Therapeutic effect of colon tumor cells expressing FLT-3 ligand plus systemic IL-2 in mice with syngeneic colon cancer.
Flt-3 ligand (FL) and interleukin-2 (IL-2) have been shown to enhance individually the antitumor response against several cancers. Therefore, treatment with a combination of FL gene-transduced tumor cell plus soluble IL-2 was studied in a murine colon adenocarcinoma model. The human full-length FL cDNA was cloned from FL-expressing cell line AML-193 by reverse transcription-polymerase chain reaction (RT-PCR). CC-36 colon tumor cells were transduced with the FL gene (CC-36-FL). In vivo and in vitro secretion of FL from CC-36-FL was confirmed by enzyme-linked immunosorbent assay (ELISA). Moreover, enhancement of dendritic cells in vivo was evaluated in mice transplanted with CC-36-FL. The therapeutic efficacy of CC-36-FL plus systemic IL-2 was tested using six groups ( n=12-13/group) of 10-week-old male Balb/c mice transplanted with 10(3) CC-36 tumor cells. Mice were treated subcutaneously with 10(6) irradiated CC-36 cells, 10(6) irradiated CC-36 cells+IL-2, 10(6) irradiated CC-36-FL cells, 10(6) irradiated CC-36-FL+IL-2, or IL-2 alone on days 4, 10 and 18 after tumor transplantation. A group of mice with no treatment served as a control. All of the treatment injections were performed subcutaneously in the left flank. IL-2 (2 x 50,000 IU) was administered intraperitoneally in 3-day cycles (days 4-6, 10-12, 17-19). Tumor growth was determined by measuring the tumor diameter. A survival experiment was performed with the same treatments, and mice were observed for survival for 100 days. The group of mice treated with the combination of CC-36-FL+IL-2 showed a significant reduction in tumor burden when compared to the no treatment group and the other control treatment groups ( P<0.05). Similarly, the group of mice treated with CC-36-FL+IL-2 displayed significant survival when compared with the other control groups (P<0.05). In Balb/c mice, the CC-36-FL plus systemic IL-2 therapy significantly decreased the tumor burden and increased the survival rate when compared to mice treated by control therapies or mice that received no treatment.
Sivanandham
Muthukumaran
M
Department of Surgery, Saint Vincent's Hospital and Medical Center of New York, New York Medical College, 153 West 12th Street, Cronin 667, New York, NY 10011, USA. msivanandham@compuserve.com
Stavropoulos
Christos I
CI
Kim
Eugene M
EM
Mancke
Brian
B
Wallack
Marc K
MK
D000818:Animals; D003110:Colonic Neoplasms / Q000401:mortality / Q000473:pathology / Q000628:therapy*; D003602:Cytotoxicity, Immunologic; D003713:Dendritic Cells / Q000502:physiology; D015316:Genetic Therapy; D007167:Immunotherapy; D007371:Interferon-gamma / Q000096:biosynthesis; D018664:Interleukin-12 / Q000096:biosynthesis; D007376:Interleukin-2 / Q000627:therapeutic use*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D008807:Mice, Inbred BALB C; D009368:Neoplasm Transplantation; D015996:Survival Rate; D014407:Tumor Cells, Cultured
D007376:Interleukin-2; D008565:Membrane Proteins; C084881:flt3 ligand protein; D018664:Interleukin-12; D007371:Interferon-gamma