CYTOTOXIC ACTIVITY AGAINST RESISTANT HUMAN TUMOR-CELL LINES BY 2 SYNTHETIC DEMETHYLPODOPHYLLOTOXIN DERIVATIVES - A SINGLE STEREOISOMERIC CHANGE PREVENTS CELL-DEATH BY APOPTOSIS

The podophyllotoxin derivative, etoposide, is currently being used in patients with variant malignant diseases. However, studies show resistance to etoposide develops, and thus new agents to overcome resistance are needed. The present study investigated the cytotoxic properties of two synthetic podophyllotoxin derivatives namely 4-o-butanoyl-4'-demethylepipodophyllotoxin (BEPT) and 4-o-butanoyl-4'-demethylpodophyllotoxin (BDPTN or BN58705). Both BEPT and BDPTN are shown to be cytotoxic against a battery of human tumor cell lines. In comparison to etoposide, the magnitude of cytotoxic activity by BEPT and BDPTN was higher. Further, both compounds were cytotoxic to drug resistant lines and also were able to overcome the etoposide and cross-resistance of an MDR+ cell line. The mechanism of cytotoxicity was also examined. Like etoposide, a topoisomerase II inhibitor and inducer of apoptosis, BEPT mediated its cytotoxic activity by an apoptotic pathway. However, BDPTN did not mediate apoptosis. These findings demonstrate that a simple modification in the stereoisomeric structure results in significant modification in both the cytotoxic patterns and the induction of apoptosis. Further, the findings show that the podophyllotoxin analogs can overcome drug resistance and suggest their possible application in the therapy of resistant tumors.