Selective in vivo radiosensitization by 5-fluorocytosine of human colorectal carcinoma cells transduced with the E. coli cytosine deaminase (CD) gene.
OBJECTIVE
The E. coli cytosine deaminase (CD) gene encodes an enzyme capable of converting the nontoxic prodrug 5-fluorocytosine (5-FC) to 5-fluorouracil (5-FU), a known radiosensitizer. Having previously shown that combined CD suicide gene therapy and radiation (RT) results in pronounced radiosensitization in vitro, we progressed to in vivo studies of combined therapy.


METHODS
WiDr human colon cancer cells were transduced in vitro with the CD gene and cells expressing CD were selected for use as xenografts in a nude mouse model. After administration of 5-FC, tumors received 10-30 Gy local field radiation (RT) and tumor growth delay was compared to control animals receiving either 5-FU, 5-FC, or RT alone.


RESULTS
Maximal growth delay was seen in mice treated with 5-FC for 6 consecutive days prior to RT. Combined treatment with 15 Gy radiation resulted in a dose-modifying factor (DMF) of 1.50, and a greater DMF was observed with higher doses of radiation. There was no appreciable toxicity using this new approach. In contrast, a similar treatment of combined 5-FU and radiation resulted in considerable toxicity and no appreciable radiosensitization.


CONCLUSIONS
The present results show that combined suicide gene therapy and RT results in pronounced antitumor effect without any notable toxicity. This indicates that the CD gene may be useful in the development of novel treatment strategies combining radiation and gene therapy in the treatment of locally advanced cancers.
Gabel
M
M
Department of Radiation Oncology, Henry Ford Hospital, Detroit, MI 48202, USA.
Kim
J H
JH
Kolozsvary
A
A
Khil
M
M
Freytag
S
S
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000532:radiotherapy / Q000628:therapy*; D003131:Combined Modality Therapy; D043525:Cytosine Deaminase; D004926:Escherichia coli / Q000201:enzymology*; D005260:Female; D005437:Flucytosine / Q000008:administration & dosage / Q000494:pharmacology*; D005472:Fluorouracil / Q000494:pharmacology; D015316:Genetic Therapy; D005822:Genetic Vectors; D006801:Humans; D051379:Mice; D008815:Mice, Inbred Strains; D008819:Mice, Nude; D009700:Nucleoside Deaminases / Q000235:genetics*; D011355:Prodrugs / Q000008:administration & dosage / Q000494:pharmacology*; D011838:Radiation-Sensitizing Agents / Q000008:administration & dosage / Q000494:pharmacology*; D011879:Radiotherapy Dosage
D000964:Antimetabolites, Antineoplastic; D011355:Prodrugs; D011838:Radiation-Sensitizing Agents; D005437:Flucytosine; D009700:Nucleoside Deaminases; D043525:Cytosine Deaminase; D005472:Fluorouracil