Biological and biochemical effects of chartreusin on mammalian cells.

Chartreusin (CT), an antibiotic produced by Strepto myceschartreusls,was recentlyfoundto be activeagainst experimental tumors B16 melanoma and L1210 and P388 leukemia. This report describes the correlation between ftsbiologicalandbiochemicaleffectson mouseL1210and P388leukemIa. CT was growthInhibitoryto L1210cells and other mam malian cells tested (drugconcentrationrequiredfor 50% inhibition of cell growth in culture, between 0.22 and 0.67 @ig/ml). The inhibitionof L1210cell growthwas rapidand dose dependent. The inhibftioncould not be eliminated after a 30-mmexposureto 2.5-@tg/ml drugdosesand was not affected by the simultaneous addftlon of various metabolites. CT lnhibfted RNA synthesis greater than It did DNAsynthesisand had least effecton proteinsynthe sis. At 2.5 ag/mI It inhibited about 60% RNA synthesis, and the inhibitioncould no longerbe reversedafter a 30mm exposure to the drug. Again, this was a doseand time-dependentphenomenon.These resultsclosely cor related to those of growth inhibItion, suggesting that inhibition of polynucleotlde synthesis by CT played an important role In its action against mouse leukemia. CT showedno effect on deoxyrlbonucleosideor rlbonu cleosidekinasesbut significantlyinhibitedDNA and RNA polymerase isolated from L1210 leukemia in culture and In vlvo. The inhibItion of highly purified DNA polymerase a and RNA polymers.. II by CT varied wIth the template used. The latter correlated well wIth the interactionbe tween CT and DNA polymers such as calf thymus, DNA, poly(dA-dT)-poly(dT-dA), and poly(dG-dC)'(poly(dC-dG), demonstratedby circular dichroismmeasurements,sug gesting that the biochemicaland biologicalactivities of CT were manifestedin part by its bindingto DNA. CT also causedsignificantdamageto DNA.