Effects of alkyl amine carboxyboranes on L1210 DNA fragmentation and nucleic acid metabolism.
Amine-carboxyboranes with varying alkyl chain lengths were observed to be potent cytotoxic agents inhibiting the growth of a number of histological types of murine, rat, and human tumors. These agents preferentially reduced L1210 DNA synthesis with marked inhibition of the activities of regulatory enzymes of the purine pathway. Other enzyme activities which were marginally reduced were DNA polymerase alpha, ribonucleoside reductase, dihydrofolate reductase, t-RNA polymerase, and nucleoside kinases. Pyrimidine nucleotide pools were not reduced but DNA strand scission occurred after 24 h incubation with the agents. The amine-carboxyboranes were not DNA topoisomerase II inhibitors at 100 microM. The agents did not cause DNA protein linked breaks themselves; nevertheless, VP-16 [etoposide] induced DNA protein linked breaks were increased two fold in the presence of the agents suggesting synergistic effects. The amine-carboxyboranes decreased protein kinase C mediated phosphorylation of L1210 topoisomerase II protein, potentially decreasing its enzymatic catalytic activity. Thus, the amine-carboxyboranes did not function like VP-16 in affording cleavable products but were synergistic with VP-16 in causing DNA fragmentation. The agents were also additive with VP-16 in reducing tumor cell number, soft-agar colony growth and DNA synthesis and in producing DNA strand scission.
Division of Medicinal Chemistry & Natural Products, School of Pharmacy, University of North Carolina, Chapel Hill 27599-7360, USA.
M C
MC
Miller
A
A
Sood
B F
BF
Spielvogel
I H
IH
Hall
D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D001880:Boranes / Q000493:pharmacokinetics / Q000494:pharmacology*; D002264:Carboxylic Acids / Q000493:pharmacokinetics / Q000494:pharmacology*; D053938:DNA Fragmentation / Q000187:drug effects*; D004273:DNA, Neoplasm / Q000187:drug effects* / Q000378:metabolism; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007939:Leukemia L1210 / Q000378:metabolism*; D008297:Male; D051379:Mice; D051381:Rats; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D001880:Boranes; D002264:Carboxylic Acids; D004273:DNA, Neoplasm