Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: HUMANGGP:036105 (DCC)
 1,274 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The title diesters (11-15; halo substituents F, Cl, Br, I) were prepared by DCC-induced cyclization of the precursor 5'-monophosphate or direct halogenation of the 2'-deoxyuridine 3',5'-cyclic monophosphate. Antitumor activities of 11-15 in cell systems (L1210 and Raji/0) were compared to those of the corresponding nucleosides and 5'-monophosphates. Thus, the 5-F- and 5-CF3-2'-deoxyuridines proved to be highly active derivatives [ID50 values (microgram/mL) for L1210, 0.002 and 0.06, respectively], with the 5'-monophosphates showing comparable potencies. The corresponding 3',5'-cyclic monophosphate diesters were 20-30 times less potent but nonetheless highly cytostatic. All derivatives including 11-15 had greatly increased ID50 values for the thymidine kinase deficient (TK-) L1210 and Raji cells. The 3',5'-cyclic diesters (11-15) evidently are not efficient prodrug sources of the nucleoside 5'-monophosphates in TK- cells. They also proved to be 100- to 2000-fold less efficient inhibitors of L1210 thymidylate synthetase than were the 5'-monophosphates. The 5-substituted 2'-deoxyuridines and their 5'-monophosphates were potent inhibitors of herpes simplex virus (MIC50 mostly 0.07-10 micrograms/mL) and vaccinia virus (MIC50 0.07-0.2 microgram/mL), with antiviral activity decreasing in the order 5-I, 5-Br greater than 5-CF3 greater than 5-Cl greater than 5-F. The 3',5'-cyclic monophosphates (11-15) were for the most part 10- to 40-fold less active than the 5'-monophosphates in the virus assay systems (e.g., MIC50 for the 5-Br and 5-I derivatives ranged 1-20 micrograms/mL). By contrast 11-15 were considerably more potent inhibitors of vaccinia virus growth (MIC50 0.4-2 micrograms/mL). As the neutral 3',5'-cyclic methyl phosphate triesters (16-18), the 5-I and 5-Br compounds were less potent in antiviral and cytostatic agents than the 3',5'-cyclic diesters, while the 5-iodo benzyl triester was in several cases as active as the 3',5'-cyclic diester. The title compounds (11-15) appear to require extracellular hydrolysis to the nucleoside before functioning as antitumor or antiviral agents.
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PMID:Synthesis and antitumor and antiviral properties of 5-halo- and 5-(trifluoromethyl)-2'-deoxyuridine 3',5'-cyclic monophosphates and neutral triesters. 302 28

The prognosis of patients with colorectal cancer is impacted by various factors at the time of diagnosis, including location of the tumor, gender, age and overall performance status of the patient. Optimal postoperative management of patients who have undergone successful tumor resection involves the utilization of reliable determninants of prognosis to help select patients who would benefit from adjuvant treatment, while sparing others from drug-related adverse effects. Tailoring chemotherapy for patients with disseminated cancer, or for patients who receive adjuvant chemotherapy, is also critical. Interpatient differences in tumor response and drug toxicity are common during chemotherapy. Genomic variability of key metabolic enzyme complexes, drug targets, and drug transport molecules is an important contributing factor. The identification of genetic markers of response and prognosis will aid in the development of more individualized chemotherapuetic strategies for cancer patients. Potential prognostic indicators in colorectal cancer include oncogenes, tumor suppressor genes, genes involved in angiogenic and apoptotic pathways and cell proliferation, and those encoding targets of chemotherapy. Specifically, molecular markers such as deletion of 18q (DCC), p27 and microsatellite instability are promising as indicators of good or poor prognosis. Molecular determinants of efficacy and host toxicity of the most commonly used drugs in colorectal cancer, fluoracil, irinotecan and oxaliplatin, are being investigated. Alterations in gene expression, protein expression and polymorphic variants in genes encoding thymidylate synthase, dihydropyrimidine dehydrogenase, dUTP nucleotidehydrolase and thymidine phosphorylase (for fluoropyrimidine-based chemotherapy), uridine diphosphate glucosyltransferase (UGT) 1A1 and carboxylesterase (for irinotecan therapy), and excision repair cross-complementing genes (ERCC1 and ERCC2) and glutathione-S-transferase P1 (for oxalilplatin-based regimens) may be useful as markers for clinical drug response, survival and host toxicity.
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PMID:Implications of genetic testing in the management of colorectal cancer. 1274 25

The treatment of colorectal cancer has advanced over the past several years with the introduction of several active agents. Determining which patients to treat with chemotherapy and choosing optimal treatment would allow practioners to maximize the benefit of chemotherapy. Several prognostic and predictive markers have been identified and include oncogenes, tumor suppressor genes, genes involved in angiogenic and apoptotic pathways and cell proliferation, and those encoding targets of chemotherapy. Specifically, prognostic markers include deletion of 18q (DCC), p27 and microsatellite instability. Predictive markers are those that may determine efficacy of drugs used in colorectal cancer such as fluropyrimidines and oxaliplatin. Alterations in gene expression, protein expression and polymorphic variants in genes encoding thymidylate synthase, dihydropyrimidine dehydrogenase, and thymidine phosphorylase and excision repair cross-complementing genes (ERCC1) may be useful as markers for clinical drug response, survival and host toxicity. The integration of these prognostic and predictive markers would allow individualized treatment for patients, maximizing therapeutic effect and minimizing exposure to toxicity.
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PMID:Tailored chemotherapy for colorectal cancer: a new approach to therapy. 1558 Oct 57