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Pharmacological and Toxicological Aspects of New Imidazoacridinone Antitumor Agents¹

Department of Toxicology, University of Hamburg Medical School, and Fraunhofer Department of Toxicology and Environmental Medicine, Grindelallee 117, D-20146 Hamburg, Germany

Imidazoacridinones represent a new group of antitumor compounds developed by J. Konopa and coworkers in Gdansk, Poland (W. M. Cholody, J. Med. Chem., 33: 49–52, 1990). The compounds exert activity against a broad spectrum of human tumors in the National Cancer Institute in vitro screening scheme. In this work, the in vitro cytotoxicity, cellular pharmacology, and genotoxic/transforming potential of five selected imidazoacridinones were studied. The compounds were highly cytotoxic (0.01–0.49 µM) to dividing cells, such as Friend erythroleukemia cells (line F4–6), V79 Chinese hamster cells, and exponentially growing C3H/M2 mouse fibroblasts. In contrast, nondividing primary rat hepatocytes and C3H/M2 cells in confluency were less sensitive to the toxicity of the imidazoacridinones. Multidrug-resistant-overexpressing F4–6 cells, 200-fold resistant to doxorubicin, showed only partial resistance (4–10 fold) to the imidazoacridinones. The cellular transport of the fluorescent imidazoacridinones occurred rapidly, and most of the drug fluorescence was localized in the nucleus. Cellular accumulation and retention of two selected imidazoacridinones (C-1310 and C-1311) in sensitive as well as in resistant F4–6 cells were determined with laser-excited flow cytometry. After an incubation with C-1311 and C-1310 for 60 min at 37°C, the cellular accumulation of the less cytotoxic compound C-1310 was greater than that of C-1311, and for both compounds, the fluorescence in the resistant F4–6 cells was one-half of that in the sensitive F4–6 cells. Lowered temperature (4°C) reduced the cellular accumulation for both compounds in the sensitive and in the resistant F4–6 cells and was comparable to the uptake in resistant F4–6 cells at 37°C. The resistant F4–6 cells at 37°C showed, despite a lower loading level, a faster initial efflux compared to the sensitive F4–6 cells. The treatment of the resistant F4–6 cells with the multidrug-resistant modulator verapamil led to an enhanced accumulation of C-1310 and C-1311 by the cells. All five compounds produced a dose-dependent inhibition of [³H]uridine and [¹⁴C]thymidine incorporation and, except for C-1336, preferentially inhibited DNA synthesis. The affinity of the imidazoacridinones to DNA is also indicated by an increase of the DNA melting point by 9–11°C. The mutagenic potential of the imidazoacridinones was investigated in the hypoxanthine guanine phosphoribosyl transferase test; the compounds C-1310 and C-1311 were additionally tested in the Salmonella typhimurium-microsome assay. Limited mutagenicity was detected in the hypoxanthine guanine phosphoribosyl transferase test, and in Salmonella typhimurium, mutagenicity was observed only in the strain TA1537. Furthermore, no induction of DNA repair synthesis was observed after treatment of primary hepatocytes with the five imidazoacridinones. The compounds did not transform C3H/M2 fibroblasts. One derivative, C-1336, led to a significant induction of cell differentiation in Friend erythroleukemia cells. The results of this study show that the imidazoacridinones display a strong cytotoxic effect in rapidly dividing cells and only a partial resistance toward multidrug resistant cells; in addition, they showed a limited mutagenic potential in V79 fibroblasts and Salmonella typhimurium and no transforming potential in C3H/M2 cells. The imidazoacridinones are, therefore, an interesting group of new antitumor agents, and further in vivo studies are warranted to explore the usefulness of these compounds for the treatment of human cancer.

¹ This work was supported by the Hamburger Stiftung zur Förderung der Krebsbekämpfung. e. V.

² To whom requests for reprints should be addressed.

Received 1/15/96. Accepted 3/ 4/96.

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