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Comparative Study of Early Effects of Epipodophyllotoxin Derivatives and Other Cytostatic Agents on Mastocytoma Cultures

Biological and Medical Research Division, Sandoz Ltd., CH-4002 Basel, Switzerland

The effects of various cytostatic agents (mechlorethamine, 1-ß-D-arabinofuranosylcytosine, 6-mercaptopurine, methotrexate, colchicine, vincristine, a podophyllotoxin derivative, bleomycin, 1,2-bis(3,5-dioxopiperazin-1-yl)propane, the epipodophyllotoxin derivatives 4'-O-demethyl-1-O-[4,6-O-2-thenylidene-ß-D-glucopyranosyl]epipodophyllotoxin and 4'-O-demethyl-1-O-[4,6-O-ethylidene-ß-D-glucopyranosyl]epipodophyllotoxin, and X-rays) on cell proliferation, mitotic index, cellular DNA, RNA, and protein content and on the incorporation of their respective isotope-labeled precursors were studied in cultures of mastocytoma cell line P-815X2 during the first 6 hr of exposure to the various agents.

Most of these agents exhibited effects compatible with their accepted mechanisms of action. An exception to this was the finding that 1-ß-D-arabinofuranosylcytosine depressed the mitotic index to less than one-half of the control value within 90 min of drug addition; this effect is not compatible with an exclusive action in G₁ or S phase of the cell cycle, but it suggests an additional block in G₂.

The two epipodophyllotoxin derivatives 4'-O-demethyl-1-O-[4,6-O-2-thenylidene-ß-D-glucopyranosyl]epipodophyllotoxin and 4'-O-demethyl-1-O-]4, 6-O-ethylidene-ß-D-glucopyranosyl]epipodophyllotoxin exhibited qualitatively identical actions. On the other hand, of the other agents only X-rays exerted some effects comparable to those of the epipodophyllotoxins. We thus conclude that, of the drugs tested, 4'-O-demethyl-1-O-[4,6-O-2-thenylidene-ß-D-glucopyranosyl]epipodophyllotoxin and 4'-O-demethyl-1-O-[4,6-O-ethylidene-ß-D-glucopyranosyl]epipodophyllotoxin possess a unique mechanism of action.

¹ To whom requests for reprints should be addressed.

Received 7/ 6/76. Accepted 5/27/77.