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)

The present studies were initiated to investigate the cell kinetics in spontaneous and transplantable mammary tumors after single doses of cyclophosphamide (Cp). The 3H-thymidine (3H-TdR) labeling index (LI), the DNA synthesis times, and the primer-dependent DNA polymerase labeling index (PDPI) were determined by in vitro methods for spontaneous mammary tumors (SMT) in C3H/HeJ retired breeders and 13762 transplantable rat mammary tumors (RMT) in Fischer 344 rats from 6 hours to 14 days after Cp treatment. The perturbations in the cell kinetics, although quantitatively different in the two tumor models, were qualitatively similar in that transient changes in both PDPI and 3H-TdR LI were observed within the first 24 hours after treatment. These changes were followed by a variable period during which cell proliferation was suppressed. Increases in the PDPI and 3H-TdR LI, presumably reflecting proliferative recovery, were observed prior to the initiation of tumor regrowth. Increases in the 3H-TdR LI and PDPI within the first 24 hours after Cp in C3H/HeJ SMT indicated an interval of increased sensitivity to adriamycin. In the 13762 RMT, combination chemotherapy protocols designed to exploit changes in cell kinetics at early times (24 hours) and during the recovery phase of the response resulted in greater long-term tumor-free survival.
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PMID:Therapeutic implications of cell kinetic changes after cyclophosphamide treatment in "spontaneous" and "transplantable" mammary tumors. 65 58

The effects of macromomycin (MCR), a high molecular weight peptide antibiotic, on cell division, DNA synthesis and DNA fragmentation were examined in cultured mammalian tumor cells. When MCR was added to HeLa cell culture simultaneously with [3H]thymidine, inhibition of DNA synthesis was observed depending on the amount of the drug present, although the inhibition was partial even at a high concentration of the drug. Preincubation of cells with MCR for 2 hours before assay was required for the complete inhibition of DNA synthesis. Cell division of synchronized L5178Y cells, arrested at metaphase, was strongly inhibited by MCR, indicating that the inhibition of cell mitosis by the drug was not dependent on the inhibition of DNA synthesis. Strand scission of DNA in MCR-treated cells was observed by alkaline sucrose gradient centrifugation. The fragmentation of cellular DNA occurred at low concentration of the drug and within a very short incubation time (37 degrees C, 5 minutes). At high concentrations of the drug, however, the size of the fragmented DNA remained constant. DNA polymerase activity in isolated nuclei from HeLa and L5178Y cells was stimulated by MCR. These data suggest that MCR works directly on cell nuclei and strand scission of DNA is one of the more important actions of the drug.
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PMID:Mechanism of action of macromomycin: DNA strand scission, inhibition of DNA synthesis and mitosis. 71 29

The chemical class of drugs known as the nitrosoureas are a recently developed group of very active alkylating-agent anticancer drugs which are best represented by BCNU, CCNU, and methyl-CCNU (meCCNU). The nitrosoureas are among the most active, if not the most active, anticancer drugs both quantitatively (log kill of sensitive tumor cells in vivo) and qualitatively (spectrum of mouse, rat, and hamster tumors responding to treatment). Therapeutic anticancer activity of the nitrosoureas has been consistently observed with oral as well as parenteral administration. The nitrosoureas are clearly the most active group of anticancer drugs observed against experimental meningeal leukemias and intracerebrally implanted transplantable primary tumors of central nervous system origin (eg, gliomas, ependymoblastomas, and astrocytomas in mice and hamsters). The nitrosoureas have been observed to be less than additive in lethal toxicity for vital normal cells in the mouse in combination with representatives of the other major classes of anticancer agents, eg, purine antagonists, pyrimidine antagonists, inhibitors of DNA polymerase(s) or ribonucleotide reductase(s), mitotic inhibitors, drugs that bind to or intercalate with DNA, and other alkylating agents. Therapeutic synergism against one or more transplantable or spontaneous tumors of mice, rats, or hamsters with one of several nitrosoureas in two-drug combinations with representatives of most of the major classes of anticancer agents listed above has been reported. With a number of advanced-stages mouse tumors, generally considered to be refractory to treatment with most anticancer agents, long-term cures have been obtained with combination-drug or combined-modality (surgery plus chemotherapy) treatment. The demonstrated lack of cross-resistance of several leukemias and solid tumors of mice selected for resistance to BCNU, meCCNU, or other alkylating agents suggests that the widely held opinion that all alkylating agents are very similar in biologic mechanism of action, and therefore resistance to one alkylating agent probably predicts cross-resistance to all alkylating agents, may no longer be tenable. If not, then alkylating-agent drug combinations, either used alone or combined with other treatment modalities (eg, surgery) which have been reported to result in therapeutic improvement in a number of experimental murine tumor systems, may be indicated for serious consideration as surgical adjuvant chemotherapy by surgeons or as primary therapy by medical oncologists.
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PMID:Nitrosoureas: a review of experimental antitumor activity. 78 94

