Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.7.7 (DNA polymerase)
17,007 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Adriamycin, daunomycin, acridylmethanesulfonanilide, and alkoxybenzophenanthridine alkaloids (coralyne acetosulfate, fagaronine chloride, and nitidine chloride) inhibit template-directed nucleic acid polymerizing enzyme activities like reverse transcriptase, DNA polymerase, and RNA polymerase. Enzyme reactions with poly(dA-dT), poly(rA)-oligo(dT) and poly(dA)-oligo(dT) are more strongly inhibited by the drugs than those with poly(dC)-poly(dG) and poly(rC)-oligo(dG). These results suggest that the antitumor drugs inhibit nucleic acid polymerases by a specific interaction with A:T base pairs of the templates.
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PMID:Base specificity in the inhibition of oncornavirus reverse transcriptase and cellular nucleic acid polymerases by antitumor drugs. 8 41

The effect of methylprednisolone (MP) on the cell kinetic response to cyclophosphamide (CP) and Adriamycin (ADR) in C3H/HeJ spontaneous mammary tumors and hematopoietic tissue was investigated. The [3H]deoxythymidine labelingg index, the primer-dependent DNA polymerase labeling index (an estimate of tumor growth fraction), and the mitotic index were determined at various intervals after treatment. Treatment consisted of CP (200 mg/kg) on Day 0 plus ADR (2 mg/kg) on Day 1 with or without MP every 12 hr for 9 doses beginning on Day 2. In tumors treated with CP and ADR alone, changes in the kinetic parameters suggested proliferative recovery between Days 3 and 4 which coincided with bone marrow recovery. In tumors treated with CP, ADR, and MP, although the timing of the hematopoietic recovery was not affected by MP, the overshoot of the [3H]deoxythymidine labelin index on Days 3 and 4 was abolished. Proliferative recovery in the tumor was delayed until after cessation of MP treatments. Cell kinetic changes in the tumor after CP, ADR, and MP were used to design effective sequential chemotherapy which obviated the hematopoietic toxicity associated with sequential therapy designed from cell kinetic changes after CP and ADR alone.
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PMID:Effect of methylprednisolone on the cell kinetic response of C3H/HeJ mammary tumors to cyclophosphamide and adriamycin. 47 17

The effect of adriamycin on DNA, RNA, and protein synthesis was investigated in cell-free systems and intact cells. In studies with purified mammalian cell enzymes, adriamycin produced a greater inhibition of DNA-dependent DNA polymerase than of RNA polymerase. The extent of inhibition of both these enzymes was decreased by increasing the concentration of the DNA template in the reaction mixture. In studies with isolated nuclei, adriamycin was also a more potent inhibitor of DNA synthesis than RNA synthesis. However, with intact cells, adriamycin inhibited both DNA and RNA synthesis to about the same extent. The inhibition produced by adriamycin on RNA synthesis in intact cells was greater than that observed in the cell-free systems. Adriamycin inhibited protein synthesis in a cell-free system consisting of polyribosomes, transfer RNA, and enzymes but did not inhibit protein synthesis in intact cells. These differences in the pattern of inhibition may be due to biotransformation of the drug and/or preferential binding to chromosomal DNA in the intact cell.
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PMID:Effect of adriamycin on DNA, RNA, and protein synthesis in cell-free systems and intact cells. 127 99

We have evaluated the feasibility of a cytokinetically oriented regimen based on the induction of cell recruitment by diethylstilbestrol (DES) in locally advanced human breast cancer. Tumor proliferative activity was evaluated by the thymidine labeling index and the primer-dependent alpha-DNA polymerase labeling index, which gives an in vitro estimation of the growth fraction. Sixteen previously untreated patients received DES (1 mg daily for 3 days) followed by FAC [5-fluorouracil (600 mg/m2): Adriamycin (50 mg/m2): Cytoxan (600 mg/m2)] i.v. on day 4 every 21 days. Radical surgery was delayed to allow for three DES-FAC regimens in responsive patients. Proliferative activity on tumor biopsies was evaluated immediately before and after treatment with DES, 24 h after chemotherapy and, in nine patients, at the time of radical surgery. DES was able to induce a significant increase in thymidine labeling index in 8 of 16 patients, while the primer-dependent alpha-DNA polymerase labeling index was significantly increased in 13 of 16 tumors, independently of their estrogen receptor content. Subsequently administered chemotherapy induced an early decrease in tumor proliferation. In the nine patients submitted to surgery after three DES plus FAC courses, the average thymidine labeling index and primer-dependent alpha-DNA polymerase labeling index were 27.8 and 73% of the pretreatment values. Our preliminary results provide the rationale for the design of new therapeutic schemes in which antitumor drugs are given at the time of estrogen-induced tumor cell recruitment. Further extended studies are required to establish whether induction of tumor cell recruitment will actually translate into appreciable improvement of the clinical response to chemotherapy.
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PMID:Chemotherapy following estrogen-induced expansion of the growth fraction of human breast cancer. 405 64

