MicroPET assessment of androgenic control of glucose and acetate uptake in the rat prostate and a prostate cancer tumor model

https://doi.org/10.1016/S0969-8051(02)00346-3Get rights and content

Abstract

PET has been used to monitor changes in tumor metabolism in breast cancer following hormonal therapy. This study was undertaken to determine whether PET imaging could evaluate early metabolic changes in prostate tumor following androgen ablation therapy. Studies were performed comparing two positron-emitting tracers, 18F-FDG and 11C-acetate, in Sprague-Dawley male rats to monitor metabolic changes in normal prostate tissue. Additional studies were performed in nude mice bearing the CWR22 androgen-dependent human prostate tumor to evaluate metabolic changes in prostate tumor. In rats, for the androgen ablation pretreatment, 1 mg diethylstilbestrol (DES) was injected subcutaneously 3 and 24 hours before tracer injection. For androgen pretreatment, 500 μg dihydrotestosterone (DHT) was injected intraperitoneally 2 and 6 hours before tracer injection. The rats were divided into three groups, Group A (no-DES, no-DHT, n = 18), Group B (DES, no-DHT, n = 18) and Group C (DES, DHT, n = 18). In each group, 10 animals received 18F-FDG, whereas the remaining eight animals were administered 11C-acetate. Rats were sacrificed at 120 min post-injection of 18F-FDG or 30 min post-injection of 11C-acetate. Pretreatment of the mouse model using DHT (200 μg of DHT in 0.1 mL of sunflower seed oil) or DES (200 μg of DES in 0.1 mL of sunflower seed oil) was conducted every 2 days for one week. Mice were imaged with both tracers in the microPET scanner (Concorde Microsystems Inc.). DES treatment caused a decrease in acetate and glucose metabolism in the rat prostate. Co-treatment with DHT maintained the glucose metabolism levels at baseline values. In the tumor bearing mice, similar effects were seen in 18F-FDG study, while there was no significant difference in 11C-acetate uptake. These results indicate that changes in serum testosterone levels influence 18F-FDG uptake in the prostate gland, which is closely tied to glucose metabolism, within 24 hours of treatment and in the prostate tumor within 1 week. These early metabolic changes could enable monitoring metabolic changes in prostate tumor following treatment by imaging using 18F-FDG PET. Further studies are needed to clarify the reason for the insensitivity of 11C-acetate for measuring metabolic change in prostate tumor.

Introduction

Prostate cancer is the most commonly diagnosed cancer and is the second leading cause of cancer death in men over the age of 40 years in the United States [2]. Most prostate cancers show androgen dependency for growth at presentation [4], hence androgen ablation therapy is a major treatment for patients with advanced disease. However, approximately 50% of those patients receiving androgen ablation therapy relapse within one year, while others respond to therapy for extended periods. This varied response to the therapy indicates that there are large differences in the androgen dependency of prostate cancer patients. To achieve a greater response rate for patients with less androgen dependent cancer, combination therapies with radiotherapy or chemotherapy are often explored. To select these patients, serum prostate specific antigen (PSA) values or prostate volume estimated by computed tomography (CT) or ultrasonography (US) are employed to monitor the effect of androgen ablation therapy. These methods often take 1 to 3 months after the initiation of treatment for the first accurate assessment to be made. A more rapid evaluation method would allow androgen ablation therapy to be used only on patients who will respond to this treatment.

Evaluation of tumor metabolism by positron-emission tomography (PET) is a relatively new procedure for assessing the early effects for cancer therapy and has already been applied to breast cancer [1]. This study showed that the efficacy of tamoxifen therapy could be predicted by measuring the agonist flare response using 2-[18F] fluoro-2-deoxy-D-glucose (18F-FDG) in a short time period (7–10 days). Prostate cancer shows hormone dependency in a manner similar to breast cancer, whereas tumor metabolism of androgen dependent prostate cancer is thought to be influenced by serum testosterone levels. Thus, this study was designed to determine whether PET imaging could detect early changes in tumor metabolism following androgen ablation therapy.

