Abstract
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.
Highlights
Estraumustine phosphate (EMP) metabolites were measured in tumour specimens, serum, CSF, and cystic fluid, EaM and EoM were analysed using gas chromatography according to a method earlier described (Andersson et al, 1981; Andersson et al, 1982)
The metabolites of EMP, EaM and EoM, were demonstrated in both serum and brain tumours with the technique described
Fourteen of the 16 patients suffered from primary intracerebral tumours
Summary
The patients were given 280mg EMP orally 12-14h before surgery. All patients received routinely 8 mg betamethason intravenously 12 and 2 h before surgery. Specimens of tumour tissue were collected and venous blood samples were taken for analysis of EaM and EoM. Additional tissue samples were taken for histopathological routine examination and immunohistochemical staining for EMBP. EMP metabolites were measured in tumour specimens, serum, CSF, and cystic fluid, EaM and EoM were analysed using gas chromatography according to a method earlier described (Andersson et al, 1981; Andersson et al, 1982). All tumours were processed the same way as above, but without addition of monoclonal antibody in order to serve as negative control. The immunohistochemical staining was evaluated by counting the proportion of cells positively stained for EMBP and semiquantitatively estimating the intensity of staining defined as missing (0), low (1), moderate (2), and high (3)
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