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3'-Deoxy-3'-18FFluorothymidine as a New Marker for Monitoring Tumor Response to Antiproliferative Therapy in Vivo with Positron Emission Tomography

3'-Deoxy-3'-18FFluorothymidine as a New Marker for Monitoring Tumor Response to Antiproliferative... 3'-Deoxy-3'- 18 Ffluorothymidine ( 18 FFLT) has been proposed as a new marker for imaging tumor proliferation by positron emission tomography (PET). The uptake of 18 FFLT is regulated by cytosolic S-phase-specific thymidine kinase 1 (TK1). In this article, we have investigated the use of 18 FFLT to monitor the response of tumors to antiproliferative treatment in vivo . C3H/Hej mice bearing the radiation-induced fibrosarcoma 1 tumor were treated with 5-fluorouracil (5-FU; 165 mg/kg i.p.). Changes in tumor volume and biodistribution of 18 FFLT and 2- 18 Ffluoro-2-deoxy- D -glucose ( 18 FFDG) were measured in three groups of mice ( n = 8–12/group): ( a ) untreated controls; ( b ) 24 h after 5-FU; and ( c ) 48 h after 5-FU. In addition, dynamic 18 FFLT-PET imaging was performed on a small animal scanner for 60 min. The metabolism of 18 FFLT in tumor, plasma, liver, and urine was determined chromatographically. Proliferation was determined by staining histological sections for proliferating cell nuclear antigen (PCNA). Tumor levels of TK1 protein and cofactor (ATP) were determined by Western blotting and bioluminescence, respectively. Tumor 18 FFLT uptake decreased after 5-FU treatment (47.8 ± 7.0 and 27.1 ± 3.7% for groups b and c , respectively, compared with group a ; P < 0.001). The drug-induced reduction in tumor 18 FFLT uptake was significantly more pronounced than that of 18 FFDG. The PET image data confirmed lower tumor 18 FFLT retention in group c compared with group a , despite a trend toward higher radiotracer delivery for group c . Other than phosphorylation in tumors, 18 FFLT was found to be metabolically stable in vivo . The decrease in tumor 18 FFLT uptake correlated with the PCNA-labeling index ( r = 0.71, P = 0.031) and tumor volume changes after 5-FU treatment ( r = 0.58, P = 0.001). In this model system, the decrease in 18 FFLT uptake could be explained by changes in catalytic activity but not translation of TK1 protein. Compared with group a , TK1 levels were lower in group b (78.2 ± 5.2%) but higher in group c (141.3 ± 9.1%, P < 0.001). In contrast, a stepwise decrease in ATP levels was observed from group a to b to c ( P < 0.001). In conclusion, we have demonstrated the ability to measure tumor response to antiproliferative treatment with 18 FFLT and PET. In our model system, the radiotracer uptake was correlated with PCNA-labeling index. The decrease in 18 FFLT uptake after 5-FU was more pronounced than that of 18 FFDG. 18 FFLT is, therefore, a promising marker for monitoring antiproliferative drug activity in oncology that warrants additional testing. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Cancer Research American Association of Cancer Research

3'-Deoxy-3'-18FFluorothymidine as a New Marker for Monitoring Tumor Response to Antiproliferative Therapy in Vivo with Positron Emission Tomography

3'-Deoxy-3'-18FFluorothymidine as a New Marker for Monitoring Tumor Response to Antiproliferative Therapy in Vivo with Positron Emission Tomography