We investigated by molecular hybridization whether T cells contain RNA sequences homologous to RNA which codes for immunoglobulin kappa-chain (k-chain). A radioactive probe of complementary DNA (cDNA) was prepared by transcription of purified k-chain mRNA from mouse myeloma MOPC-41 with reverse transcriptase (RNA-dependent-DNA nucleotidyltransferase) from avian myeloblastosis virus. The cDNA probably corresponded only to the constant region and 3'-terminus of k-chain mRNA. Kappa-chain cDNA was found to hybridize efficiently with RNA from both thymus cells and an established culture of thymoma cells. The thymus and thymoma cells contained 99.8% and 100% theta-positive cells, respectively. Quantitatively the average thymus T cell (thymus derived lymphocyte) contained about one half as much k-chain mRNA as the average spleen B cell ("bursa" dependent lymphocyte), whereas the thymoma cells contained only 1/33 as much. Control hybridizations of k-chain cDNA with myeloma and liver RNA support the conclusion that T cells in the thymus and in the thymoma cell line synthesize k-chain mRNA-like molecules. The thermal stability of hybrids of k-chain cDNA with RNA from spleen, thymus, thymoma, and another k-chain producing myeloma tumor was lower than that with MOPC-41 RNA. This finding may be due to the existence of several slightly different ck genes in the mouse as suggested by various control experiments.
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PMID:Sequences related to immunoglobulin kappa chain messenger RNA in T cells. 82 Oct 55

Transplantable fibrosarcomas were developed in two B-locus-defined chicken strains from primary tumors induced by im injection of 2 mg 7,12-dimethylbenz[a]anthracene in 0.1 ml dimethyl sulfoxide into 1- to 2-week-old chicks. Viruses were not important factors in transmission of these tumors as evidenced by 1) transplantability only within the chicken strain of origin, 2) lack of evidence for a filterable agent, 3) maintenance of donor karyotypic characteristics upon transplantation, 4) lack of DNA polymerase and avian leukosis virus group-specific protein production in vitro. Bursectomized inbred SC chickens had a higher incidence of tumor induction than did normals of the same strain. Although the exact interpretation of this finding posed some problems, as discussed, an important function of enhancing antibody in tumor growth appeared excluded.
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PMID:Chemical carcinogen-induced transplantable fibrosarcomas in histocompatible chickens. I. Incidence of tumor induction in normal and bursectomized chickens. 82 48

A total of 18 compounds consisting of 7 alphatic and 7 aromatic bis(guanylhydrazones), p-quinone-bis(guanylhydrazone), one monoguanylhydrazone, one diamidine and one diguanidine were studied spectrophotometrically to determine their ability to interact with native calf-thymus DNA and the possible correlation of binding with biological activity. In each case, the ability of a compound to bind to DNA correlate with its ability to inhibit the activity of DNA-dependent DNA polymerase (EC 2.7.7.7) extracted from mouse leukemia L1210 cells. For example, all the aromatic bis-guanylhydrazones and diamidine (hydroxystilbamidine), which were good inhibitors of the enzyme activity, showed a biphasic interaction with DNA. All the aliphatic compounds displayed no detectable interaction with DNA in the Tris buffer used, and were also poor inhibitors of the polymerase activity. Interaction of decamethylene diguanide (Synthalin with DNA could not be determined because the compound does not absorb light in the UV-VIS region. However, in similarity with other aliphatic compounds, this agent was a poor inhibitor of DNA polymerase reduction. The p-quinone-bis(guanyl-hydrazone) and p-phenylbenzaldehyde-monoguanylhydrazone showed only a monophasic interaction with DNA and caused an intermediate inhibition of the enzyme activity. When tested for possible anti-leukemic activity against i.p. L1210 leukemia in syngeneic DBA/2J mice, all the aromatic bis-guanylhydrazones as well as hydroxystilbamidine caused prolongation of survival of tumor-bearing mice. Among the aliphatic bisguanylhydrazones, all of which showed no binding to DNA and caused at the most only a very slight inhibition of DNA polymerase, only methylglyoxal-bis(guanylhydrazone) (CH3--G) had antileukemic activity. Synthalin also inhibited leukemia growth. Evidences presented indicate that the mechanisms of action of aliphatic and aromatic bisguanylhydrazones may be quite different. Furthermore, the ability to bind to DNA may be a useful criterion to predict the antileukemic activity of aromatic guanylhydrazones and possibly other aromatic-bis-cationic compounds, but not that of aliphatic congeners.
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PMID:Studies on the structure--activity relationship among aliphatic and aromatic bisguanylhydrazones and some related compounds. 83 65

