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)

Cyclooxygenase 2 (COX-2) overexpression is found in a wide variety of human cancers and is linked to all stages of tumorigenesis. Elevated tumor COX-2 expression is associated with increased angiogenesis, tumor invasion, suppression of host immunity and promotes tumor cell resistance to apoptosis. Previous reports have linked the COX-2 product prostaglandin E2 (PGE2) to the abnormal activation of the mitogen-activated protein kinase/Erk kinase pathway. Here we show that PGE2 is able to rapidly stimulate Erk phosphorylation in a subset of non-small cell lung cancer (NSCLC) cell lines. This effect is not evident in bronchial epithelial cells. In contrast to previous reports in colon cancer, we found that Erk activation as well as cellular proliferation induced by PGE2 was not inhibited by pretreatment of the cells with epidermal growth factor receptor (EGFR) inhibitors. Activation of the Erk pathway by PGE2 was also resistant to src kinase inhibitors but sensitive to the protein kinase C inhibition. PGE2 effects are mediated through four G protein-coupled receptors. Selective inhibition of EP receptors revealed the possible involvement of Ca2+-dependent signaling in PGE2-mediated activation of Erk. Our data indicate the presence of an EGFR-independent activation of the mitogen-activated protein kinase/Erk pathway by PGE2 in NSCLC cells. These findings provide evidence for the possible link between tumor COX-2 overexpression and elevated Erk-mediated cancer cell proliferation and migration. Importantly, these findings suggest that COX-2 overexpression may contribute to EGFR inhibitor resistance in NSCLC.
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PMID:Prostaglandin E2 activates mitogen-activated protein kinase/Erk pathway signaling and cell proliferation in non-small cell lung cancer cells in an epidermal growth factor receptor-independent manner. 1602 29

Cyclooxygenase (COX)-2 is implicated in the oncogenesis of many cancers, and COX-2 inhibitors are effective in preventing the development of tumours, such as in colon cancer. Its expression is increased in nonsmall cell lung cancer and is associated with poor prognosis. The present study assessed COX-2 expression in normal bronchial epithelium, as well as in all the putative precursors of squamous cell carcinomas. COX-2 expression was studied by immunohistochemistry in 106 biopsies collected during autofluorescence bronchoscopy in consecutive patients at high-risk for lung cancer. All biopsies corresponding to normal epithelium or low-grade lesions (lesions up to moderate dysplasia) did not show increased COX-2 expression. Lesions were positive for COX-2 in eight out of 14 severe dysplasia patients, eight out of 14 in situ carcinomas and five out of eight invasive carcinomas. A strong statistically significant difference in COX-2 expression was found between normal epithelium or low-grade lesions and high-grade lesions (severe dysplasia or worse). The positive and negative predictive values of COX-2 expression for high-grade lesion were 100% and 82.35%, respectively. In conclusion, bronchial precursors of squamous cell carcinoma showed increased cyclooxygenase-2 expression and were segregated into low- versus high-grade with a high positive predictive value. Thus, cyclooxygenase-2 appears as a potential early marker of squamous cell carcinoma.
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PMID:COX-2 expression during early lung squamous cell carcinoma oncogenesis. 1605 66

Persons over the age of 65 years are the fastest growing segment of the U.S. population. In the next 30 years, they will comprise more than 20% of the population. Fifty percent of all cancers occur in this age group, and therefore, there is an expected rise in the total cancer burden. Data are becoming available that will better guide the use of chemotherapy in the older patient population. In this paper, information regarding age-related physiologic changes and their relationship to pharmacology, functional status, and hematopoiesis is presented. The adjuvant treatment of breast and colon cancer, as well as the primary therapy of aggressive non-Hodgkin lymphoma is reviewed. The treatment of more advanced breast, ovarian, and non-small cell lung cancer is also discussed.
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PMID:Clinical pharmacology issues relevant to the dosing and toxicity of chemotherapy drugs in the elderly. 1617 84

