Reference

Effects of podophyllotoxin and VP-16-213 on microtubule assembly in vitro and nucleoside transport in HeLa cells

Effects of podophyllotoxin and VP-16-213 on microtubule assembly in vitro and nucleoside transport in HeLa cells. Loike, John D.; Horwitz, Susan B. (Dep. Pharmacol., Albert Einstein Coll. Med., New York, N. Y., USA).Some commonly used reagents like 33419-42-0 and 518-28-5 are used in this experiment. Biochemistry, 15(25), 5435-43 (English) 1976. CODEN: BICHAW. DOCUMENT TYPE: Journal CA Section: 1 (Pharmacodynamics) Section cross-reference(s): 3 The effects of VP-16-213 (I) [33419-42-0] and podophyllotoxin [518-28-5] on microtubule assembly in vitro and nucleoside transport in HeLa cells are compared. At 100 .mu.M, I does not inhibit microtubule assembly in vitro, while 5 .mu.M podophyllotoxin completely prevents the formation of microtubules. The presence of the glucoside moiety in I is responsible for the inactivity of I in this system because 4'-demethylepipodophyllotoxin [6559-91-7], the nonglucoside congener of I, inhibits microtubule assembly. In HeLa cells I and podophyllotoxin share a common biol. property; both agents inhibit the uptake of thymidine and uridine into cells by inhibiting the facilitated diffusional component of nucleoside transport. The concns. of drug necessary to inhibit thymidine and uridine uptake into HeLa cells by 50% are 10 and 5 .mu.M, resp., for podophyllotoxin, and 25 and 20 .mu.M for I. The action of podophyllotoxin on nucleoside transport appears unrelated to its effect on microtubule assembly, since I, which does not inhibit microtubule assembly, inhibits nucleoside transport. .

Effect of VP-16-213 on the intracellular degradation of DNA in HeLa cells

Effect of VP-16-213 on the intracellular degradation of DNA in HeLa cells. Loike, John D.; Horwitz, Susan B. (Dep. Pharmacol., Albert Einstein Coll. Med., New York, N. Y., USA). Biochemistry, 15(25), 5443-8 (English) 1976. CODEN: BICHAW. DOCUMENT TYPE: Journal CA Section: 1 (Pharmacodynamics) The effect of VP-16-213 (I) [33419-42-0] on cellular DNA was studied by following the sedimentation profiles of radioactive DNA in HeLa cells on alk. sucrose gradients. 518-29-6 and 3590-93-0 which are cas registry numbers are also used here. In I-treated cells, high-mol.-wt. DNA is converted to a lower mol.-wt. from in a dose-dependent, temp.-dependent reaction. The effect of I on cellular DNA is reversed after the drug has been removed from the growth medium for 150 min. These results suggest that I induces single-stranded breaks in DNA in HeLa cells and that HeLa cells can repair these breaks within 150 min. The nonglucoside deriv. of VP-16-213, 4'-demethylepipodophyllotoxin [6559-91-7], also induces the cleavage of cellular DNA but podophyllotoxin [518-28-5], has no effect on DNA. A structure-activity relationship study, in which the effects of various I 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 I as an antitumor agent. .