Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0598934 (tumor growth)
 58,965 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Chronic weekly administration of FUra to CD8F1 female mice bearing spontaneous mammary tumors produced body weight loss during the first 2 weeks of treatment, which became less severe during subsequent weeks of therapy. To our knowledge, the development of such a decrease in FUra toxicity in vivo during chronic treatment with the drug has not been described previously, and a study of this phenomenon was therefore undertaken in tumor-free CD8F1 female mice. Weekly administration of FUra at 85 mg/kg resulted in toxicity expressed in body weight loss and in depressed peripheral WBC levels; however, the magnitude of these toxic effects decreased significantly by the 5th week of treatment. Pretreatment of normal mice with FUra for 7 weeks resulted in a dose-related shift in the LD50 of FUra administered as a subsequent challenge. Compared with an LD50 of 240 mg/kg for FUra in normal mice, the LD50 in mice pretreated with FUra at 50 or 85 mg/kg per week was found to be significantly elevated to 370 and 460 mg/kg, respectively. Pretreatment with FUra at 85 mg/kg for 7 weeks did not alter the activity of the enzymes responsible for the activation of FUra, namely uridine kinase or orotate phosphoribosyltransferase, in the intestinal epithelium or bone marrow, but it did decrease the 24-h urinary excretion of intact [3H]FUra by almost 40% (P less than 0.01). In addition, the FUra pretreatment schedule resulted in a 31% (P = 0.14) increase in the activity of dihydrouracil dehydrogenase in the liver. These results suggest that increased degradation of FUra can be induced by chronic treatment with the drug. Finally, knowledge of the development of increased drug catabolism was used to increase the therapeutic effectiveness of FUra by its incorporation into an increasing-dose regimen. Mice bearing 24-h transplants of the murine breast tumor were treated with a constant dose of FUra for 12 weeks or with a dose that was increased, after 7 weeks, to a dose normally causing a high degree of drug-related mortality. The group receiving the incremented FUra dose had a significantly slower tumor growth rate without an increase in drug-related toxicity. These results are discussed in light of their obvious clinical implications.
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PMID:Decreased host toxicity in vivo during chronic treatment with 5-flourouracil. 396 61

Natural killer (NK) cells target and kill tumor cells by direct anti-tumor cytotoxicity. NK lytic-associated molecule (NKLAM) is a protein involved in this cytolytic function. Acting as an E3 ubiquitin ligase, NKLAM binds to and ubiquitinates a novel protein, uridine-cytidine kinase like-1 (UCKL-1), targeting it for degradation. However, UCKL-1's function in tumor cell survival and NK cell cytotoxicity is unknown. UCKL-1's homology to uridine kinases and over expression in tumor cells suggests a role for UCKL-1 in tumor growth and/or survival. We propose that NKLAM and UCKL-1 interact in the tumor cell, where degradation of UCKL-1 leads to increased tumor cell apoptosis. Here we use RNA interference to downregulate UCKL-1 expression in K562 erythroleukemia cells. It was seen that downregulation of UCKL-1 initiated apoptosis and slowed the cell cycle, resulting in lower growth in the small interfering UCKL-1 RNA treated K562 cell culture. In addition, the chemotherapeutic agent staurosporine was seen to be more effective in inducing cell death by apoptosis in UCKL-1 depleted K562 cells compared with controls. We also found that UCKL-1 depleted K562 cells were more susceptible to NK mediated cytolysis than controls. These results indicate a role for UCKL-1 in tumor cell survival and suggest possible therapeutic potential of UCKL-1 inhibitors in cancer treatment.
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PMID:Downregulation of uridine-cytidine kinase like-1 decreases proliferation and enhances tumor susceptibility to lysis by apoptotic agents and natural killer cells. 1965