Persons over the age of 65 are the fastest growing segment of the United States population. In the next 30 years, they will comprise over 20 percent of the population. Fifty percent of all cancers occur in this age group and, therefore, there will be an expected rise in the total cancer burden. Data is becoming available that will better guide the use of chemotherapy in the older patient population. Information regarding age-related physiologic changes are presented with their relationship to pharmacology, functional status, and hematopoiesis. Treatments are reviewed in regard to the adjuvant treatment of breast and colon cancer as well as primary therapy of aggressive non-Hodgkin's lymphoma. The treatment of more advanced breast, ovary and non-small cell lung cancer also are discussed.
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PMID:Treatment of elderly cancer patients with chemotherapy. 1620 62

Pemetrexed, a new generation antifolate recently approved for the treatment of mesothelioma and non-small cell lung cancer, is an excellent substrate for the reduced folate carrier (RFC). To explore the carrier's effect on pemetrexed activity, RFC was inactivated in HCT-15 colon cancer cells by mutagenesis and PT632 selective pressure. A clone (PT1) was obtained with a glycine to arginine substitution at amino acid 401, resulting in the loss of RFC function. PT1 cells were resistant to PT632 (178-fold), methotrexate (4-fold), and ZD1694 (Tomudex, raltitrexed; 20-fold), but were 3-fold collaterally sensitive to pemetrexed when grown in 25 nmol/L of 5-formyltetrahydrofolate. PT1 cells transfected with wild-type RFC had antifolate sensitivities comparable to that of wild-type HCT-15 cells, indicating that the RFC mutation was the sole basis for resistance. Folate pools were contracted in PT1 cells by 32% or 60%, as measured by radiolabeling intracellular folates or by an enzyme binding assay, respectively. This was reflected in marked (6.5-fold) collateral sensitivity to trimetrexate. The initial uptake of pemetrexed in PT1 cells was markedly reduced ( approximately 85%) but intracellular pemetrexed levels increased to approximately 60% and approximately 70% to that of wild-type cells after 2 hours and 6 days, respectively. There was increased pemetrexed inhibition of glycinamide ribonucleotide transformylase and, to a lesser extent, thymidylate synthase in PT1 cells growing in 5-formyltetrahydrofolate based on nucleoside protection analyses. Hence, loss of RFC function leads to collateral sensitivity to pemetrexed in HCT-15 cells, likely due to cellular folate pool contraction resulting in partial preservation of pemetrexed polyglutamylation and increased target enzyme inhibition. micro
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PMID:The inverse relationship between reduced folate carrier function and pemetrexed activity in a human colon cancer cell line. 1650 19

A new series of substituted benzylamino- and heterocyclylmethylamino carbodithioate derivatives of 4-(3H)-quinazolinone were synthesized via four steps starting from 2-amino-5-methylbenzoic acid and initially screened against A-549 (human non-small cell lung cancer), HCT-8 (human colon cancer), and Bel-7402 (human liver cancer) cell lines at the single concentration of 5 microg/mL using the colorimetric MTT assay. The IC50 values were determined for the compounds reaching > or = 70% inhibition in primary screening by serial dilution. Among the newly synthesized compounds, 9n exhibited potent in vitro cytotoxicity against A-549, HCT-8, and Bel-7402 cell lines with the IC50 values of 1.65, 0.93, and 1.43 microM, respectively.
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PMID:Synthesis of substituted benzylamino- and heterocyclylmethylamino carbodithioate derivatives of 4-(3H)-quinazolinone and their cytotoxic activity. 1661 82

