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)

Liposomes as drug carriers in cancer chemotherapy have attracted considerable interest. To enhance the therapeutic effect of Adriamycin entrapped in liposomes (Lip-ADM) on human solid tumors, we investigated the therapeutic effects of Lip-ADM in combination with recombinant human tumor necrosis factor-alpha (rTNF-alpha), which is known to have specific effects on tumor vasculature. rTNF-alpha or saline solution was injected intravenously into nude mice bearing a human colon cancer strain, HC-1, at 1 hour before intravenous administration of Lip-ADM. The significant therapeutic effect of Lip-ADM in combination with rTNF-alpha was demonstrated by the evaluation with tumor growth curve and the actual tumor weights, in comparison with groups of mice treated with saline solution, rTNF-alpha alone, or with a Lip-ADM after saline. Levels of Adriamycin in tumor tissue in the Lip-ADM in combination with rTNF-alpha-treated group were higher than those in Lip-ADM with saline solution-treated group.
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PMID:Therapeutic effects of liposomal adriamycin in combination with tumor necrosis factor-alpha. 154 76

Intercellular adhesion molecule (ICAM-1), vascular cell adhesion molecule (VCAM-1), and the lymphocyte function-associated antigen (LFA-1) are cell adhesion molecules thought to play an important role in the complex process of airway inflammation and tumor cell growth. The aim of this study was to examine the distribution of ICAM-1, VCAM-1, and LFA-1 in adenocarcinoma of lung and in major cellular compartments of non-neoplastic lung tissue. We examined cellular compartments in tissue from five bronchoalveolar carcinomas, three acinar adenocarcinomas, and one colon cancer metastatic to the lung. The compartments in neoplasms included the tumor cells proper, endothelial cells within the tumor vasculature, tumor stromal cells, and tumor-infiltrating lymphocytes. The compartments in non-neoplastic lung tissue included lung endothelial cells, pulmonary lymphocytes, interstitial fibroblasts, Type II alveolar pneumocytes, and bronchial epithelial cells. ICAM-1 was expressed in tumor cells from all of the nine adenocarcinomas. In contrast, VCAM-1 expression was not identified in tumor cells from any of the nine adenocarcinomas. ICAM-1 was expressed in all cellular compartments of the non-neoplastic lung tissue, whereas VCAM-1 was expressed only in pulmonary lymphocytes and interstitial fibroblastic cells. LFA-1 was uniformly expressed in tumor-infiltrating lymphocytes from each of the nine tumors and all of the lymphocytes in non-neoplastic lung tissue. This study showed major differences in the expression of ICAM-1 and VCAM-1 in tumor cells from pulmonary adenocarcinoma and also provided evidence for a wider distribution of ICAM-1, compared with VCAM-1, in non-neoplastic cellular compartments of the lung. ICAM-1 expression was particularly noticeable in bronchial and alveolar epithelial cells. Upregulation of ICAM-1 in pulmonary adenocarcinoma might foster binding by LFA-1-bearing lymphocytes, with a possible impact on the vulnerability of tumor cells to host defense mechanisms.
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PMID:Expression of ICAM-1, VCAM-1, and LFA-1 in adenocarcinoma of the lung with observations on the expression of these adhesion molecules in non-neoplastic lung tissue. 987 50

Hyperthermia (HT) may increase tumor targeting of a radiolabeled antibody by its effects on tumor vasculature and antigen expression. Expression of a 45-kDa glycoprotein antigen on LS180 colon cancer cells was 2.7-fold enhanced 2 days after heating at 43 degrees C for 1 h. Preferential tumor accumulation of 125I-A7 recognizing this antigen was doubled and the antitumor effect of 131I-A7 was significantly improved by HT. Hyperthermia also increased tumor uptake of an irrelevant antibody but its radioactivity was rapidly cleared. These results indicate that HT increased the initial delivery of an antibody to a tumor by its vascular effect, and radioactivity was retained in tumors by increased specific binding, resulting in a better radioimmunotherapy outcome.
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PMID:Combination radioimmunotherapy with local hyperthermia: increased delivery of radioimmunoconjugate by vascular effect and its retention by increased antigen expression in colon cancer xenografts. 1040 61

