The cytotoxic action of 1,3,5-triazabicyclo[3.1.0]hexane-2,4-diones and 1,3,5-triazine-4,6-(1 H,5 H)-diones in murine and human tumor cells.
1,3,5-Triazabicyclo[3.1.0]hexane-2,4-diones proved to be potent antineoplastic and cytotoxic agents in murine and human cancer cells. In L1210 lymphoid leukemia cells DNA synthesis was significantly suppressed over 60 min by the agents from 25 to 100 microM. DNA synthesis was blocked at multiple sites including DNA polymerase alpha, ribonucleoside reductase, dihydrofolate reductase, PRPP-amido transferase, and nucleoside kinases which would be additive overall in suppressing DNA synthesis. The DNA molecule itself did not appear to be at target of the agents since no alkylation of nucleotide bases, intercalation between base-pairs or cross-linking of strands occurred after 24 h incubation at 100 microM. Nevertheless, L1210 DNA fragmentation did occur after 24 h incubation at 100 microM which is usually associated with tumor cell apoptosis.
Division of Medicinal Chemistry and Natural Products, School of Pharmacy, University of North Carolina, Chapel Hill, USA.
I H
IH
Hall
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K
Taylor
R A
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Izydore
D E
DE
Coleman
J A
JA
Mitchell
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Cummings
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D002286:Carcinoma, Ehrlich Tumor / Q000188:drug therapy; D002417:Cattle; D004273:DNA, Neoplasm / Q000096:biosynthesis; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007202:Indicators and Reagents; D007939:Leukemia L1210 / Q000188:drug therapy / Q000378:metabolism; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D012334:RNA, Neoplasm / Q000096:biosynthesis; D014227:Triazines / Q000138:chemical synthesis* / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D007202:Indicators and Reagents; D012334:RNA, Neoplasm; D014227:Triazines