FUNDAMENTAL STUDY OF ENDOCRINE THERAPY FOR RENAL CELL CARCINOMA

PROGESTERONE AND ANDROGEN RECEPTORS IN NORMAL KIDNEYS AND RENAL CELL CARCINOMAS

Abstract

Recent advances in tumor biology of renal cancer, obtained in estrogen dependent tumor of hamster, leads to a clinical utilization of progesterone and testosterone as adjunct therapy for human renal cancer, and now it is generally recognized that some patients respond to endocrine therapy to a certain degree objectively or subjectively.
At present, however, there is no knowledge about what kind of patient should be selected for this therapy or which of the steroids is indicated. To answer these questions, direct measurement of progesterone receptor (PR) and androgen receptor (AR) was carried out in the cytosol of 8 normal renal tissues and 25 renal cell carcinoma tissues.
PR and AR were detected mainly by dextran coated charcoal (DCC) method, utilizing synthetic progesterone and androgen, R5020 and R 1881 respectively.
Specific binding molecules to R5020 detected by DCC assay were determined 7-8s sedimentation constants with sucrose density gradient centrifugation. And the ability to this binding was not inhibited by cortisol competitively. For these reasons, it was confirmed that the specific binding protein was not a corticosteroid binding globulin (CBG) but PR itself.
Specific binding protein to R 1881 detected by DCC was 8-9s molecules with sucrose density gradient. This binding was not inhibited by estradiol, therefore, the contamination of serum sex hormone binding globulin (SHBG) was avoided. But it was slightly inhibited by progesterone and R5020 competitively. Therefore, it was thought that AR was detected with non-negligible contamination of PR.
The results obtained were as follows:
1) PR was detected in all 8 normal kidneys. PR contents were lower in those below 50 years of age than in those over 50.
Out of 25 renal cell carcinoma tissues, PR was detected in 7 cases (28.0%). There was no correlation between the presence of PR and age, sex, cell type or malignancy.
2) AR was detected in 5 out of 8 normal kidneys. Since AR-negative 3 kidneys were normal portion obtained by nephrectomy due to renal cancer, it was speculated that some unknown endocrinological change had already processed in normal portion of tumor bearing kidneys.
Out of 25 renal cell carcinomas, AR was detected in 11 cases (44.0%), and no obvious correlation was found between the level of AR and the histological character of the tumor.
3) In 6 cases, comparative study of concentration of these receptors in cancerous tissue against their normal counterpart was performed and it was revealed that in 4 cases, AR concentration was higher than that in normal controls, but lower or almost equal in other 2 cases. On the other hand, PR was surely detected in all 6 normal tissues but not detected or lower in malignant part of these specimens. This finding might show the disappearance of the differentiated biochemical function accompanied by malignant transformation.