Camptothecin and 9-nitrocamptothecin (9NC) as anti-cancer, anti-HIV and cell-differentiation agents. Development of resistance, enhancement of 9NC-induced activities and combination treatments in cell and animal models.
The anticancer drug, 9-nitrocamptothecin (9NC), has demonstrated an unprecedented activity against human caner cells grown in cultures and as xenografts in nude mice. 9NC-induced apoptosis of cancer cells is mediated by the nuclear enzyme, topoisomerase I, and executed by pathways that involve cytochrome c release from the mitochondrion and/or activation of death receptors depending on the cell type. Alternatively, 9NC has exhibited ability to induce differentiation or senescence of certain cell types in vitro. In several instances, the 9NC activities can be regulated by Bcl-2 family proteins and cell cycle-associated proteins, p53, p21 and Cdks. Also, 9NC can inhibit HIV replication in infected T- and monocytic cells in vitro. Development of resistance to 9NC, associated with mutations in the topoisomerase I gene, can be overcome by regulating specific proteins, such as RKIP, other than topoisomerase I. Finally, derivatives (i.e., alkyl esters) of 9NC, liposome-encapsulated 9NC and combined treatment of 9NC with ionizing radiation or hyperthermia are other approaches to enhance the apoptotic activity of 9NC against human cancer cells.
Pantazis
Panayotis
P
University of Miami, Department of Biology, Laboratory of Molecular Cancer Biology, Cox Science Building, Room 215, 1301 Memorial Drive, Coral Gables, FL 33146, USA. pantazis@bio.miami.edu
Han
Zhiyong
Z
Balan
Kannan
K
Wang
Yongbao
Y
Wyche
James H
JH
D000818:Animals; D019380:Anti-HIV Agents / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D015497:HIV-1 / Q000187:drug effects; D006801:Humans; D014779:Virus Replication / Q000187:drug effects
D019380:Anti-HIV Agents; D000970:Antineoplastic Agents; C079905:rubitecan; D002166:Camptothecin