The feasibility of a cytokinetic chemotherapy based on estrogenic recruitment has been evaluated in 5 patients, affected by locally advanced breast cancer with low or absent receptor content. Tumor proliferative activity was evaluated by the thymidine labeling index (TLI) and the primer-dependent alpha DNA polymerase assay (PDP-LI) which gives an in vitro estimation of tumor growth fraction. The patients have been treated with diethylstilbestrol (DES) 1 mg/die. for 3 days, followed by FAC (5-Fluorouracil 600 mg/m2, Adriamycin 50 mg/m2, Cytoxan 600 mg/m2) i.v. on day 4 q. 21 days. Radical surgery was performed after 3 DES-FAC regimens. Tumor biopsies for evaluation of tumor proliferative activity were performed immediately before and after DES and 24 h after chemotherapy. Our results demonstrate that DES was able to induce an increase in TLI in 3/5 of the patients while the PDP-LI was significantly increased in 5/5 of the patients; subsequent chemotherapy induced a sharp decrease in tumor proliferation. These results provide the rationale for the design of cytokinetic regimens where chemotherapy is administered at the time of estrogen induced tumor cell recruitment.
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PMID:Estrogen induced expansion of the growth fraction in receptor negative human breast cancer. 409 31

CC-1065, a novel antibiotic produced by Streptomyces zelensis, was active against several experimental tumors in vivo and a broad spectrum of human tumor cells in vitro. This report describes its biological and biochemical effects of L1210 leukemia cells. CC-1065 is one of the most cytotoxic agents known. The concentrations required for a 50 and 90% inhibition of cell growth are 0.02 and 0.05 ng/ml, respectively. It is about 400 times more cytotoxic than was Adriamycin. The action of CC-1065 is rapid and is dose and time dependent. CC-1065 inhibits DNA synthesis much more than it inhibits RNA and protein synthesis. The concentrations required for a 50% inhibition of DNA synthesis and RNA synthesis are 4 to 6 and 45 to 60 ng/ml, respectively. Although the drug inhibition of DNA synthesis cannot completely account for its cytotoxic effects on L1210 cells, these results, along with those generated by other investigators, suggest that the inhibition of DNA synthesis represents a major mode of action of CC-1065. CC-1065 inhibited both thymidine kinase and DNA polymerase alpha activities, but the effect on highly purified DNA polymerase alpha was more pronounced. At 1 microgram/ml, CC-1065 inhibited more than 70% of the enzyme activity. In order to elucidate the mechanism of inhibition of DNA polymerase alpha, the interaction between CC-1065 and DNA was investigated. The studies with thermal melting of DNA and difference circular dichroism measurement indicate that CC-1065 is one of the strongest DNA-binding agents. It induced an increase in thermal melting temperature of calf thymus DNA by at least 31 degrees. The circular dichroism studies also reveal that CC-1065 binds only to double-stranded DNA but not to heat-denatured DNA or yeast RNA. These observations were supported by those obtained with two other experimental approaches. CC-1065 also appeared to interact with proteins, but the interaction was weak and reversible.
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PMID:CC-1065 (NSC 298223), a novel antitumor agent that interacts strongly with double-stranded DNA. 617 20

