Virally directed cytosine deaminase/5-fluorocytosine gene therapy enhances radiation response in human cancer xenografts.
Gene therapy combined with radiation therapy to enhance selectively radiation cytotoxicity in malignant cells represents a new approach for cancer treatment. We investigated the efficacy of adenoviral (Ad5)-directed cytosine deaminase/5-fluorocytosine (CD/5-FC) enzyme/prodrug gene therapy to enhance selectively the tumoricidal action of ionizing radiation in human cancer xenografts derived from a human squamous carcinoma cell line (SQ-20B). Tumor xenografts grown in hindlimbs of nude mice were transfected with an adenoviral vector (Ad.CMV.CD) containing the cytosine deaminase (CD) gene under the control of a cytomegalovirus (CMV) promoter. Mice were injected i.p. with 800 mg/kg of 5-FC for 12 days, and tumors were treated with fractionated radiation at a dose of 5 Gy/day to a total dose of 50 Gy. In larger tumors with a mean volume of 1069 mm3, marked tumor regression to 11% of the original tumor volume was observed at day 21 (P = 0.01). The volumetric regression of smaller tumors with a mean volume of 199 mm3, which received the same combined treatment protocol, was significant at day 12 (P = 0.014). However, unlike large tumors, regression of the smaller tumors continued until day 36 (P = 0.01), with 43% cured at day 26. No cures or significant volumetric reduction in size was observed in tumors treated with radiation alone; Ad.CMV.CD with or without radiation; or with Ad.CMV.CD and 5-FC. These results suggest that the CD/5-FC gene therapy approach is an effective radiosensitizing strategy and may lead to substantial improvement in local tumor control that would translate into improved cure rates and better survival.
Hanna
N N
NN
Department of Surgery, Pritzker School of Medicine, University of Chicago, Illinois 60637, USA.
Mauceri
H J
HJ
Wayne
J D
JD
Hallahan
D E
DE
Kufe
D W
DW
Weichselbaum
R R
RR
D000260:Adenoviruses, Human / Q000235:genetics; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000532:radiotherapy / Q000628:therapy; D003131:Combined Modality Therapy; D043525:Cytosine Deaminase; D005260:Female; D005437:Flucytosine / Q000627:therapeutic use*; D015316:Genetic Therapy; D005822:Genetic Vectors; D006801:Humans; D007822:Laryngeal Neoplasms / Q000188:drug therapy / Q000532:radiotherapy / Q000628:therapy; D051379:Mice; D008819:Mice, Nude; D009364:Neoplasm Recurrence, Local; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000473:pathology / Q000532:radiotherapy / Q000628:therapy*; D009700:Nucleoside Deaminases / Q000235:genetics / Q000627:therapeutic use*; D011836:Radiation Tolerance; D011838:Radiation-Sensitizing Agents / Q000627:therapeutic use*; D011993:Recombinant Fusion Proteins / Q000627:therapeutic use; D014162:Transfection; D014183:Transplantation, Heterologous
D000964:Antimetabolites, Antineoplastic; D011838:Radiation-Sensitizing Agents; D011993:Recombinant Fusion Proteins; D005437:Flucytosine; D009700:Nucleoside Deaminases; D043525:Cytosine Deaminase