C. Heidelberger et al left great gifts to us. Approximately 50 years have elapsed since their discovery of 5-FU in 1957 before eventually elucidating the mechanisms by which the drug exerts its pharmacological actions and provokes its adverse reactions. Namely, 5-FU is a typical antimetabolite with strong time dependency, and continuous venous infusion(CVI) is considered to be its optimal regimen. The following facts may be mentioned to explain why such a long period of time has been spent to reach this level of research: 1) 5-FU, when administered to the living individual, is mostly inactivated by hepatic catabolic enzymes without delay and is then excreted in the urine, thus making it difficult to precisely analyze the relationship of blood 5-FU concentrations with concentration persistence, anticancer activity, and adverse reactions; and 2) unlike other anticancer agents, an antimetabolite 5-FU separately generates metabolites which show anticancer activity and adverse reactions, as well as metabolites which show adverse reactions only. For the last 30 years, we paid attention especially to 5-FU among chemotherapeutic agents for cancer and have sought for a long-lasting therapeutic modality which maintains quality of life of the patient and patient compliance by considering the balancing between its effects and adverse reactions. Consequently, we concretized an innovative therapeutic drug, TS-1 (S-1). We have a long history of research before developing S-1, which is represented by a series of investigations consisting in the developments of Futrafur (FT)--an oral anticancer agent of a 5-FU derivative (prodrug)-in 1970 subsequent to the above discovery of 5-FU, of UFT(FT: Ura=1 : 4) in 1976, and of S-1 in 1999. To date, we took the initiative in the world to devise S-1, the first self-rescuing concept(SRC)-based anticancer agent with dual actions, i.e., enhancement of pharmacological actions of 5-FU and reduction of its adverse reactions, by making use of the biochemical and enzymological properties of 5-FU and by combining FT, which is gradually converted to 5-FU in the body, with a 5-FU's effect-enhancing substance and a 5-FU's adverse reaction-reducing substance. S-1 is an oral anticancer agent in capsule, in which the following 2 modulators for 5-FU are combined to FT: one is CDHP(5-chloro-2,4-dihydroxypyridine) which increases blood concentrations and enhances pharmacological actions of 5-FU by potently inhibiting the degradation of 5-FU; and another is Oxo(potassium oxonate) which is localized in the mucosa of the gastrointestinal (GI) tract after oral administration and reduces GI toxicities provoked by 5-FU. S-1 is an oral anticancer agent in which these 3 components, FT, CDHP, and Oxo, are combined at a molar ratio of 1 : 0.4 : 1. Our conception to develop an SRC-based therapeutic drug and the preclinical concepts validated by numerous basic studies were demonstrated also in the clinical trials. In January 1999, S-1 was approved for the treatment of advanced and recurrent gastric cancers through the priority review system. From 2001 to 2005, S-1 was approved for the treatment of head and neck cancer, colon cancer, non-small cell lung cancer, and breast cancer. S-1 has been applied to acquire its expanded indications for the treatment of pancreatic cancer and biliary tract cancer. We are confident that the combined regimen of S-1 with other anticancer agents and with other therapeutic modalities will contribute to the routine medical practice of cancer treatment in the future.
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PMID:[Timeline from discovery of 5-FU to development of an oral anticancer agent S-1 and its drug concept]. 1689 67

Adjuvant chemotherapy is considered a standard of care for many malignancies, the most well known being breast and colon cancer. Unfortunately, less than a third of patients with non-small cell lung cancer (NSCLC) present with resectable disease and despite resection outcomes are often poor with a median 5-year survival of 40-50%. Modern chemotherapy for NSCLC provides both a survival advantage and an improvement in quality of life in the palliative setting. Several large studies using modern platinum-based regimens have been presented since the 1995 meta-analysis. This demonstrated a nonsignificant benefit for older platinum-based regiments. These studies have consistently shown a survival benefit across all stages of resection with acceptable toxicity. The absolute magnitude of benefit is consistent with that achieved in other malignancies where adjuvant chemotherapy is offered as a standard of care.
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PMID:Adjuvant chemotherapy in non-small cell lung cancer. 1691 71

In this study, we synthesized a series of enantiomerically pure (2R,3R)-disubstituted tetrahydropyrans with diverse functional groups. The in vitro antiproliferative activities were examined in the human solid tumor cell lines A2780 (ovarian cancer), SW1573 (non-small cell lung cancer), and WiDr (colon cancer). Overall, the results show the relevance for antiproliferative activity of the alpha,beta-unsaturated ester side chain at position 2 of the THP ring.
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PMID:Synthesis and antiproliferative activity of (2R,3R)-disubstituted tetrahydropyrans. 1695 Jun 18

In this study, we synthesized a series of enantiomerically pure (2R,3R)- and (2R,3S)-disubstituted tetrahydropyrans bearing a CH2O spacer group on the side chain at position 2 of the heterocyclic ring. The in vitro antiproliferative activities of the compounds were examined in the human solid tumor cell lines A2780 (ovarian cancer), SW1573 (non-small cell lung cancer), and WiDr (colon cancer). Overall, the results point out the relevance for antiproliferative activity of the distance between the heterocycle and the unsaturated group.
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PMID:Synthesis and antiproliferative activity of (2R,3R)-disubstituted tetrahydropyrans. Part 2: Effect of side chain homologation. 1711 Jan 7


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