Effect of derivatives of chrysophanol, a new type of potential antitumor agents of anthraquinone family, on growth and cell cycle of L1210 leukemic cells.
The new C-methyl modified derivatives of the anthraquinones chrysophanol and emodin, recently synthesized by us, are potentially bifunctional agents having the ability to intercalate to nucleic acids and also having alkylating properties. Two of these compounds, namely 3-(N,N-bis(2-chloroethyl)-amino)methyl-1,8-dihydroxy-9,10-anthraquinone (Compound 31.662) and its 1,8-di-O-methylated analog (Compound 31.655) have been presently tested on murine leukemic L1210 cells in vitro with respect to their cell cycle specificity. During the initial 24 h of treatment the cytostatic effects of the drugs predominated, manifesting as suppression of cell progression through S (especially through the early portion of S phase) and G2. After 24 h, the cytotoxic effects became apparent, and there was also the appearance of cells with doubled DNA content suggestive of either endoreduplication or impairment of cytokinesis; these cells at higher ploidy level were progressing through S and G2. The observed effects were time- and dose-dependent, occurring at 0.1-0.4 micrograms/ml concentration of 31.662 and 2.0-10.0 micrograms/ml of its methylated analog, either during continuous- or after a 4-h pulse-treatment. Modulation of the cell cycle by the studied drugs is similar to that generally caused by intercalators as well as alkylating agents. However, because no positive evidence of intercalation of the studied drugs to nucleic acids was found, it is possible that alkylation of DNA or other cell constituents may be the primary lesion(s) leading to perturbation of the cell cycle.
Darzynkiewicz
Z
Z
Laboratory of Experimental Cell Research, Sloan-Kettering Institute for Cancer Research, Walker Laboratories, Rye, NY 10580.
Carter
S P
SP
Kapuscinski
J
J
Watanabe
K A
KA
D000818:Animals; D000880:Anthraquinones / Q000494:pharmacology*; D000970:Antineoplastic Agents; D002452:Cell Count; D002453:Cell Cycle / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004247:DNA / Q000032:analysis; D004642:Emodin / Q000494:pharmacology; D005434:Flow Cytometry; D007939:Leukemia L1210 / Q000473:pathology*; D051379:Mice; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000880:Anthraquinones; D000970:Antineoplastic Agents; D004247:DNA; D004642:Emodin; C027113:chrysophanic acid