title: Fractionated radiation therapy in combination with adenoviral delivery of the cytosine deaminase gene and 5-fluorocytosine enhances cytotoxic and antitumor effects in human colorectal and cholangiocarcinoma models.
abstract: Radiosensitization of human gastrointestinal tumors by 5-fluorouracil (5-FU) has been studied in vitro and clinically in human cancer therapy trials. The bacterial enzyme cytosine deaminase (CD) converts the nontoxic prodrug 5-fluorocytosine (5-FC) into 5-FU. Human colon cancer cells stably expressing CD have been shown by other investigators to be sensitized to radiation following treatment with 5-FC. We previously used an adenoviral vector under control of the cytomegalovirus promoter (AdCMVCD) encoding the CD gene in combination with 5-FC and a single fraction of radiation exposure to enhance cytotoxicity to human cholangiocarcinoma cells in vitro and in vivo. The purpose of this study was to determine whether AdCMVCD infection and 5-FC with multiple fraction low-dose radiotherapy results in enhanced cytotoxicity. In the present study, we utilized AdCMVCD and 5-FC with single fraction radiotherapy to demonstrate enhanced cytotoxicity to WiDr human colon carcinoma cells in vitro. Additionally, we tested this gene therapy/prodrug treatment strategy employing a fractionated radiation dosing schema in animal models of WiDr colon carcinoma and SK-ChA-1 cholangiocarcinoma. A prolonged WiDr tumor regrowth delay was obtained with AdCMVCD infection in combination with systemic delivery of 5-FC and fractionated external beam radiation therapy compared with control animals treated without radiation, without 5-FC, or without AdCMVCD. The results of treatment with AdCMVCD + 5-FC + radiation therapy to cholangiocarcinoma xenografts were equivalent to those obtained with systemic 5-FU administration + radiation. Thus, the use of AdCMVCD can be effectively combined with clinically relevant 5-FC and radiation administration schemes to achieve enhanced tumor cell killing and increased control of established tumors of human gastrointestinal malignancies.
authors.affiliation: Department of Radiation Oncology, University of Alabama at Birmingham, 35233-6832, USA.
authors.forename: M A
authors.initials: MA
authors.lastname: Stackhouse
authors.forename: L C
authors.initials: LC
authors.lastname: Pederson
authors.forename: W E
authors.initials: WE
authors.lastname: Grizzle
authors.forename: D T
authors.initials: DT
authors.lastname: Curiel
authors.forename: J
authors.initials: J
authors.lastname: Gebert
authors.forename: K
authors.initials: K
authors.lastname: Haack
authors.forename: S M
authors.initials: SM
authors.lastname: Vickers
authors.forename: M S
authors.initials: MS
authors.lastname: Mayo
authors.forename: D J
authors.initials: DJ
authors.lastname: Buchsbaum
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D001650:Bile Duct Neoplasms / Q000473:pathology / Q000532:radiotherapy*; D001653:Bile Ducts, Intrahepatic; D002470:Cell Survival / Q000528:radiation effects; D018281:Cholangiocarcinoma / Q000473:pathology / Q000532:radiotherapy*; D015179:Colorectal Neoplasms / Q000473:pathology / Q000532:radiotherapy*; D043525:Cytosine Deaminase; D004307:Dose-Response Relationship, Radiation; D005437:Flucytosine / Q000627:therapeutic use; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009700:Nucleoside Deaminases / Q000235:genetics; D011355:Prodrugs / Q000627:therapeutic use; D011836:Radiation Tolerance; D011838:Radiation-Sensitizing Agents; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
chemical_list: D011355:Prodrugs; D011838:Radiation-Sensitizing Agents; D005437:Flucytosine; D009700:Nucleoside Deaminases; D043525:Cytosine Deaminase