The use of chelated radionuclide (samarium-153-ethylenediaminetetramethylenephosphonate) to modulate phenotype of tumor cells and enhance T cell-mediated killing.
OBJECTIVE
Exposing human tumor cells to sublethal doses of external beam radiation up-regulates expression of tumor antigen and accessory molecules, rendering tumor cells more susceptible to killing by antigen-specific CTLs. This study explored the possibility that exposure to palliative doses of a radiopharmaceutical agent could alter the phenotype of tumor cells to render them more susceptible to T cell-mediated killing.


METHODS
Here, 10 human tumor cell lines (4 prostate, 2 breast, and 4 lung) were exposed to increasing doses of the radiopharmaceutical samarium-153-ethylenediaminetetramethylenephosphonate ((153)Sm-EDTMP) used in cancer patients to treat pain due to bone metastasis. Fluorescence-activated cell sorting analysis and quantitative real-time PCR analysis for expression of five surface molecules and several tumor-associated antigens involved in prostate cancer were done. LNCaP human prostate cancer cells were exposed to (153)Sm-EDTMP and incubated with tumor-associated antigen-specific CTL in a CTL killing assay to determine whether exposure to (153)Sm-EDTMP rendered LNCaP cells more susceptible to T cell-mediated killing.


RESULTS
Tumor cells up-regulated the surface molecules Fas (100% of cell lines up-regulated Fas), carcinoembryonic antigen (90%), mucin-1 (60%), MHC class I (50%), and intercellular adhesion molecule-1 (40%) in response to (153)Sm-EDTMP. Quantitative real-time PCR analysis revealed additional up-regulated tumor antigens. Exposure to (153)Sm-EDTMP rendered LNCaP cells more susceptible to killing by CTLs specific for prostate-specific antigen, carcinoembryonic antigen, and mucin-1.


CONCLUSIONS
Doses of (153)Sm-EDTMP equivalent to palliative doses delivered to bone alter the phenotype of tumor cells, suggesting that (153)Sm-EDTMP may work synergistically with immunotherapy to increase the susceptibility of tumor cells to CTL killing.
Chakraborty
Mala
M
Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland 20892, USA.
Wansley
Elizabeth K
EK
Carrasquillo
Jorge A
JA
Yu
Sarah
S
Paik
Chang H
CH
Camphausen
Kevin
K
Becker
Michael D
MD
Goeckeler
William F
WF
Schlom
Jeffrey
J
Hodge
James W
JW
D001943:Breast Neoplasms / Q000628:therapy*; D045744:Cell Line, Tumor; D002469:Cell Separation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000628:therapy*; D008297:Male; D009942:Organometallic Compounds / Q000627:therapeutic use*; D009943:Organophosphorus Compounds / Q000627:therapeutic use*; D010641:Phenotype; D011471:Prostatic Neoplasms / Q000628:therapy*; D011868:Radioisotopes / Q000494:pharmacology*; D012493:Samarium / Q000494:pharmacology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000378:metabolism; D016896:Treatment Outcome
D009942:Organometallic Compounds; D009943:Organophosphorus Compounds; D011868:Radioisotopes; D012493:Samarium; C061972:samarium Sm-153 lexidronam