CI-937 and
CI-942 belong to a new class of
DNA complexers, the anthra[1,9-cd]pyrazol-6(2H)-ones (anthrapyrazoles), and are being further developed as
antitumor drugs based on their curative properties against murine solid tumour models. The biochemical effects of these agents were studied in
L1210 leukemia in relation to other clinically used
intercalators. After a 1-hr exposure,
CI-937 and
CI-942 reduced the cloning efficiency of L1210 cells by 50% at 3.0 X 10(-8) and 1.5 X 10(-7) M respectively. Based on an
ethidium displacement assay, these drugs bound strongly to
DNA, reducing the fluorescence of an
ethidium-DNA complex by 50% at concentrations of 23 and 33 nM for
CI-937 and
CI-942 respectively. This was comparable to
mitoxantrone at 15 nM, but much more potent than
Amsacrine which required over 1.3 microM. A distinct property of the anthrapyrazoles was a much more potent inhibitory effect on whole cell
DNA synthesis than on
RNA synthesis. After L1210 cells were exposed to
drug for 2 hr the concentration needed to inhibit
DNA synthesis by 50% was 0.33 and 0.57 microM for
CI-937 and
CI-942, respectively, whereas 2.0 and 11.3 microM were required to inhibit
RNA synthesis by the same extent. This was in contrast to
Adriamycin and
mitoxantrone which inhibited both activities equally at similar concentrations. It was apparent that the inhibition of these processes was not due to substrate depletion since intracellular ribonucleoside and deoxyribonucleoside triphosphates either remained constant or were elevated after a 2-hr exposure to 1 or 10 microM
drug. A similar discriminatory effect was observed on
DNA and
RNA polymerase in permeabilized cells, and the inhibition of
nucleic acid synthesis in this system could be reversed by exogenously added
DNA. Since the high incidence of
cardiotoxicity associated with the administration of
anthracyclines has been related to the formation of
reactive oxygen species, the ability of the anthrapyrazoles to augment
superoxide dismutase sensitive oxygen consumption was observed in a rat liver microsomal system.
CI-937 and
CI-942 induced 5- and 10-fold less oxygen consumption than
Adriamycin, producing rates of 12.4, 24.2 and 138.9 nmoles/min/mg microsomal
protein, respectively, at a
drug concentration of 0.5 mM.(ABSTRACT TRUNCATED AT 400 WORDS)