MMI-166 is a selective inhibitor of matrix metalloproteinase (MMP)-2 and MMP-9. Mice implanted a human colon cancer orthotopically received 200 mg/kg of MMI-166 orally for 5 weeks. Gelatin zymography demonstrated that the administration of MMI-166 remarkably decreased the active MMP-2 expression. Histological examination revealed that MMI-166 showed prominent effect on reduction of the invasive feature of the cancer cells and showed inhibitory effect on tumor vasculature, resulting in the significant decrease of microvessel density of the implanted tumor and liver metastasis compared with the control group. Conclusively, MMI-166 is a potent antiangiogenic oral agent for a human colon cancer.
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PMID:Prevention of liver metastasis of human colon cancer by selective matrix metalloproteinase inhibitor MMI-166. 1173 35

We investigated the efficacy of interferon (IFN)-beta therapy against colon cancer using a novel approach mediated by a lyophilized preparation of High 5 (H5) insect cells transduced with a recombinant baculovirus encoding murine IFN-beta (H5BVIFN-beta). The orthotopic model of CT-26 murine colon cancer in syngeneic BALB/c mice was used in the study, and H5BVIFN-beta was intratumorally delivered. Two injections of H5BVIFN-beta (on days 14 and 21 after tumor cell implantation), but not lyophilized H5 cells (control), significantly reduced the size of cecal tumors and the number of liver metastases. Immunohistochemical analysis revealed that cecal tumors injected with saline or H5 contained many proliferating cells (PCNA+) and few apoptotic cells (TUNEL+). In sharp contrast, H5BVIFN-beta-treated tumors contained fewer PCNA+ cells and significantly more TUNEL+ cells. The H5BVIFN-beta-treated tumors were infiltrated by a large number of CD8+ and F4/80+ cells and expressed a high level of inducible nitric oxide synthase (iNOS). Immunofluorescent double staining technique demonstrated a significant increase of apoptotic endothelial cells (CD-31+/TUNEL+) in tumors treated with H5BVIFN-beta. In conclusion, the data show that intralesional injections of H5BVIFN-beta can suppress the progressive growth of established orthotopic tumors of colon cancer cells and occult liver metastasis. The therapeutic effects directly correlate with destruction of tumor vasculature.
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PMID:Regression of primary murine colon cancer and occult liver metastasis by intralesional injection of lyophilized preparation of insect cells producing murine interferon-beta. 1268 62

Two of the most promising new targets in the treatment of colorectal cancer are the epithelial growth factor receptor (EGFR) and the vascular endothelial growth factor (VEGF). Agents that inhibit the EGFR or bind to VEGF have demonstrated clinical activity as single agents and in combination with chemotherapy in phase II and phase III clinical trials. The most promising of these agents are cetuximab, which blocks the binding of EGF and transforming growth factor alpha (TGF-alpha) to EGFR, and bevacizumab, which binds free VEGF. Cetuximab and irinotecan have been evaluated in two clinical studies in the USA (IMCL CP02-0141 and IMCL CP02-9923). Study IMCL CP02-0141 evaluated the antitumor activity of single-agent cetuximab in patients with irinotecan-refractory, EGFR-positive metastatic colorectal carcinoma. There were 6 partial responses in 57 treated patients, for a response rate of 10.5%. Study IMCL CP02-9923 evaluated the combination of cetuximab and irinotecan in a total of 139 patients enrolled at 27 study sites. In this trial 22.5% of patients with progressive disease on irinotecan achieved an objective response (19% by investigator assessment) showing that the combination of cetuximab and irinotecan has antitumor activity in this population. A large randomized phase II trial evaluating similar study populations in Europe confirmed these findings, demonstrating response rates for cetuximab/irinotecan and cetuximab alone of 22.9% and 10.8%, respectively. The other promising agent bevacizumab is a humanized variant of the anti-VEGF monoclonal antibody. VEGF is produced by healthy and neoplastic cells. Its activities are mediated by two receptor tyrosine kinases. VEGF signaling is often a rate-limiting step in physiologic and pathologic angiogenesis. Bevacizumab has been studied as an antiangiogenic cancer therapeutic as a single agent and in combination with chemotherapy in patients with stage III and IV colon cancer. In addition to its direct antiangiogenic effects, bevacizumab may allow more efficient delivery of chemotherapy by altering tumor vasculature and decreasing the elevated interstitial pressure common in tumors. In this regard, some of the most robust phase II data using bevacizumab are from a randomized study of chemotherapy [fluorouracil (5-FU) and leucovorin (LV)] with or without bevacizumab in metastatic colorectal cancer. In this study, treatment with bevacizumab plus 5-FU/LV resulted in higher response rates, longer median time to disease progression, and longer median survival. Recently, a phase III, multicenter, double-blind, randomized, placebo-controlled trial was designed to investigate the addition of bevacizumab to first-line irinotecan, 5-FU, and LV chemotherapy (IFL). The trial showed a higher response rate, longer time to tumor progression, and prolonged overall survival in patients with metastatic colorectal cancer. It was the first large, randomized, phase III survival trial to assess the importance of targeting VEGF and tumor angiogenesis for the treatment of human cancer. Integration of novel agents targeting VEGF and EGFR with irinotecan-based chemotherapy has shown clinical activity in patients with metastatic colorectal cancer. The goal in the future will be to predict which specific chemotherapy and targeted agent combination will most likely benefit individual patients.
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PMID:Integration of novel agents in the treatment of colorectal cancer. 1530 12

