after curative resection. The purpose of postoperative CEA monitoring would be to detect recurrence of cancer at an early, surgically curable stage. There is good evidence that routine CEA monitoring postresection of colon cancer detects metastatic disease on average 5 months before routine follow-up evaluation without CEA monitoring detects recurrence. Also, studies demonstrate that some patients with recurrent cancer detected by CEA monitoring may be cured by surgical resection of metastases. However, the overall cost-effectiveness of this approach is not clear, and convincing definition of the role of postoperative CEA monitoring awaits the results of large randomized clinical trials.
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PMID:Carcinoembryonic antigen screening: pros and cons. 1052 4

A gene related to cell differentiation was identified by differential display as a candidate suppressor of metastases in colon cancer. This gene, with a full-length cDNA of 3 kb, is expressed in normal colon and primary colon cancer tissues and cell lines but not in their metastatic counterparts. A GenBank search found that it is identical to a recently cloned gene, differentiation-related gene-1 (Drg-1), isolated from differentiated HT-29 colon cancer cells. Stable transfection of the SW620 metastatic colon cancer cell line with Drg-1 cDNA induced morphological changes consistent with differentiation and up-regulated the expression of several colonic epithelial cell differentiation markers (alkaline phosphatase, carcinoembryonic antigen, and E-cadherin). Moreover, the expression of Drg-1 is controlled by several known cell differentiation reagents, such as ligands of peroxisome proliferator-activated receptor gamma (troglitazone and BRL46593) and of retinoid X receptor (LG268), and histone deacetylase inhibitors (trichostatin A, suberoylanilide hydroxamic acid, and tributyrin). A synergistic induction of Drg-1 expression was seen with the combination of tributyrin and a low dose of 5'-aza-2'-dexoycytidine (100 nM), an inhibitor of DNA methylation. Functional studies revealed that overexpression of Drg-1 in metastatic colon cancer cells reduced in vitro invasion through Matrigel and suppressed in vivo liver metastases in nude mice. We propose that Drg-1 suppresses colon cancer metastasis by inducing colon cancer cell differentiation and partially reversing the metastatic phenotype.
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PMID:Drg-1 as a differentiation-related, putative metastatic suppressor gene in human colon cancer. 1067 63

Currently used rodent tumor models, including transgenic tumor models, or subcutaneously-growing human tumors in immunodeficient mice, do not sufficiently represent clinical cancer, especially with regard to metastasis and drug sensitivity. In order to obtain clinically accurate models, we have developed the technique of surgical orthotopic implantation (SOI) to transplant histologically-intact fragments of human cancer, including tumors taken directly from the patient, to the corresponding organ of immunodeficient rodents. It has been demonstrated in 70 publications describing 10 tumor types that SOI allows the growth and metastatic potential of the transplanted tumors to be expressed and reflects clinical cancer. Unique clinically-accurate and relevant SOI models of human cancer for antitumor and antimetastatic drug discovery include: spontaneous SOI bone metastatic models of prostate cancer, breast cancer and lung cancer; spontaneous SOI liver and lymph node ultra-metastatic model of colon cancer, metastatic models of pancreatic, stomach, ovarian, bladder and kidney cancer. Comparison of the SOI models with transgenic mouse models of cancer indicate that the SOI models have more features of clinical metastatic cancer. Cancer cell lines have been stably transfected with the jellyfish Aequorea victoria green fluorescent protein (GFP) in order to track metastases in fresh tissue at ultra-high resolution and externally image metastases in the SOI models. Effective drugs can be discovered and evaluated in the SOI models utilizing human tumor cell lines and patient tumors. These unique SOI models have been used for innovative drug discovery and mechanism studies and serve as a bridge linking pre-clinical and clinical research and drug development.
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PMID:Orthotopic metastatic mouse models for anticancer drug discovery and evaluation: a bridge to the clinic. 1075 2


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