A. Marocchi

RENAL CANCER STEROID RECEPTORS: BIOCHEMICAL BASIS FOR ENDOCRINE THERAPY

Estradiol receptor (ER) and progesterone receptor (PR), found in experimental renal cancer as well as in normal human kidney and in human renal cell carcinoma (RCC), have been measured in 27 RCCs from patients submitted to surgery and endocrine therapy in an attempt to predict the response to progestational therapy. Of these 27 tumors 59% were positive for ER and 59% for PR; 37% were positive and 19% negative for both ER and PR. The follow-up of 23 patients showed that progestational therapy, started in 18 patients, has given favorable results in 14 patients and negative results in 3 patients with ER-PR- renal cancer. Antiestrogenic therapy, started soon after nephrectomy in 1 patient with ER+PR- renal cancer and lung metastases, failed since the patient died 8 months after surgery.

Human kidney steroid receptors

Abstract Saturation analyses, binding kinetics and agar gel electrophoresis performed on normal human kidney tissue revealed the presence of a specific progesterone receptor in all the specimens studied and in one, a specific estradiol receptor was observed, Progesterone binding had a rapid association and a slow dissociation reaction. The binding capacity for estradiol and progesterone was not significantly different, whereas the binding affinity for progesterone was lower than that for estradiol. These results on progesterone receptors in the cytosol of normal human kidney tissue offer an interesting field of investigation considering the estrogen-induced renal adenocarcinoma in animals and the possibility of progestational therapy for tumour regression in humans.

Progestational therapy in human renal carcinoma and steroid receptors

Abstract Normal human kidney and human renal adenocarcinoma have been studied for progesterone and estradiol receptors by means of agar gel electrophoresis technique. Progesterone receptor was found in the eytosol fraction of all the normal kidneys and of the adenocarcinoma studied, while estradiol cytosol receptor was found only in some of the tissues examined. No correlation between the degree of the differentiation of the tumours and the progesterone binding capacity has been detected. Furthermore the binding affinity for estradiol was greater than that for progesterone. The low affinity of progesterone receptor could explain the large mass (pharmacological doses) of progesterone needed to obtain a marked tumour regression as well as a favorable effect on the clinical course of the advanced renal cancer. Like human breast cancer, responsive to endocrine ablation when both estradiol and progesterone receptors are present, it could be hypothesized that progestational therapy may be useful in the treatment of renal adenocarcinoma in which both estradiol and progesterone receptors are present.

Nuclear androgen receptor as marker of responsiveness to medroxyprogesterone acetate in human renal cell carcinoma

Abstract The presence of steroid receptors in human renal cell carcinoma (RCC) has been reported by many authors. However some controversy exists regarding the response of human RCC to medroxyprogesterone acetate (MPA). The hypothesis that the MPA effect on tumor growth might be due to the androgenic action of the progestin was suggested since 1976. Based on the recent report that in mouse kidney the androgenic action of progestins correlates with nuclear uptake but not with cytosol androgen receptor (AR c ), 24 human RCC were studied for the presence of AR c and 14 for the presence of AR c and nuclear androgen receptor (AR n ) in order to establish a parameter more suitable to define the tumor responsiveness to MPA. Tritiated methyltrienolone (R1881) plus cold triamcinolone acetonide and R1881 was employed with the dextran-coated charcoal method. AR c was detected in 19 out of 38 (50%) and AR n in 8 out of 14 (57%) of the tumors examined. Therefore androgen receptors not only help to define, with estrogen and progesterone receptors, the hormone-dependent human RCC, but may also be useful in the selection of patients to be treated with MPA. In fact, the androgenic activity of MPA could counteract the promoting action of estrogens on tumor growth only in the patients with AR n positive tumor.

Steroid receptors in CNS: estradiol(ER) and progesterone(PR) receptors in human spinal cord tumors.

To investigate the role of steroid hormones in the occurrence and growth of human spinal cord tumors and to study the biochemical basis of the sex related difference in the incidence of the various spinal oncotypes, ER and PR have been measured in 24 human spinal cord tumors (12 neurinomas, 6 meningiomas, 5 ependymomas and 1 astrocytoma) by means of sodium thiocyanate exchange assay at low temperature and with dextran-coated charcoal method and R5020 for PR. Cytoplasmic and nuclear receptors have been evaluated. Neurinomas are the oncotypes which contained both ER (usually in the nuclear fraction) adn PR: estradiol binding has been found only in one meningioma; ependymomas contained cytoplasmic ER and the astrocytoma had nuclear ER and cytoplasmic PR. The dissociation constant is in favour of a high affinity binding (Kd = 0.15 X 10(-9)M for ERc; Kd = 3.85 X 10(-9)M for ERn; Kd = 8.07 X 10(-9)M for PRc). The overall incidence of steroid receptors in the spinal oncotypes studied is higher in male than in female patients (63.64 vs 46.15% for ER and 100 vs 71.43% for PR). Further studies on a greater number of patients will help to define the correlation between different spinal oncotypes and steroid receptors as well as the possibility of an endocrine therapy as adjuvant treatment for selected patients.

Specific progesterone receptor in human renal cancer.

Abstract It was possible, using a synthetic progestin R5020, to identify a specific progesterone cytosol receptor in six human renal adenocarcinoma. The receptor has a low capacity but a high affinity, with a dissociation constant ranging between 0.13 and 3.72 × 10 −9 M. Comparison between the results of quantitative experiments obtained with d -Norgestrel and R5020 is reported.

A simple procedure for the combined determination of plasma estrogen and androgen concentrations by competitive protein binding analysis

Abstract A simple method for the measurement of estradiol-17β, estrone, testosterone and androstenedione in 4–6 ml of human male and female plasma is described. By ether extraction of alkalinized plasma followed by a single celite column Chromatographic step or by two column Chromatographic steps on Sephadex LH 20, purified extracts are obtained for competitive protein binding radioassay. Cytosol from six-day pregnant rabbit uteri (according to Korenman) was used for estrogen assays, and human plasma from the third trimester of pregnancy (according to Sciarra) was used for androgen assays. The plasma values of testosterone and androstenedione were comparable with those obtained after t.l.c. and competitive protein binding. The specificity and sensitivity of the method enabled determinations of plasma estrogen to be made not only in normal adults, but also in hypogonadal patients where estradiol-17β values are at very low levels. The accuracy of these determinations was confirmed by repeated measurements of blanks which range from 0 to 5 pg/ml, and by recovery experiments of known amounts of added estradiol-17β.