This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Dow, L. W. Articles by Evans, W. E. Search for Related Content PubMed PubMed Citation Articles by Dow, L. W. Articles by Evans, W. E.

Comparative Cytotoxic and Cytokinetic Effects of the Epipodophyllotoxins 4'-Demethylepipodophyllotoxin-9-(4,6-O-2-ethylidene-ß-D-glucopyranoside) and 4'-Demethylepipodophyllotoxin-9-(4,6-O-2-thenylidene-ß-D-glucopyranoside) and Their Metabolites on Human Leukemic Lymphoblasts¹

Division of Hematology-Oncology [L. W. D., A. T. L., A. H.], and the Pharmacokinetics and Pharmacodynamics Section [J. A. S., W. E. E.], St. Jude Children's Research Hospital, Memphis, Tennessee 38101

We compared the effects of the epipodophyllotoxins 4'-demethylepipodophyllotoxin-9-(4,6-O-2-ethylidene-ß-D-glucopyranoside) (VP-16-213) and 4'-demethylepipodophyllotoxin-9-(4,6-O-2-thenylidene-ß-D-glucopyranoside) (VM-26) and several of their derivatives on cell cycle progression and viability of human leukemic lymphoblasts (CCRF-CEM). The cis-(picro)-lactone derivatives, like both VP-16-213 and VM-26, produced G₂-phase arrest and cytotoxicity, but only at concentrations 100 times greater than required with the parent compounds. The epiaglycone derivative showed potent cytotoxicity: at 100 to 250 nM, it reduced cloning efficiency by 50%, an effect requiring 25 to 40 nM VM-26 and 340 to 425 nM VP-16-213. In contrast to VM-26 and VP-16-213, the epiaglycone arrested cells in M, consistent with evidence that it, like podophyllotoxin, is an inhibitor of microtubule assembly. At concentrations resulting in 50% cell kill and an increase of cells in M, however, the epiaglycone produced little change in the proportion of cells in G₁ or early S phase, while podophyllotoxin produced a shift of cells to midand late S. The hydroxy acid derivatives, although found in detectable quantities in patients' urine and serum, were inactive in vitro. Structural differences among the compounds account for their different biochemical and cell kinetic effects and, hence, different cytotoxic activities. Because the epiaglycone is a potent compound and combines activities of both the podophyllotoxins and 4'-demethyl derivatives, further studies of its cytotoxicity are indicated.

¹ Supported by Leukemia Program Project Grant CA 20180 and Childhood Cancer Center Support (Core) Grant CA 21765 from the National Cancer Institute and by ALSAC.

² To whom requests for reprints should be addressed, at 332 North Lauderdale, Memphis, Tenn. 38101.

³ Recipient of Grant RR-05584-18 from the Division of Research Resources, NIH.

Received 1/10/83. Accepted 8/24/83.