Sequential administration of camptothecin and etoposide circumvents the antagonistic cytotoxicity of simultaneous drug administration in slowly growing human colon carcinoma HT-29 cells.
We compared the cytotoxicity of simultaneous and sequential combination chemotherapy with camptothecin and etoposide, in slowly growing human colon carcinoma, HT-29 cells. Simultaneous treatments of HT-29 cells with etoposide and camptothecin produced no marked enhancement of cytotoxicity over single agent administration. This finding demonstrates antagonism of one drug's cytotoxicity over the other. When these studies were repeated in sequential treatment protocols, we observed that antagonism could be circumvented if the period between individual drug administration was separated by 6-8 h. The cytotoxicity that was observed with this approach was never more than additive and the order of camptothecin or etoposide administration did not significantly affect the extent of combined cytotoxicity observed. The protective effect of simultaneous camptothecin and etoposide exposure was not due to reduced formation or alterations in the rate of cleavable complex reversal, and protection persisted for a considerably longer period of time than DNA strand breaks. Protection correlated with the kinetics of DNA and RNA synthesis inhibition produced by either drug. Remarkably, full cytotoxic protection could be afforded by one drug over the other, in the presence of only partial inhibition of DNA or RNA synthesis (50-60%). Our findings suggest that sequential rather than simultaneous administration of topoisomerase I and II inhibitors in future cancer chemotherapy schedules will enhance cytotoxicity over single-agent administration.
Bertrand
R
R
Laboratory of Molecular Pharmacology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892.
O'Connor
P M
PM
Kerrigan
D
D
Pommier
Y
Y
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000494:pharmacology*; D002166:Camptothecin / Q000008:administration & dosage* / Q000037:antagonists & inhibitors; D002455:Cell Division / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D004249:DNA Damage; D004273:DNA, Neoplasm / Q000096:biosynthesis; D004277:DNA, Single-Stranded / Q000187:drug effects; D004334:Drug Administration Schedule; D004347:Drug Interactions; D005047:Etoposide / Q000008:administration & dosage* / Q000037:antagonists & inhibitors; D006801:Humans; D007700:Kinetics; D012334:RNA, Neoplasm / Q000096:biosynthesis; D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors; D014407:Tumor Cells, Cultured / Q000187:drug effects
D004273:DNA, Neoplasm; D004277:DNA, Single-Stranded; D012334:RNA, Neoplasm; D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors; D005047:Etoposide; D002166:Camptothecin