title: A cell-delivered and cell-activated SN38-dextran prodrug increases survival in a murine disseminated pancreatic cancer model.
abstract: Enzyme-activated prodrugs have been investigated and sought after as highly specific, low-side-effect treatments, especially for cancer therapy. Unfortunately, excellent targets for enzyme-activated therapy are rare. Here a system based on cell delivery that can carry both a prodrug and an activating enzyme to the cancer site is demonstrated. Raw264.7 cells (mouse monocyte/macrophage-like cells, Mo/Ma) are engineered to express intracellular rabbit carboxylesterase (InCE), which is a potent activator of the prodrug irinotecan to SN38. InCE expression is regulated by the TetOn® system, which silences the gene unless a tetracycline, such as doxycycline, is present. Concurrently, an irinotecan-like prodrug, which is conjugated to dextran and can be loaded into the cytoplasm of Mo/Ma, is synthesized. To test the system, a murine pancreatic cancer model is generated by intraperitoneal (i.p.) injection of Pan02 cells. Engineered Mo/Ma are loaded with the prodrug and are injected i.p. Two days later, doxycycline was given i.p. to activate InCE, which activated the prodrug. A survival study demonstrates that this system significantly increased survival in a murine pancreatic cancer model. Thus, for the first time, a prodrug/activating enzyme system, which is self-contained within tumor-homing cells and can prolong the life of i.p. pancreatic tumor bearing mice, is demonstrated.
authors.affiliation: Department of Anatomy and Physiology, Kansas State University, 1600 Denison Ave., Coles Hall 228, Manhattan, KS 66506, USA. mbasel@vet.ksu.edu
authors.forename: Matthew T
authors.initials: MT
authors.lastname: Basel
authors.forename: Sivasai
authors.initials: S
authors.lastname: Balivada
authors.forename: Tej B
authors.initials: TB
authors.lastname: Shrestha
authors.forename: Gwi-Moon
authors.initials: GM
authors.lastname: Seo
authors.forename: Marla M
authors.initials: MM
authors.lastname: Pyle
authors.forename: Masaaki
authors.initials: M
authors.lastname: Tamura
authors.forename: Stefan H
authors.initials: SH
authors.lastname: Bossmann
authors.forename: Deryl L
authors.initials: DL
authors.lastname: Troyer
mesh_terms: D000818:Animals; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives*; D003911:Dextrans / Q000008:administration & dosage*; D004195:Disease Models, Animal; D000077146:Irinotecan; D051379:Mice; D010190:Pancreatic Neoplasms / Q000473:pathology*; D011355:Prodrugs / Q000008:administration & dosage*; D011817:Rabbits
chemical_list: D003911:Dextrans; D011355:Prodrugs; D000077146:Irinotecan; D002166:Camptothecin