Abstract
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 150min. 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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 5443-5448 |
| Number of pages | 6 |
| Journal | Biochemistry |
| Volume | 15 |
| Issue number | 25 |
| DOIs | |
| State | Published - Dec 1 1976 |
ASJC Scopus subject areas
- Biochemistry