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Potent Antileukemic Activity of the Novel Cytostatic Agent Avarone and Its Analogues in Vitro and in Vivo¹

Wemer E. G. Müller², Armin Maidhof, Rudolf K. Zahn, Heinz C. Schröder, Miroslav J. Gasi, Detlev Heidemann, August Bernd, Branko Kurelec, Eckart Eich and Gerhard Seibert

Institut für Physiologische Chemie [W. E. G. M., A. M., R. K. Z., H. C. S.]; Poliklinik für Zahnerhaltungskunde [D. H.]; Fachbereich Pharmazie [E. E.], Universität, Duesbergweg, 6500 Mainz; Zentrum für Dermatologie und Venerologie, Universität, 6000 Frankfurt am Main [A. B.]; Hoechst AG, Abteilung Chemotherapie, 6230 Frankfurt am Main 80 [G. S.], West Germany; Faculty of Science, Department of Chemistry, Belgrade [M. J. G.]; and Rudjer Boskovi Institute, Zagreb [B. K.], Yugoslavia

Avarone and avarol are novel cytostatic agents which have potent antileukemic activity both in vitro and in vivo (mice). Cell culture experiments revealed that the cytostatic activity of these two compounds on L5178Y mouse lymphoma cells was 13- to 14-fold higher than that determined for HeLa cells and 40- to 43-fold higher than that for human melanoma cells. Nontumor cells (human fibroblasts and human gingival cells) were highly resistant against the two compounds. The inhibitory potency of avarone on L5178Y cells (50% inhibitory concentration, 0.62 µM) was significantly higher than the avarol activity (50% inhibitory concentration, 0.93 µM). Modification of the molecule at the quinone ring or the double bond in the terpenoid skeleton resulted in a significant loss of activity. In vivo studies with L5178Y cells in the ascites of mice confirmed the strong antileukemic effect determined in vitro. At doses of 10 mg/kg given i.p. once daily for 5 days to mice bearing approximately 10⁸ leukemia cells, avarone was found to be curative in about 70% of the mice (20% for avarol). The optimal daily i.p. dose of avarone increased life span over controls by 146% when treatment was begun 1 day after tumor implantation and by 87% when treatment was delayed until day 8. Avarol, although active, was less effective. Based on the determined log₁₀ kill values, avarone can be classified as a highly active and avarol as a markedly active cytostatic agent. The efficacy of the two compounds is also emphasized by the therapeutic index of 11.7 for avarone and of 4.5 for avarol. The two agents were determined not to be either direct mutagens or premutagens in the Ames test.

¹ This investigation was supported in part by a grant from the Deutsche Krebshilfe e.V. (W. E. G. M., E. E.), and by a grant from the Bundesministerium für Forschung und Technologie (German-Yugoslavic cooperation program). We are also grateful to the Ministry of Fisheries, Male, Maldives. This paper is dedicated to Dr. Mildred Scheel.

² To whom requests for reprints should be addressed, at Institut für Physiologische Chemie, Universität, Duesbergweg, 6500 Mainz, West Germany.

Received 3/25/85. Revised 6/10/85. Accepted 6/19/85.

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