Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.7.7 (DNA polymerase)
 17,007 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We determined the correlation between DNA strand breaks and the toxicity of carboquone (CQ) in HeLa cells in vitro and in mouse sarcoma 180 (S-180) cells in vivo, using in situ nick translation. The break sites in the DNA were translated artificially in the presence of Escherichia coli DNA polymerase I and [3-H]-labelled dTTP, and sites in the DNA were visualized by autoradiographic observation of grains in the nuclei. These breaks appeared as early as 5 min in the CQ-treated HeLa cells and increased in a dose- and time-dependent manner compared to findings in the control cells, i.e., 10.2-fold at 3 x 10(-6) M in 60 min. Strand breaks in the S-180 cells appeared in a dose- and time-dependent manner, i.e., 6.1-fold after the mice had been exposed to CQ (3.6 mg/kg) for 2 h. This level correlated with the increase in host life span. Our findings show that the survival response of cells decreases, while the level of DNA strand breaks increases following exposure to CQ. The nick translation method is a rapid in situ assay for determining drug-induced DNA damage of tumor cells, under in vitro and in vivo conditions and in a semiquantitative manner.
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PMID:Detection of DNA strand breaks in HeLa cells in vitro and in mouse sarcoma 180 cells in vivo induced by an alkylating agent, carboquone, using in situ nick translation. 234 71

In our laboratory, we have studied the mechanism of action of tumor-inhibitory antibiotics, including bleomycin, phleomycin, adriamycin, aclarubicin, neothramycin, macromomycin, auromomycin, chartreusin, pluramycin, neopluramycin, xanthomycin A, angustmycins A and C, blasticidin S and phenomycin. The recent advances are summarized. Screening of microorganism for new antitumor antibiotics based upon our studies on mechanism of action are currently ongoing. We are interested in drug-resistance of tumor cells, and have obtained drug-resistant sublines of murine lymphoblastoma L5178Y cells. We have found that glycoprotein synthesis and alkaline phosphodiesterase (APD) activity of the plasma membrane are higher in adriamycin (ADM)-, aclarubicin (ACR)- and bleomycin (BLM)-resistant cell sublines than in the parental cells. An inhibitor of APD has been isolated from a soil Streptomyces, and identified with 2-crotonyloxymethyl-4,5,6-trihydroxycyclohex-2-enone (COTC). COTC inhibits growth of the drug-resistant cells more significantly than the parental cells, and exhibits synergistic activity with ACR against ACR-resistant cells. COTC is a SH inhibitor. Although COTC is a multifunctional drug, the inhibition of DNA polymerase alpha and some mitotic process may be related to its lethal action. In the course of our screening, we have found that a strain of Sterptomyces hygroscopicus produces two substances: one inhibits thymidine and uridine uptake of human leukemic K562 cells, and the other stimulates it. The inhibiting substance has been identified with tubercidin, and the stimulating one has been found to be a novel pyrrolo [2,3-d] pyrimidine antibiotic, cadeguomycin. Cadeguomycin shows low acute toxicity in mice, enhances DTH reaction, and inhibits Ehrlich ascitic carcinoma in mice. The antibiotic exhibits synergistic effects with arabinosylcytosine against growth of K562 cells. Saframycin, discovered by Prof. Arai, Chiba University, is effective against Ehrlich ascitic carcinoma, P388 and L1210 leukemia, and B16 melanoma in mice. The target is DNA. Stubomycin, discovered by Dr. Umezawa, Kitasato Institute, is effective against Sarcoma 180, Ehrlich carcinoma, P388 leukemia, IMC carcinoma and Meth-A tumor in mice, and shows low acute toxicity. The target is plasma membrane.
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PMID:[Study of new antineoplastic antibiotics based on newly discovered action mechanisms]. 619 73