title: Structure-activity relationship of alkyl camptothecin esters.
abstract: The cytotoxicity of camptothecin (CPT) esters 1-6 was measured. Like parental camptothecin, esters 2 and 3, but not 1, 4, 5, and 6, inhibited proliferation of human leukemia cells in culture and induced programmed cell death as assessed by flow cytometry studies. Exhibition of similar levels of antiproliferative activities of CPT 2 and 3 required different incubation time periods in cell cultures, with CPT and 3 requiring the shortest and longest periods, respectively. Both 2 and 3 were inactive against cells resistant to the semisynthetic CPT derivative 9-nitrocamptothecin and unable to stabilize DNA-topoisomerase I (Topo I) "cleavable complexes" in a cell-free system, suggesting that Topo I activity was required but insufficient for the mechanism of action of 2 and 3. Mouse liver homogenate converted esters to parental CPT, but the conversion rates were different with different esters. Of four tested esters in this experiment, ester 2 had the fastest conversion rate. In vivo studies showed that ester 2 had an exceptional lack of toxicity in nude mice, even at enormous doses, and demonstrated extensive activity against human breast and colon tumors grown as xenografts in immunodeficient nude mice, whereas no antitumor activity was observed for the other esters. In conclusion, ester 2 is a prodrug of the antitumor compound CPT, and it can be administered at very high doses in mice with no appearance of toxicity. This study provides a basis for further evaluation of CPT ester 2 as an investigational anticancer agent.
authors.affiliation: Stehlin Foundation for Cancer Research, 1918 Chenevert Street, Houston, TX 77003, USA. zcao@pipeline.com
authors.forename: Z
authors.initials: Z
authors.lastname: Cao
authors.forename: P
authors.initials: P
authors.lastname: Pantazis
authors.forename: J
authors.initials: J
authors.lastname: Mendoza
authors.forename: J
authors.initials: J
authors.lastname: Early
authors.forename: A
authors.initials: A
authors.lastname: Kozielski
authors.forename: N
authors.initials: N
authors.lastname: Harris
authors.forename: D
authors.initials: D
authors.lastname: Vardeman
authors.forename: J
authors.initials: J
authors.lastname: Liehr
authors.forename: J S
authors.initials: JS
authors.lastname: Stehlin
authors.forename: B
authors.initials: B
authors.lastname: Giovanella
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D001943:Breast Neoplasms / Q000188:drug therapy / Q000473:pathology; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D002455:Cell Division / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D004952:Esters / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D005260:Female; D018922:HL-60 Cells / Q000166:cytology / Q000187:drug effects; D006801:Humans; D051379:Mice; D013329:Structure-Activity Relationship; D020298:U937 Cells / Q000166:cytology / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D004791:Enzyme Inhibitors; D004952:Esters; D002166:Camptothecin