Cancer Research , Volume 63 (13): 3791 – Jul 1, 2003

Abstract

3'-Deoxy-3'- 18 Ffluorothymidine ( 18 FFLT) has been proposed as a new marker for imaging tumor proliferation by positron emission tomography (PET). The uptake of 18 FFLT is regulated by cytosolic S-phase-specific thymidine kinase 1 (TK1). In this article, we have investigated the use of 18 FFLT to monitor the response of tumors to antiproliferative treatment in vivo . C3H/Hej mice bearing the radiation-induced fibrosarcoma 1 tumor were treated with 5-fluorouracil (5-FU; 165 mg/kg i.p.). Changes in tumor volume and biodistribution of 18 FFLT and 2- 18 Ffluoro-2-deoxy- D -glucose ( 18 FFDG) were measured in three groups of mice ( n = 8–12/group): ( a ) untreated controls; ( b ) 24 h after 5-FU; and ( c ) 48 h after 5-FU. In addition, dynamic 18 FFLT-PET imaging was performed on a small animal scanner for 60 min. The metabolism of 18 FFLT in tumor, plasma, liver, and urine was determined chromatographically. Proliferation was determined by staining histological sections for proliferating cell nuclear antigen (PCNA). Tumor levels of TK1 protein and cofactor (ATP) were determined by Western blotting and bioluminescence, respectively. Tumor 18 FFLT uptake decreased after 5-FU treatment (47.8 ± 7.0 and 27.1 ± 3.7% for groups b and c , respectively, compared with group a ; P < 0.001). The drug-induced reduction in tumor 18 FFLT uptake was significantly more pronounced than that of 18 FFDG. The PET image data confirmed lower tumor 18 FFLT retention in group c compared with group a , despite a trend toward higher radiotracer delivery for group c . Other than phosphorylation in tumors, 18 FFLT was found to be metabolically stable in vivo . The decrease in tumor 18 FFLT uptake correlated with the PCNA-labeling index ( r = 0.71, P = 0.031) and tumor volume changes after 5-FU treatment ( r = 0.58, P = 0.001). In this model system, the decrease in 18 FFLT uptake could be explained by changes in catalytic activity but not translation of TK1 protein. Compared with group a , TK1 levels were lower in group b (78.2 ± 5.2%) but higher in group c (141.3 ± 9.1%, P < 0.001). In contrast, a stepwise decrease in ATP levels was observed from group a to b to c ( P < 0.001). In conclusion, we have demonstrated the ability to measure tumor response to antiproliferative treatment with 18 FFLT and PET. In our model system, the radiotracer uptake was correlated with PCNA-labeling index. The decrease in 18 FFLT uptake after 5-FU was more pronounced than that of 18 FFDG. 18 FFLT is, therefore, a promising marker for monitoring antiproliferative drug activity in oncology that warrants additional testing.

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Publisher
American Association of Cancer Research
Copyright
Copyright © 2003 by the American Association for Cancer Research.
ISSN
0008-5472
Publisher site

Abstract

3'-Deoxy-3'- 18 Ffluorothymidine ( 18 FFLT) has been proposed as a new marker for imaging tumor proliferation by positron emission tomography (PET). The uptake of 18 FFLT is regulated by cytosolic S-phase-specific thymidine kinase 1 (TK1). In this article, we have investigated the use of 18 FFLT to monitor the response of tumors to antiproliferative treatment in vivo . C3H/Hej mice bearing the radiation-induced fibrosarcoma 1 tumor were treated with 5-fluorouracil (5-FU; 165 mg/kg i.p.). Changes in tumor volume and biodistribution of 18 FFLT and 2- 18 Ffluoro-2-deoxy- D -glucose ( 18 FFDG) were measured in three groups of mice ( n = 8–12/group): ( a ) untreated controls; ( b ) 24 h after 5-FU; and ( c ) 48 h after 5-FU. In addition, dynamic 18 FFLT-PET imaging was performed on a small animal scanner for 60 min. The metabolism of 18 FFLT in tumor, plasma, liver, and urine was determined chromatographically. Proliferation was determined by staining histological sections for proliferating cell nuclear antigen (PCNA). Tumor levels of TK1 protein and cofactor (ATP) were determined by Western blotting and bioluminescence, respectively. Tumor 18 FFLT uptake decreased after 5-FU treatment (47.8 ± 7.0 and 27.1 ± 3.7% for groups b and c , respectively, compared with group a ; P < 0.001). The drug-induced reduction in tumor 18 FFLT uptake was significantly more pronounced than that of 18 FFDG. The PET image data confirmed lower tumor 18 FFLT retention in group c compared with group a , despite a trend toward higher radiotracer delivery for group c . Other than phosphorylation in tumors, 18 FFLT was found to be metabolically stable in vivo . The decrease in tumor 18 FFLT uptake correlated with the PCNA-labeling index ( r = 0.71, P = 0.031) and tumor volume changes after 5-FU treatment ( r = 0.58, P = 0.001). In this model system, the decrease in 18 FFLT uptake could be explained by changes in catalytic activity but not translation of TK1 protein. Compared with group a , TK1 levels were lower in group b (78.2 ± 5.2%) but higher in group c (141.3 ± 9.1%, P < 0.001). In contrast, a stepwise decrease in ATP levels was observed from group a to b to c ( P < 0.001). In conclusion, we have demonstrated the ability to measure tumor response to antiproliferative treatment with 18 FFLT and PET. In our model system, the radiotracer uptake was correlated with PCNA-labeling index. The decrease in 18 FFLT uptake after 5-FU was more pronounced than that of 18 FFDG. 18 FFLT is, therefore, a promising marker for monitoring antiproliferative drug activity in oncology that warrants additional testing.

Journal

Cancer ResearchAmerican Association of Cancer Research

Published: Jul 1, 2003

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