Pharmacology of camptothecin esters.
An intact lactone ring of camptothecins is a structural requirement for their anticancer activity. Propionate esters of camptothecin (CPT) and 9-nitrocamptothecin (9NC), CZ48 and CZ112, respectively, have been synthesized as derivatives resistant to lactone hydrolysis and are chemotherapeutically active. In this study, we have examined the mechanism of action of CZ48 and CZ112 and their distribution, metabolism, and toxicity. CZ112 incubated in human plasma retained its lactone structure longer than 9NC (t1/2: 10.5 and < 1 hr for CZ112 and 9NC, respectively). This resistance to lactone hydrolysis was also observed in mouse plasma or albumin solutions. Neither CZ48 nor CZ112 inhibit topoisomerase I and thus are prodrugs dependent on hydrolysis to CPT or 9NC, respectively. Rates of hydrolysis of CZ48 to CPT are higher by homogenates of mouse liver, spleen, lung, and kidney than by plasma. Rates of hydrolysis by tumor cells in culture vary and were higher by breast cancer and melanoma cells than by colon cancer cells. On the basis of these and other data, it is proposed that CZ48 and CZ112 may act as anticancer agents by resisting hydrolysis to camptothecins while in circulation. Hydrolysis in tissues may release intact lactone in target tissues.
Liehr
J G
JG
Stehlin Foundation for Cancer Research, Christus St. Joseph Hospital, 1918 Chenevert, Houston, TX 77003, USA.
Harris
N J
NJ
Mendoza
J
J
Ahmed
A E
AE
Giovanella
B C
BC
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology / Q000633:toxicity; D006801:Humans; D011422:Propionates / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity; D059004:Topoisomerase I Inhibitors
D000972:Antineoplastic Agents, Phytogenic; D004791:Enzyme Inhibitors; D011422:Propionates; D059004:Topoisomerase I Inhibitors; C079905:rubitecan; D002166:Camptothecin