Effect of VP-16-213 on the intracellular degradation of DNA in HeLa cells.
The effect of VP-16-213 on cellular DNA was studied by following the sedimentation profiles of radioactive DNA in HeLa cells on alkaline sucrose gradients. In VP-16-213 treated cells, high-molecular-weight DNA is converted to a lower molecular-weight form in a dose-dependent, temperature-dependent reaction. The effect of VP-16-213 on cellular DNA is reversed after the drug has been removed from the growth medium for 150 min. These results suggest that VP-16-213 induces single-stranded breaks in DNA in HeLa cells and that HeLa cells can repair these breaks within 150 min. The nonglucoside derivative of VP-16-213, 4'-demethylepipodophyllotoxin, also induces the cleavage of cellular DNA but podophyllotoxin has no effect on DNA. A structure-activity relationship study, in which the effects of various VP-16-213 and podophyllotoxin congeners were tested for their ability to cleave cellular DNA,revealed that an hydroxyl group at the C-4' position is required for activity and that the configuration of the C-4 carbon influences the activity of a congener. These results may offer insights into the mechanism of action of VP-16-213 as an antitumor agent.
D000260:Adenoviruses, Human; D004247:DNA / Q000378:metabolism*; D004279:DNA, Viral / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005047:Etoposide / Q000494:pharmacology*; D006367:HeLa Cells / Q000187:drug effects / Q000378:metabolism; D008970:Molecular Weight; D011034:Podophyllotoxin / Q000031:analogs & derivatives* / Q000494:pharmacology; D013696:Temperature
D004279:DNA, Viral; D005047:Etoposide; D004247:DNA; D011034:Podophyllotoxin