estramustine and Astrocytoma

Experimental and early clinical investigations have demonstrated encouraging results for estramustine in the treatment of malignant glioma. The present study is an open randomized clinical trial comparing estramustine phosphate (Estracyt) in addition to radiotherapy with radiotherapy alone as first line treatment of astrocytoma grade III and IV. The 140 patients included were in a good clinical condition with a median age of 55 years (range 22-87). Estramustine was given orally, 280 mg twice daily, as soon as the diagnosis was established, during and after the radiotherapy for a period of in total 3 months. Radiotherapy was delivered on weekdays 2 Gy daily up to 56 Gy. Eighteen patients were excluded due to misclassification, leaving 122 patients eligible for evaluation. Overall the treatment was well tolerated. Mild or moderate nausea was the most common side effect of estramustine. The minimum follow-up time was 5.2 years for the surviving patients. For astrocytoma grade III the median survival time was 10.6 (1.3-92.7) months for the radiotherapy only group and 17.3 (0.4-96.9+) months for the estramustine + radiotherapy group. In grade IV the corresponding median survival time was 12.3 (2.1-89.2) and 10.3 (0.3-91.7+) months, respectively. Median time to progress for radiotherapy only and radiotherapy and estramustin group in grade III tumours was 6.5 and 10.1 months, respectively. In grade IV tumours the corresponding figures were 5.1 and 3.3 months, respectively. Although there was a tendency for improved survival in grade III, no statistical significant differences were found between the treatment groups. No differences between the two treatment groups were evident with respect to quality of life according to the EORTC QLQ-protocol. In conclusion, this first randomized study did not demonstrate any significant improvement of using estramustine in addition to conventional radiotherapy, however, a trend for a positive response for the estramustine group was found in patients with grade III glioma.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents, Alkylating; Astrocytoma; Brain Neoplasms; Combined Modality Therapy; Estramustine; Female; Humans; Male; Middle Aged; Quality of Life; Radiotherapy Dosage; Severity of Illness Index; Survival Analysis; Treatment Outcome

Estramustine-binding protein (EMBP) is a M(r) 46,000 heterodimeric protein originally isolated from prostatic tissue. It has a demonstrated high affinity for, and selective binding of, estramustine, which is a derivative of 17 beta-estradiol and nornitrogen mustard with antimitotic activity. In this study, we have analysed the expression of an EMBP-like protein in astrocytoma specimens. Immunohistochemistry revealed a pronounced reactivity for EMBP in astrocytoma grades III-IV as well as in metastatic prostatic adenocarcinoma used as positive control. In astrocytoma grades I-II, the expression was weak. The EMBP-like protein was quantified by radioimmunoassay in astrocytoma tumor tissue with higher concentrations in malignant astrocytoma, grades III-IV, compared to grades I-II tumors. Western immunoblotting of immunoaffinity purified EMBP-like protein under nonreducing conditions revealed an immunoreactivity corresponding to M(r) 138,000 and 200,000, indicating a different structure of EMBP in astrocytoma compared to prostatic tissue. Specific binding and the presence of saturable binding sites for 3H-labeled estramustine were demonstrated in astrocytoma tissues expressing EMBP-like protein. Scatchard plot analysis showed a Kd at approximately 30 nM, which suggests a binding affinity for estramustine in the same range as previously reported for EMBP in the prostate. Moreover, the number of estramustine binding sites/g tumor as calculated from the Scatchard plots was well correlated with the EMBP levels determined in the radioimmunoassay. In conclusion, an EMBP-like protein is expressed in astrocytoma. This protein may be responsible for the specific binding of estramustine in the tumor tissue. Whether this specific binding of estramustine is of importance for the cytotoxic effect in glioma cells remains to be evaluated.

Topics: Astrocytoma; Blotting, Western; Brain Neoplasms; Carrier Proteins; Estramustine; Glioblastoma; Humans; Immunohistochemistry; Prostatic Secretory Proteins; Radioimmunoassay

Estraumustine phosphate (EMP), a cytotoxic drug used in the treatment of prostatic carcinoma, has been shown to exert cytotoxic effects on glioma cells in vitro. The drug uptake is assumed to depend on a specific estramustine binding protein (EMBP). One of the main difficulties in achieving cytotoxic effect in malignant brain tumours is believed to be due to the poor penetration of cytotoxic drugs into tumour tissue. In patients with malignant supratentorial brain tumours we have analysed the uptake of EMP metabolites in tumour tissue after oral administration and demonstrated EMBP in the same tissue specimens. Sixteen patients were given 280 mg EMP orally 14 h prior to surgery. Specimens from brain tumour tissue, cystic fluid, and serum were collected during surgery. Using gas chromatography the metabolites of EMP, estramustine (EaM) and estromustine (EoM), were quantified, EMBP was demonstrated by immunohistochemistry. The mean concentrations of EaM and EoM, expressed in ng g-1, were 60.3 and 38.4 in tumour tissue and 3.5 and 56.3 in serum, respectively. An accumulation of EaM in tumour tissue was found with a mean concentration gradient of 16.1 versus serum, while the gradient for EoM was 0.76. EMBP was demonstrated with a high degree of staining in all but one tumour. The high concentrations of EaM and EoM found in malignant brain tumour tissue correspond to potentially cytotoxic levels. The present results as well as the earlier in vitro demonstrated cytotoxic effects on glioma cells strengthen the possibility of a therapeutic effect of EMP in the treatment of malignant brain tumours.

Topics: Adult; Aged; Astrocytoma; Brain Neoplasms; Carrier Proteins; Ependymoma; Estramustine; Estrone; Female; Glioma; Humans; Immunohistochemistry; Male; Middle Aged; Nitrogen Mustard Compounds; Prostatic Secretory Proteins

Estramustine, an estradiol-17 beta and nornitrogen mustard complex, is used in the treatment of advanced prostatic carcinoma. A specific estramustine binding protein (EMBP) is important for its cytotoxic action, and the presence of EMBP has previously been demonstrated in rat and human prostatic cancer tissue. Significant levels of EMBP were detected by radioimmunoassay in human brain-tumor tissue. The EMBP concentrations (expressed as ng/mg protein) in 16 astrocytomas (mean 2.6 ng/mg, range 0.5 to 6.2 ng/mg) and seven meningiomas (mean 5.1 ng/mg, range 0.3 to 9.3 ng/mg) were significantly higher than that found in four samples of epileptic brain (mean 0.7 ng/mg, range 0.5 to 1 ng/mg) and 18 samples of normal brain (mean 0.5 ng/mg, range 0.2 to 1.0 ng/mg). The uptake, metabolism, and antiproliferative effects of the prostatic anticancer agent estramustine have been previously demonstrated in cultured glioma cells. The presence of EMBP may suggest a selective binding and effectiveness in human brain-tumor tissue.

Topics: Astrocytoma; Brain; Brain Neoplasms; Carrier Proteins; Epilepsy; Estramustine; Female; Glioma; Humans; Male; Meningeal Neoplasms; Meningioma; Prostatic Hyperplasia; Prostatic Secretory Proteins; Radioimmunoassay; Reference Values