Comparative study of early effects of epipodophyllotoxin derivatives and other cytostatic agents on mastocytoma cultures.

Abstract

Summary The effects of various cytostatic agents (mechlorethamine, 1-β-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-β-d-glucopyranosyl]epipodophyllotoxin and 4′- O -demethyl-1- O -[4,6- O -ethylidene-β-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-β-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 G 1 or S phase of the cell cycle, but it suggests an additional block in G 2 . The two epipodophyllotoxin derivatives 4′- O -demethyl-1- O -[4,6- O -2-thenylidene-β-d-glucopyranosyl]epipodophyllotoxin and 4′- O -demethyl-1- O -]4, 6- O -ethylidene-β-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-β-d-glucopyranosyl]epipodophyllotoxin and 4′- O -demethyl-1- O -[4,6- O -ethylidene-β-d-glucopyranosyl]epipodophyllotoxin possess a unique mechanism of action.