In our experimental work we intended to study the effect of certain anthracycline antibiotics, like Adriamycin, Daunomycin, Carminomycin on the RNA dependent DNA polymerase, i.e. reverse transcriptase (RT) system. Over the direct effect on the RT our aim was to find out the rate of selectivity of above antibiotics on the RT. For doing this we compared the above effects to those found on natural nucleic acid polymerases. These experiments were confirmed using synthetic polynucleotid template poly(rA)n(dT)12-18 for the Rauscher RT enzyme and poly(dA)n . poly(dT)n for E. coli DNA polymerase I. In our work we have shown that Carminomycin, in contrast to Adriamycin and Daunomycin, possesses a highly specific inhibitory effect on the RT enzyme system.
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PMID:Inhibition of RNA dependent DNA polymerases by anthracycline antibiotics. 617 12

An inhibitor of alkaline phosphodiesterase was isolated from a soil Streptomyces. The agent was identified with 2-crotonyloxymethyl-4,5,6-trihydroxycylohex-2-enone (COTC) by UV, IR, 1H HMR and 13C NMR spectrometry. The mechanism of tumor-inhibitory action of COTC was studied with murine lymphoblastma L5178Y cells. COTC blocked alkaline phosphodiesterase; IC 50 was 60 micrograms/ml by the method employed. The growth of L5178Y cells was inhibited by COTC; IC50 was 4.4 micrograms/ml. DNA biosynthesis was preferentially prevented by COTC over RNA and protein syntheses; IC50 of DNA synthesis was 7 or approximately 25 micrograms/ml. COTC significantly inhibited DNA polymerase alpha even in the presence of dithiothreitol. The mitosis was markedly blocked by COTC; complete inhibition was observed at a drug concentration of 20 microgram/ml. Adriamycin-, aclarubicin- and bleomycin-resisant cell subline showed collateral sensitivity to COTC. COTC and aclarubicin exhibited synergistic activity on aclarubicin-resistant cells, but not on the parental cells. COTC increased uptake of [3H]adriamycin or blocked the drug efflux in the resistance cells, but not in the parental cells. The effects of COTC on macromolecular syntheses, mitosis and membrane functions may be attributed to the interaction with the sulfhydryl group of various enzymes. Although COTC is multifunctional drug, the inhibition of DNA polymerase alpha and a certain mitotic process seems to be related to the lethal action.
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PMID:Mechanism of action of 2-crotonyloxymethyl-4,5,6-trihydroxycyclohex-2-enone, a SH inhibitory antitumor antibiotic, and its effect on drug-resistant neoplastic cells. 714 23

Adriamycin, daunomycin and ethidium, intercalating drugs which bind to double- as well as single-stranded DNA, inhibit phage T4 antimutator mutant CB121 DNA polymerase more strongly than the T4 wild-type and the mutator L98 polymerase. In contrast, all three enzymes are inhibited equally by distamycin A and actinomycin C. The latter two inhibitors bind only to double-stranded DNA.
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PMID:Inhibitor studies of phage T4 wild-type and mutant DNA polymerases. III. Distamycin A, actinomycin D, adriamycin, daunomycin and ethidium. 721 Jul 7

The unperturbed cell kinetics of 13762 mammary tumors in Fischer 344/CRBL rats were studied by fraction labeled mitoses (FLM) and in vitro methods. The 3H-thymidine (3H-TdR) labeling index (LI) was 32.5% and the volume doubling time was approximately 96 hours 14 days after inoculation. The cell cycle, G1, G2, and DNA synthesis times by computer analysis of the FLM data were 11.5, 3.5, 1.3, and 5.4 respectively. The primer available DNA-dependent DNA polymerase labeling index (69%) was similar to the growth fraction calculated from the FLM data. Estimates of cell kinetic parameters from this tumor model, by in vitro methods, were very similar to those obtained by FLM analysis. The effect of Adriamycin (Adr) on the cell kinetics of 13762 tumors was also studied by monitoring the changes in the 3H-TdR LI, the primer available DNA-dependent DNA polymerase labeling index, and the flux of cells from S to G2 phase by the 3H-TdR and 14C-TdR double-labeling method. The results indicated that cell proliferation was inhibited for at least 3 days after 5 mg/kg of Adr. Recovery of cell proliferation was noted between Days 4 and 7 after treatment. Sequential chemotherapy with cyclophosphamide was most effective when administered to coincide with the proliferative recovery after Adr.
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PMID:Effect of adriamycin on the cell kinetics of 13762 rat mammary tumors and implications for therapy. 740 64


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