title: A Trojan horse in drug development: targeting of thapsigargins towards prostate cancer cells.
abstract: Available chemotherapeutics take advantage of the fast proliferation of cancer cells. Consequently slow growth makes androgen refractory prostate cancer resistant towards available drugs. No treatment is available at the present, when the cancer has developed metastases outside the prostate (T4 stage). Cytotoxins killing cells irrespective of the phase of the cell cycle will be able to kill slowly proliferating prostate cancer cells. Lack of selectivity, however, prevents their use as systemic drugs. Prostate cancer cells secrete characteristic proteolytic enzymes, e.g. PSA and hK2, with unusual substrate specificity. Conjugation of cytotoxins with peptides, which are selective substrates for PSA or hK2, will afford prodrugs, from which the active drug only will be released in close vicinity of the cancer cells. Based on this strategy prodrugs targeted at prostate cancer cells have been constructed and evaluated as potential drugs for prostate cancer. The potency of the thapsigargins as apoptotic agents make these naturally occurring sesquiterpene lactones attractive lead compounds. Intensive studies on structure-activity relationships and chemistry of the thapsigargins have enabled construction of potent derivatives enabling conjugation with peptides. Studies on the mechanism of action of the thapsigargins have revealed that the cytoxicity is based on their ability to inhibit the intracellular sarco-/endoplasmtic calcium pump.
authors.affiliation: Department of Medicinal Chemistry, University of Copenhagen, Denmark. sbc@farma.ku.dk
authors.forename: S Brøgger
authors.initials: SB
authors.lastname: Christensen
authors.forename: Dorthe Mondrup
authors.initials: DM
authors.lastname: Skytte
authors.forename: Samuel R
authors.initials: SR
authors.lastname: Denmeade
authors.forename: Craig
authors.initials: C
authors.lastname: Dionne
authors.forename: Jesper Vuust
authors.initials: JV
authors.lastname: Møller
authors.forename: Poul
authors.initials: P
authors.lastname: Nissen
authors.forename: John T
authors.initials: JT
authors.lastname: Isaacs
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008297:Male; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000037:antagonists & inhibitors; D013329:Structure-Activity Relationship; D019284:Thapsigargin / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D019284:Thapsigargin; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases