Monitoring of therapy in androgen-dependent prostate tumor model by measuring tumor proliferation.
3'-Deoxy-3'-(18)F-fluorothymidine ((18)F-FLT) has been recently described as a radiopharmaceutical for measuring cellular proliferation using PET imaging. Evaluation of tumor proliferative activity by PET using (18)F-FLT could be a procedure to assess the viability of tumor, such as histologic grade, clinical stage, and prognosis as well as the early effects of cancer therapy. This study was undertaken to determine whether (18)F-FLT is useful in the detection of prostate cancer as well as monitoring therapeutic effects in a human tumor model.


METHODS
The androgen-dependent human prostate tumor, CWR22, was implanted into athymic mice. This well-established model of prostate cancer was used in all studies. To determine the optimal imaging times for (18)F-FLT, a biodistribution was performed in CWR22 mice. (18)F-FLT (740 kBq [20 micro Ci]) was administered via the tail vein and uptake was determined in selected tissues at 5 min, 20 min, and 1, 2, and 4 h after injection (n = 5, each time point). Androgen ablation studies were conducted in the CWR22 model with either diethylstilbestrol (DES) or surgical castration. Animals received DES every 2 d for 3 wk. The effectiveness of therapy was monitored using (18)F-FLT microPET as baseline, during treatment, and after treatment. Tracer accumulation in the tumor was then analyzed by comparing tumor-to-muscle ratios derived from reconstructed microPET data.


RESULTS
At 2 h after injection, the (18)F-FLT uptake in tumor was 0.69 +/- 0.14 percentage injected dose per gram of tissue, showing the highest activity of all organs measured. The microPET study with dynamic imaging showed that (18)F-FLT uptake in blood reached its plateau within 1 min and was rapidly cleared, whereas (18)F-FLT uptake in tumor reached its plateau in 30 min and remained up to 60 min. microPET using (18)F-FLT successfully imaged the implanted CWR22 tumor in the mice at both 1 and 2 h after injection. There was a marked reduction of (18)F-FLT uptake in tumor after castration or DES treatment; however, there were no differences in (18)F-FLT uptake in the tumor in the control group. These changes of (18)F-FLT uptake in tumor parallel the changes of actual tumor measurement.


CONCLUSIONS
These results indicate that (18)F-FLT is a useful tracer for detection of prostate cancer in an animal model. (18)F-FLT has the potential for monitoring the therapeutic effect of androgen ablation therapy in prostate cancer.
Mallinckrodt Institute of Radiology, Washington University School of Medicine, Saint Louis, Missouri 63110, USA.
Nobuyuki
N
Oyama
Datta E
DE
Ponde
Carmen
C
Dence
Joonyoung
J
Kim
Yuan-Chuan
YC
Tai
Michael J
MJ
Welch
D000728:Androgens / Q000378:metabolism; D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use; D045744:Cell Line, Tumor; D015224:Dideoxynucleosides; D004054:Diethylstilbestrol / Q000627:therapeutic use*; D008297:Male; D008657:Metabolic Clearance Rate; D051379:Mice; D008819:Mice, Nude; D009367:Neoplasm Staging / Q000379:methods; D009919:Orchiectomy; D011379:Prognosis; D011471:Prostatic Neoplasms / Q000000981:diagnostic imaging* / Q000378:metabolism / Q000628:therapy*; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D014018:Tissue Distribution; D014055:Tomography, Emission-Computed / Q000379:methods; D016896:Treatment Outcome
D000728:Androgens; D018931:Antineoplastic Agents, Hormonal; D015224:Dideoxynucleosides; D019275:Radiopharmaceuticals; D004054:Diethylstilbestrol; C002854:alovudine