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.
Keywords: Prostate cancer, targeted drugs, thapsigargin, PSA, hK2, Prodrug, SERCA
Anti-Cancer Agents in Medicinal Chemistry
Title: A Trojan Horse in Drug Development: Targeting of Thapsigargins Towards Prostate Cancer Cells
Volume: 9 Issue: 3
Author(s): S. Brogger Christensen, Dorthe Mondrup Skytte, Samuel R. Denmeade, Craig Dionne, Jesper Vuust Moller, Poul Nissen and John T. Isaacs
Affiliation:
Keywords: Prostate cancer, targeted drugs, thapsigargin, PSA, hK2, Prodrug, SERCA
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.
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Cite this article as:
Christensen Brogger S., Skytte Mondrup Dorthe, Denmeade R. Samuel, Dionne Craig, Moller Vuust Jesper, Nissen Poul and Isaacs T. John, A Trojan Horse in Drug Development: Targeting of Thapsigargins Towards Prostate Cancer Cells, Anti-Cancer Agents in Medicinal Chemistry 2009; 9 (3) . https://dx.doi.org/10.2174/1871520610909030276
DOI https://dx.doi.org/10.2174/1871520610909030276 |
Print ISSN 1871-5206 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5992 |
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