estramustine and Pancreatic-Neoplasms

Topics: Adenocarcinoma; Androgens; Animals; Carrier Proteins; Estramustine; Estrogens; Female; Humans; Islets of Langerhans; Male; Pancreas; Pancreatic Neoplasms; Prostatic Secretory Proteins; Rats; Receptors, Estrogen

Topics: Androgens; Animals; Clinical Trials as Topic; Estramustine; Female; Humans; Islets of Langerhans; Mice; Molecular Weight; Pancreatic Neoplasms; Rats; Receptors, Estradiol; Receptors, Estrogen; Tamoxifen

The tissue distribution of estramustine and estromustine, two cytotoxic lipophilic metabolites of estramustine phosphate (Estracyt, EMP) was studied in rats and humans. A single dose of [3H]-estramustine was given i.v. to groups of rats. At 24 h after administration, the concentration of radioactivity in fat was about 20, 12, and 2 times that in muscle, plasma, and liver, respectively. Liquid chromatography verified that the radioactivity represented estramustine and estromustine. The clinical relevance of these results was investigated in pancreas cancer patients treated with a single oral dose of Estracyt at 12-16 h before surgery. As judged by gas chromatography, the concentration of estromustine, which is the main metabolite in man, was about 13 times higher in fat than in plasma and was also higher in adipose tissue than in muscle and liver. After 5 days of Estracyt treatment, the adipose uptake of estromustine was even higher, namely, about 40 times that in plasma and 8 times that in muscle and liver. Thus, our results demonstrate that estramustine and estromustine are stored in adipose tissue after the administration of EMP; this is important for the pharmacokinetics and, consequently for the therapeutic effects of Estracyt.

Topics: Adipose Tissue; Aged; Animals; Estramustine; Estrone; Female; Germ-Free Life; Humans; Liver; Male; Middle Aged; Muscles; Nitrogen Mustard Compounds; Pancreatic Neoplasms; Plasma; Preoperative Care; Rats; Rats, Inbred Strains; Time Factors

The interaction of estramustine and estromustine, cytotoxic metabolites of estramustine phosphate (Estracyt), with protein-binding sites in rat pancreatic tissue was examined. These compounds were bound with relatively high affinity (Kd 10 nmol/L) to binding sites constituting 0.02-0.03% of total protein. Further characterization of these binding sites revealed a native molecular weight of 24-30,000 a sedimentation coefficient of 3.4 S, and a heterogenous surface-charge distribution by ion-exchange chromatography. Removal of endogenously bound ligand(s) by acetone precipitation or charcoal treatment increased binding significantly. Similar binding sites were present in two of two human pancreatic tumors, but was low or absent in the only histopathologically normal pancreas examined as well as in serum and pancreatic juice. These binding sites were distinct from the "estrogen-binding protein" reported in normal pancreas from various species, but were similar to the "estramustine-binding protein" (EMBP) in rat ventral prostate with respect to ligand specificity and the positive effect of endogenous ligand removal on binding. Furthermore, specimens demonstrating presence of these binding sites also indicated cross-reactivity with antibodies raised against the latter protein, suggesting an immunochemical relation between estra-/estromustine-binding sites in the pancreas and rat prostate EMBP. The presence of high-affinity sites for estramustine and estromustine in human pancreatic carcinomas make this type of tumor a possible target tissue for compounds that exert antiproliferative as well as antimitotic activity in vitro.

Topics: Aged; Animals; Binding Sites; Binding, Competitive; Carrier Proteins; Chemical Phenomena; Chemistry, Physical; Estradiol; Estramustine; Estrone; Female; Humans; Male; Middle Aged; Molecular Weight; Nitrogen Mustard Compounds; Pancreas; Pancreatic Neoplasms; Rats; Rats, Inbred Strains; Receptors, Estrogen