Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.1.21 (thymidine kinase)
 7,561 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mechanism of synergism and clinical results of methotrexate and 5-fluorouracil (MTX/5-FU) combination therapy for gastric cancer were studied. The response rate against poorly differentiated gastric cancers was 35% in this treatment. This treatment also showed a remarkable effect against cases with pleural and abdominal effusion caused by cancerous disseminations. A promising result was obtained by this treatment as neoadjuvant and postoperative chemotherapy against Borrmann type 4 gastric cancer. A greater dependence on the de novo pathway of pyrimidine synthesis against poorly differentiated gastric carcinoma, which was estimated by the fact that the thymidylate synthetase/thymidine kinase ratio was significantly higher in poorly differentiated gastric cancer than in well differentiated cancer, may potentiate therapeutic results of this treatment.
 ...
PMID:[Mechanism of synergism and clinical results of sequential methotrexate and 5-fluorouracil in the treatment of gastric cancer]. 162 50

An overview was presented of our approach of inhibition of de novo and salvage pathways in pyrimidine and purine metabolism. 1. Combination of acivicin, an inhibitor of de novo biosynthesis, and dipyridamole, a transport inhibitor, provided synergistic cytotoxicity in hepatoma and colon carcinoma cells. 2. AZT, a competitive inhibitor of the salvage enzyme, thymidine kinase, and 5-FU or MTX provided synergistic cytotoxicity in hepatoma 3924A. In human colon carcinoma HT-29 cells AZT and methotrexate yielded synergistic cytotoxicity and thymidine and hypoxanthine together provided protection from the action of these drugs. 3. These observations are significant because in rat hepatoma 3924A and in human cell lines HT-29, HL-60 and K562 thymidine kinase activity was 16- to 67-fold higher than that of dTMP synthase. Therefore, inhibition of dTMP synthase activity alone may provide poor responses because the salvage pathways can circumvent this block. 4. In leukemic patients treated with tiazofurin, an inhibitor of IMP dehydrogenase, the rate-limiting enzyme of GTP biosynthesis, and with allopurinol, which inhibits GPRT activity through raising plasma hypoxanthine levels, synergistic therapeutic results were obtained. The responses in sensitive patients entailed a decrease in IMP dehydrogenase activity and GTP concentration in leukemic cells and down-regulation of the ras and myc oncogenes. The down-regulation of the ras oncogene by tiazofurin through the decrease of GTP concentration has now been shown in K562, HL-60 and hepatoma cells and in patients with chronic granulocytic leukemia in blast crisis. Tiazofurin may be useful in studies on selective depression of the expression of the ras oncogene. 5. In 27 consecutive patients 50% responded positively to tiazofurin treatment. From this group, 10 out of 12 patients (83%) with chronic granulocytic leukemia in blast crisis responded to tiazofurin treatment.
 ...
PMID:Regulation of de novo and salvage pathways in chemotherapy. 187 99

Deoxyuridine (dU) suppression test (i.e. ability of exogenous dU to suppress the incorporation of subsequently added 3H-thymidine into DNA) and the incorporation of 3H-thymidine (3H-TdR) alone without dU were studied in bone marrow cultures from 10 patients with erythroleukaemia, 10 patients with vitamin B12/folate-deficient megaloblastic anaemia and 10 haematologically normal subjects. Despite morphological resemblance between megaloblastosis in erythroleukaemia and nutritional megaloblastosis, the dU suppression values in erythroleukaemia were within normal range in contrast to abnormal dU suppression in vitamin B12/folate-deficient megaloblastic bone marrows. The incorporation of 3H-thymidine alone was significantly lower in erythroleukaemia than in normal or vitamin B12/folate-deficient megaloblastic bone marrows. Autoradiographic studies showed that 3H-TdR labelling indices as well as mean grain count (MGC) of basophilic and polychromatic erythroblasts were significantly lower in erythroleukaemia than in normal or vitamin B12/folate-deficient bone marrows. The reduced incorporation of 3H-TdR in erythroleukaemia erythroblasts was probably not due to deficiency of the salvage pathway enzyme, thymidine kinase, since MTX (10(-5) M) which blocks the de novo pathway of thymine-DNA synthesis, enhanced the incorporation of 3H-TdR into erythroblasts in erythroleukaemia as well as in normal bone marrows. A high intracellular pool of thymidine-triphosphate (dTTP) due to defective DNA synthesis may allosterically inhibit thymidine kinase and 3H-TdR incorporation.
 ...
PMID:Derangement of DNA synthesis in erythroleukaemia. Normal deoxyuridine suppression and impaired thymidine incorporation in bone marrow culture. 677 44

(1) The currently used clinical anti-metabolites are targeted against-key enzymes of de novo purine and pyrimidine biosynthesis. However, the activities of salvage enzymes in each of the biosynthetic segments are markedly higher than those of the rate-limiting enzymes of de novo biosynthesis. Enzyme-pattern-targeted chemotherapy has been suggested to overcome the circumvention activity of salvage. Combination of inhibition of de novo and salvage pathways does provide a synergistic impact. Examples that enzyme-pattern-targeted drug treatment yields synergism include the following: tiazofurin (against IMP DH) and allopurinol (by raising serum hypoxanthine levels it inhibits GPRT); methotrexate or 5-FU lead to inhibition of the dTMP synthase reaction and AZT (a competitive inhibitor of thymidine kinase) or dipyridamole (a nucleoside transport inhibitor); acivicin, an inhibitor and inactivator of glutamine-utilizing enzymes in the de novo pathways of purine and pyrimidine biosynthesis, and dipyridamole. (2) Administration of MTX, 5-FU, tiazofurin or acivicin causes inhibition and/or inactivation of target enzymes. That these drugs are effective in spite of the presence of highly active salvage enzymes is now accounted for, at least in part, by new observations showing that these drugs markedly reduce (but do not eliminate) the activities (amounts) of CdR and TdR kinases, dTMP synthase and GPRT. This action is attributed to the rapid decay rate of these enzymes. (3) Studies on the bone marrow enzymic programs indicate that there is a window of opportunity for strengthening therapy and for the protection of bone marrow by administering salvage metabolites when the salvage enzymes are still present in high enough activities, i.e., 2-6 hr after administration of the blockers of de novo enzyme activities. (4) These results are a strong argument for discovering and utilizing inhibitors of purine and pyrimidine salvage enzymes to achieve more successful enzyme-pattern-targeted chemotherapy and to avoid development of resistant clones of cancer cells. (5) These approaches provide greater explanatory coherence than the previous accounts because recognition of (a) the importance of salvage and (b) rapid decay of key and salvage enzymes reveals a paradigm shift. The problem-solving process in chemotherapy should now be not only data-driven but also explanation-driven.
 ...
PMID:Targeted and non-targeted actions of anti-cancer drugs. 794 86