title: Anticancer activity of new haloalkyl camptothecin esters against human cancer cell lines and human tumor xenografts grown in nude mice.
abstract: All chemotherapeutic agents currently in use have a narrow window of therapeutic index of 1 to 1.2. Camptothecin ester compounds are reported to have a wider therapeutic index when being used to treat human xenografts in nude mice. As a continuous effort in searching for better chemotherapeutic agents for treating cancers, new haloalkyl camptothecin and 9-nitrocamptothecin ester derivatives 2a-b and 3a-d were prepared by respective acylation of camptothecin 1a and 9-nitrocamptothecin 1b with the corresponding acylating agents. These new derivatives were tested in vitro against 8 human cancer cell lines using 7 different concentrations ranging from 5 to 300 nM and also in vivo against various types of human tumor xenografts grown in nude mice. Most of these new compounds started showing inhibitory effects on the growth of 8 cancer cell lines at concentration of 80 nM and achieved greater than 70% inhibitions against these cell lines when the concentration increased to 300 nM. Compound 2a and 3a showed good activity against human tumor xenografts in nude mice. Compared to mother compound camptothecin, 3a was much less toxic in mice with a better therapeutic index, having the potential to be further developed as a safer treatment for cancers.
authors.affiliation: The CHRISTUS Stehlin Foundation for Cancer Research, 10301 Stella Link, Houston, TX 77025, USA. zcao@stehlin.org
authors.forename: Zhisong
authors.initials: Z
authors.lastname: Cao
authors.forename: John
authors.initials: J
authors.lastname: Mendoza
authors.forename: Anthony
authors.initials: A
authors.lastname: Kozielski
authors.forename: Xing
authors.initials: X
authors.lastname: Liu
authors.forename: Albert
authors.initials: A
authors.lastname: Dejesus
authors.forename: Yang
authors.initials: Y
authors.lastname: Wang
authors.forename: Chang-Guo
authors.initials: CG
authors.lastname: Zhan
authors.forename: Dana
authors.initials: D
authors.lastname: Vardeman
authors.forename: Beppino
authors.initials: B
authors.lastname: Giovanella
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D004264:DNA Topoisomerases, Type I / Q000378:metabolism; D004952:Esters / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008958:Models, Molecular; D009369:Neoplasms / Q000188:drug therapy*; D011355:Prodrugs / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D014183:Transplantation, Heterologous
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D004952:Esters; D011355:Prodrugs; D004264:DNA Topoisomerases, Type I; C079905:rubitecan; D002166:Camptothecin