Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.5.1.3 (dihydrofolate reductase)
 5,819 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Camptothecin is a widely used anti-tumor drug that specifically inhibits DNA topoisomerase I. It is believed that topoisomerase I participates in the process of transcription by relaxing torsional stress induced in the duplex DNA by the elongating RNA polymerase. We have assessed the effects of camptothecin on RNA polymerase II transcription from the dihydrofolate reductase (DHFR) gene in Chinese hamster ovary (CHO) cells. Using in vivo [3H]uridine pulse labeling and in vitro nuclear run-on techniques to estimate relative rates of transcription, it was found that camptothecin stimulated RNA synthesis from promoter-proximal sequences of the DHFR gene, while transcription from promoter-distal sequences was reduced. Furthermore, camptothecin caused a significant accumulation of RNA polymerases in the 5'-end of the DHFR gene. The effect of camptothecin on transcription was reversible, resulting in a wave of RNA synthesis recovery in a 5' to 3' direction through the DHFR gene following a chase with camptothecin-free medium. We conclude that camptothecin stimulates initiation but inhibits elongation of the RNA polymerase II transcribed DHFR gene.
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PMID:The anti-cancer drug camptothecin inhibits elongation but stimulates initiation of RNA polymerase II transcription. 856 33

N6-Benzoyladenine-cyanoborane (2), and 6-triphenylphosphonylpurine-cyanoborane (3) were selected for investigation of cytotoxicity in murine and human tumor cell lines, effects on human HL-60 leukemic metabolism and DNA strand scission to determine the feasibility of these compounds as clinical antineoplastic agents. Compounds 2 and 3 both showed effective cytotoxicity based on ED(50) values less than 4 mug/ml for L1210, P388, HL-60, Tmolt(3), HUT-78, HeLa-S(3) uterine, ileum HCT-8, and liver Hepe-2. Compound 2 had activity against ovary 1-A9, while compound 3 was only active against prostate PL and glioma UM. Neither compound was active against the growth of lung 549, breast MCF-7, osteosarcoma HSO, melanoma SK2, KB nasopharynx, and THP-1 acute monocytic leukemia. In mode of action studies in human leukemia HL-60 cells, both compounds demonstrated inhibition of DNA and protein syntheses after 60 min at 100 muM. These compounds inhibited RNA synthesis to a lesser extent. The utilization of the DNA template was suppressed by the compounds as determined by inhibition of the activities of DNA polymerase alpha, m-RNA polymerase, r-RNA polymerase and t-RNA polymerase, which would cause adequate inhibition of the synthesis of both DNA and RNA. Both compounds markedly inhibited dihydrofolate reductase activity, especially in compound 2. The compounds appeared to have caused cross-linking of the DNA strands after 24 hr at 100 muM in HL-60 cells, which was consistent with the observed increased in ct-DNA viscosity after 24 hr at 100 muM. The compounds had no inhibitory effects on DNA topoisomerase I and II activities or DNA-protein linked breaks. Neither compound interacted with the DNA molecule itself through alkylation of the nucleotide bases nor caused DNA interculation between base pairs. Overall, these antineoplastic agents caused reduction of DNA and protein replication, which would lead to killing of cancer cells.
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PMID:Synthesis and cytotoxicity of cyanoborane adducts of n6-benzoyladenine and 6-triphenylphosphonylpurine. 1847 22