Cell kinetics in spontaneous C3H/HeJ mammary tumors of retired-breeder mice was studied by in vivo and in vitro techniques. The [3H]TdR labeling index (LI), the DNA synthesis time (TS), and the primer-dependent DNA polymerase assay LI [an in vitro estimate of tumor growth fraction (GF)] were compared to similar measurements made in vivo. These measurements as well as the calculated cell kinetic parameters derived from these data were not different in in vivo and in vitro studies. Furthermore, the cell kinetic parameters in tumors classified histologically as type A or type B mammary tumors were also similar. Although considerable variation in volume doubling times (Td's), [3H]TdR LI's, potential doubling times, cell cycle times (Tc's), and cell loss was found, Ts's were similar in all mammary tumors. No correlation between tumor volume or tumor weight and cell kinetic parameters was seen. However, the most slowly growing tumors (i.e., tumors with the longest Td's) tended to have the lowest [3H]TdR LI's, the longest Tc's, and the highest cell loss factors. No correlation was found between the GF and Td. However, tumors with the most rapidly proliferating cell populations tended to have the highest GF's.
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PMID:Cell kinetics in vivo and in vitro for C3H/He spontaneous mammary tumors. 90 95

Using new in vitro techniques developed at the Cancer Research Unit, cell kinetic measurements were obtained in primary and metastatic human colonic tumors, polyps and normal bowel that did not require in vivo 3HTdR and required only single samples of tissue. These techniques included the measurement of the number of cells in DNA synthesis (LI), an estimate of the DNA synthesis time (Ts) and the growth fraction of tissues by means of the primer-available DNA-dependent DNA polymerase assay (PDP). From these data, the potential doubling time and the cell cycle time (Tc) of the tumors were calculated. Early preliminary data on human colonic specimens presented in Tables 1 and 2 indicate that there is an increase in LI from the low polyps to higher adenocarcinomas. There is little difference between primary and metastatic tumor cell kinetics. Growth fraction estimates (PDP) of the various colonic tissue types are also not significantly different and except for villous adenomas, DNA synthesis times are constant. The median 3HTdR labeling indices of 7% primary adenocarcinomas include a number of samples (approximately 20% of all samples) with high labeling indices (in the 10--20% range). These high labeling tumors may be those that show objective response to S-phase active drugs, e.g., 5-FU.
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PMID:Human colonic tumor cell kinetics: potential for therapy. 92 8

The nonhistone proteins of Ehrlich ascites tumor chromatin have been separated into a loosely bound and two tightly bound protein fractions by sequential extraction of chromatin with 0.35 M NaCl and 2 M NaCl:5 M urea. The nonhistone proteins thus obtained were examined for their chemical composition and distribution of DNA polymerase, RNA polymerase, and protein kinase activities. In addition, the effect of these nonhistone proteins on transcription of DNA in vitro has been determined. The results indicate that these nonhistone proteins, fractionated on the basis of their extractability, exhibit varied compositional characteristics and play different functional roles in the synthesis of DNA and RNA and in the possible control of gene activity.
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PMID:A comparison of the loosely bound and tightly bound nonhistone proteins from Ehrlich ascites tumor chromatin. 97 79

Adenovirus 12 (Ad12) (Huie) (highly oncogenic group A) readily induces tumors in newborn rodents. Since Ad12 is isolated from human fecal samples, we investigated whether it plays a role in the etiology of human gastrointestinal cancer. If Ad12 is a causal agent of human cancer, then human tumors should contain Ad12 transforming genes, as indicated by studies of cells transformed in vitro and in vivo by oncogenic viruses. Ad12 DNA and the Ad12 transforming restriction fragment (EcoRI-C fragment, left 16% of the viral genome) were labeled in vitro to 10(7) to 4 X 10(8) cpm/mug by the nick translation reaction of DNA polymerase of Escherichia coli. The fidelity and sensitivity of these probes were established by (i) analysis of DNA from Ad12-transformed cells and from hamsters with tumors induced by Ad12, (ii) reconstruction experiments with added Ad12 DNA and EcoRI restriction fragments, and (iii) comparison of annealing characteristics with Ad12 probes labeled in vivo. With Ad12 [3H]DNA as probe, no viral DNA sequences were detected in 18 normal gastrointestinal tissues and 34 gastrointestinal tumors, including cancers of the colon, rectum, small intestine, and stomach, under conditions that would detect 0.1 copy of the Ad12 genome per tumor cell. Similar analyses of Ad12-transformed hamster cells and Ad12 primary hamster tumors indicated 6-18 copies per cell of over 90% of the viral genome. With the Ad12 EcoRI-C transforming fragment as probe, no hybridization was detected with 32 human gastrointestinal tumors and five normal tissues; this result excludes 1-2% of the Ad12 genome per tumor cell. Our date are strong evidence that Ad12 is not a major cause of human gastrointestinal cancer. The Ad12 transforming EcoRI-C fragment hybridized (50-68% efficiency) with other Ad12 isolates and with Ad18 and 31 (members of oncogenic group A), but not at all with 28 other human Ad serotypes (manuscript in preparation). Thus other group A members probably are also not involved in human gastrointestinal cancer. No viral DNA sequences were detected in 12 normal lungs and 22 lung tumors, suggesting that respiratory cancer does not involve an Ad12 etiology.
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PMID:Do highly oncogenic group A human adenoviruses cause human cancer? Analysis of human tumors for adenovirus 12 transforming DNA sequences. 107 16


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