Lipoplatin, a liposomal formulation of cisplatin, was developed with almost negligible nephrotoxicity, ototoxicity and neurotoxicity, as demonstrated in preclinical and Phase I human studies. A polyethylene-glycol coating of the liposome nanoparticles is supposed to result in tumor accumulation of the drug by extravasation through the altered tumor vasculature. We explored the hypothesis that intravenous infusion of Lipoplatin results in tumor targeting in four independent patient cases (one with hepatocellular adenocarcinoma, two with gastric cancer and one with colon cancer) who underwent Lipoplatin infusion followed by a prescheduled surgery approximately 20 h later. Direct measurement of the platinum levels in specimens from the excised tumors and normal tissues showed that the total platinum levels were on average 10-50 times higher in malignant tissue compared to the adjacent normal tissue specimens; most effective targeting was observed in colon cancer, with an accumulation up to 200-fold higher in colon tumors compared to normal colon tissue. Of the several surgical specimens, gastric tumors displayed the highest levels of total platinum suggesting Lipoplatin as a candidate anticancer agent for gastric tumors; gastric tumor specimens had up to 260 micrograms platinum /g tissue, that was higher than any tissue level in animals treated at much higher doses. Fat tissue displayed a high accumulation of total platinum in surgical specimens in three different patients, correlating to the lipid capsule of cisplatin in its Lipoplatin formulation. It was also inferred that normal tissue had more platinum trapped in the tissue but not reacted with macromolecules, whereas tumor tissue displayed platinum that reacted with cellular macromolecules; the data were consistent with a model where Lipoplatin damages more tumor compared to normal cells. In conclusion, Lipoplatin has the ability to preferentially concentrate in malignant tissue both of primary and metastatic origin following intravenous infusion to patients. In this respect, Lipoplatin emerges as a very promising drug in the arsenal of chemotherapeutics.
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PMID:Systemic Lipoplatin infusion results in preferential tumor uptake in human studies. 1608 May 62

With recent Food and Drug Administration approval of the anti-vascular endothelial growth factor (VEGF) antibody for the treatment of colon cancer, it may be possible to achieve similar progress in the treatment of locally advanced lung cancer. Antiangiogenic therapies in the clinic are a reality, and it is important to demonstrate that they can be used safely with conventional modalities, including radiation therapy (RT). Strategies under scrutiny in preclinical and clinical studies include the use of endogenous inhibitors of angiogenesis, use of agents that target VEGF and VEGF receptor signaling, targeting endothelial-related integrins during angiogenesis, and targeting the preexisting immature vessels growing within tumors (ie, vascular targeting). Regardless of the approach, it is necessary to address whether angiogenesis is a consistent phenomenon within the lung parenchyma around a cancer and a relevant target and whether inhibiting angiogenesis will improve current lung cancer therapies without increasing toxicity. Vascular-targeting agents (VTAs) are an interesting class of agents that have the potential to enhance RT, but their clinical promise has yet to be realized. In preclinical models, these agents selectively destroy the tumor vasculature, initiating a rapid centralized necrosis within established tumors. Characteristically, after treatment with VTAs, a rim of viable tumor cells remains at the periphery of the tumor, which remains well perfused and should therefore be relatively sensitive to radiation-induced cytotoxicity. This review will focus on VTAs in the treatment of lung cancer and includes a discussion of combination studies with RT in the laboratory and some of the hurdles in the clinical application of these agents.
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PMID:Vascular-targeting agents and radiation therapy in lung cancer: where do we stand in 2005? 1635 11

