Biological and biochemical effects of chartreusin on mammalian cells.

Abstract

Chartreusin (CT), an antibiotic produced by Streptomyces chartreusis , was recently found to be active against experimental tumors B16 melanoma and L1210 and P388 leukemia. This report describes the correlation between its biological and biochemical effects on mouse L1210 and P388 leukemia. CT was growth inhibitory to L1210 cells and other mammalian cells tested (drug concentration required for 50% inhibition of cell growth in culture, between 0.22 and 0.67 µg/ml). The inhibition of L1210 cell growth was rapid and dose dependent. The inhibition could not be eliminated after a 30-min exposure to 2.5-µg/ml drug doses and was not affected by the simultaneous addition of various metabolites. CT inhibited RNA synthesis greater than it did DNA synthesis and had least effect on protein synthesis. At 2.5 µg/ml it inhibited about 60% RNA synthesis, and the inhibition could no longer be reversed after a 30-min exposure to the drug. Again, this was a dose- and time-dependent phenomenon. These results closely correlated to those of growth inhibition, suggesting that inhibition of polynucleotide synthesis by CT played an important role in its action against mouse leukemia. CT showed no effect on deoxyribonucleoside or ribonucleoside kinases but significantly inhibited DNA and RNA polymerase isolated from L1210 leukemia in culture and in vivo . The inhibition of highly purified DNA polymerase α and RNA polymerase II by CT varied with the template used. The latter correlated well with the interaction between CT and DNA polymers such as calf thymus, DNA, poly(dA-dT) · poly(dT-dA), and poly(dG-dC) · (poly(dC-dG), demonstrated by circular dichroism measurements, suggesting that the biochemical and biological activities of CT were manifested in part by its binding to DNA. CT also caused significant damage to DNA.