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Influence of Formycin B on Polyadenosine Diphosphoribose Synthesis in Vitro and in Vivo¹

Institut für Physiologische Chemie, Universität, Johann Joachim Becher Weg 13, 65 Mainz, West Germany [W. E. G. M., H. J. R., R. S., A. M., M. L., R. K. Z.], and Microbial Chemistry Research Foundation, Institute of Microbial Chemistry, Tokyo, Japan [H. U.]

Formycin B inhibited growth of L5178Y mouse leukemia cells in concentrations of less than twice the concentration that inhibits cell proliferation at 50% by cytostasis; at higher concentrations (more than twice the 50% concentration mentioned), the cells were killed. In cells treated with the concentration that inhibits cell proliferation at 50%, the average cell volume did not change. The formycin B inhibitory effect on cell proliferation was reduced by coincubation with nicotinamide adenine diphosphate or adenosine. The biosyntheses of DNA,RNA, and protein in whole cells were sensitively inhibited by formycin B as checked by incorporation studies with radioactive precursors. In addition, the formation of polyadenosine diphosphoribose was reduced even with higher sensitivity; in particular the extent of adenosine diphosphate ribosylation of histone subfraction H1 was reduced.

Formycin B has been shown to be an inhibitor for the polyadenosine diphosphoribose polymerase, isolated from oviduct nuclei of quails. Both the chromatin-bound and the soluble enzyme are inhibited competitively; the relative affinity (K₁/K_m) of formycin B to the polyadenosine diphosphoribose polymerase is 1.5.

¹ We gratefully acknowledge loans from the Fonds der chemischen Industrie.

² This work was performed in partial fulfillment of the requirements for the degree of Medical Doctor, University of Mainz.

Received 5/15/75. Accepted 8/26/75.