We administered an adenoviral vector, Onyx-015, into the hepatic artery of patients with metastatic colorectal cancer involving the liver. Thirty-five patients enrolled in this multi-institutional phase I/II trial received up to eight arterial infusions of up to 2 x 10(12) viral particles. Hepatic toxicity was the primary dose-limiting toxicity observed in preclinical models. However, nearly 200 infusions of this adenoviral vector were administered directly into the hepatic artery without significant toxicity. Therefore, we undertook this analysis to determine the impact of repeated adenoviral exposure on hepatic function. Seventeen patients were treated at our institution, providing a detailed data set on the changes in hepatic function following repeated exposure to adenovirus. No changes in hepatic function occurred with the first treatment of Onyx-015 among these patients. Transient increases in transaminase levels occurred in one patient starting with the second infusion and transient increases in bilirubin was observed in two patients starting with the fifth treatment. These changes occurred too early to be explained by viral-mediated lysis of hepatocytes. In addition, viremia was observed starting 3-5 days after the viral infusion in half of the patient, but was not associated with hepatic toxicity. To further understand the basis for the minimal hepatic toxicity of adenoviral vectors, we evaluated the replication of adenovirus in primary hepatocytes and tumor cells in culture and the expression of the coxsackie-adenoviral receptor (CAR) in normal liver and colon cancer metastatic to the liver. We found that adenovirus replicates poorly in primary hepatocytes but replicates efficiently in tumors including tumors derived from hepatocytes. In addition, we found that CAR is localized at junctions between hepatocytes and is inaccessible to hepatic blood flow. CAR is not expressed on tumor vasculature but is expressed on tumor cells. Spatial restriction of CAR to the intercellular space in normal liver and diminished replication of adenovirus in hepatocytes may explain the minimal toxicity observed following repeated hepatic artery infusions with Onyx-015.
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PMID:Minimal hepatic toxicity of Onyx-015: spatial restriction of coxsackie-adenoviral receptor in normal liver. 1713 21

One of the most promising new strategies for the development of efficacious cancer therapies relies on the targeted delivery of biopharmaceutical to the tumor environment by the use of selective and specific antibodies. The identification of accessible perivascular proteins selectively overexpressed in cancer tissue may facilitate the development of antibody-based biopharmaceutical administration. This approach is potentially highly selective and specific, combining the presence of tumor biomarkers readily accessible from the blood vessels and the high rate of angiogenesis characteristic of cancer tissues. We performed ex vivo perfusions of surgically resected human colon cancer using a reactive ester derivative of biotin, thus achieving a selective covalent modification of accessible proteins in vascular structures and stroma. After extraction and purification, biotinylated proteins were digested and the resulting peptides submitted to a comparative mass spectrometry-based proteomic analysis, revealing quantitative differences between normal and cancer colon. Sixty-seven of the total 367 proteins identified were found to be preferentially expressed at the tumor site. We generated human monoclonal antibodies against 2 potential tumor targets, NGAL and GW112, and we proved their selective expression in cancer colon and not or barely in healthy tissues. This article presents the first proteomic analysis of human colorectal cancer structures readily accessible from the tumor vasculature, revealing the overexpression of novel tumor antigens which may serve as selective targets for antibody-based imaging and therapeutic biomolecular strategies.
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PMID:Identification of new accessible tumor antigens in human colon cancer by ex vivo protein biotinylation and comparative mass spectrometry analysis. 1879 64


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