Section snippets

Radiochemical synthesis

18F-fluoride is produced via the 18O(p, n) 18F nuclear reaction by irradiating isotopically enriched 18O-water with 15–16 MeV protons using either the Washington University Cyclotron Corporation CS-15 or the Japan Steel Works (JSW) BC-16/8 medical cyclotron located in the MIR Cyclotron Facility. 18F-FDG was prepared using the Coincidence Technologies 18F-FDG synthesis module. This method of preparation is based on the methods of Hamacher et al. [3]. 11C-carbon dioxide will be produced via the 14

Normal rat prostate study

For in vivo uptake studies, in order to suppress in vivo androgen biosynthesis, rats were treated with 1 mg of DES in 0.2 mL sunflower oil per rat, at 3 hr and 24 hr prior to injection of 18F-FDG and 11C-acetate. Biodistribution at 2 hr was performed with 18F-FDG (Table 1). Biodistribution of 11C-acetate was performed at 30 min (Table 2). The biodistribution results of 18F-FDG indicate that androgen ablation (DES treatment) caused a decrease of 18F-FDG uptake in prostate, with DHT recovering

Discussion

There is a need to find better ways to distinguish between patients with prostate cancers who show poor prognosis from those who show better prognosis. In patients with localized disease receiving prostatectomy, Gleason grade, cancer volume, positive lymph node findings, and intraprostatic vascular invasion were independently associated with cancer progression [12]. Most patients receiving androgen ablation therapy show advanced clinical stage at initiation of therapy. In this patient group, it

Conclusion

These findings confirm that 18F-FDG is a promising tracer to evaluate changes in tumor metabolism, and may be able to predict the androgen dependency of prostate cancer in the early phase of androgen ablation therapy. These results indicate that changes in serum testosterone levels influence glucose metabolism in the prostate cancer within a week of treatment in mice and that it is possible to measure these changes using 18F-FDG-microPET. These encouraging results will likely lead to human

Acknowledgements

This study is supported by a grant from the U. S. Department of Energy (Grant DOE DE-FG02-84ER-60218. The microPET imaging is supported by an NIH/NCI SAIRP grant (1 R24 CA83060). We would also like to thank the Small Animal Imaging Core of the Alvin J. Siteman Cancer Center at Washington University and Barnes-Jewish Hospital in St. Louis, Missouri for additional support of the microPET imaging. The Core is supported by an NCI Cancer Center Support (Grant 1 P30 CA91842). The authors wish to

References (15)

There are more references available in the full text version of this article.

Cited by (52)

  • Radiation dosimetry estimates of [ <sup>18</sup>F]-fluoroacetate based on biodistribution data of rats

    2012, Applied Radiation and Isotopes
    Citation Excerpt :

    The biodistribution of FAC shows that it has rapd uptake rate as that of CAC, while the clearance is slower. This difference in the rate of clearance between FAC and CAC is due to the difference in oxidative metabolism associated with the organ tissue (Oyama et al., 2002b). However the CAC clearance from the pancreas is slower compared with FAC clearance because of the incorporation of CAC into the acid cycle (Shreve and Gross, 1997).

  • Pelvis

    2010, Leibel and Phillips Textbook of Radiation Oncology, Third Edition
  • PET and Radiation Therapy Planning and Delivery for Prostate Cancer

    2009, PET Clinics
    Citation Excerpt :

    For example, filtered-back projection is typically used for image reconstruction, but iterative reconstruction may be preferable for visualization of prostatic activity with FDG-PET.52 Despite these issues, a growing body of evidence suggests that FDG-PET may be helpful in specific clinical scenarios.53–68 In the setting of primary untreated disease, FDG-PET may be used for patients with more aggressive histologic grades (ie, Gleason scores of 8–10) and more locally advanced or metastatic disease.

View all citing articles on Scopus
View full text