Estramustine binding protein (EMBP) in rat R3327 Dunning tumors: partial characterization and effect of hormonal withdrawal, hormonal replacement, and cytotoxic treatment on its expression.
Expression of estramustine-binding protein (EMBP) was determined in eight variants of the Dunning R3327 rat prostate adenocarcinoma. This secretory protein was previously isolated from the normal rat prostate and binds estramustine and estromustine, the metabolites exerting anti-mitotic and anti-proliferative activity of the anticancer agent estramustine phosphate (EstracytR). EMBP was found in relatively high amounts only in the androgen-responsive G and H tumors from intact hosts, whereas low (AT-1, HI-F) or nondetectable levels (HI-S, AT-3, MAT-LyLu, MAT-Lu) were obtained in the androgen-independent tumors. Castration decreased EMBP expression in both G and H tumors, as did estradiol and estramustine when given separately to intact rats. Supplementation of castrates with exogenous androgen stimulated EMBP expression above the pre-castration level and was further enhanced when combined with estradiol and in particular estramustine. Partial physicochemical characterization of EMBP in G and H tumors was performed by using ligand-based and immunoblotting techniques. [3H]Estromustine was bound to cytosols and salt extracts from tumors with the same affinity and displayed similar surface-charge distribution, sedimentation behavior, and subunit composition as found for ventral and dorsolateral prostatic tissue from tumor-bearing rats. This study indicates that the synthesis of EMBP is under androgenic control and that its expression may be correlated to androgen responsiveness, metastatic potential, and androgen receptor content but not to growth rate and morphology of the tumors. EMBP may therefore provide a mechanism for concentration of cytotoxic activity at the target site in EMBP-positive tumors and help in the evaluation of antitumor effects obtained when administering estramustine.
Björk
P
P
Department of Cancer Immunology, Research Labs., Pharmacia LEO Therapeutics AB, Helsingborg, Sweden.
Isaacs
J T
JT
Hartley-Asp
B
B
D000230:Adenocarcinoma / Q000737:chemistry*; D000818:Animals; D002352:Carrier Proteins / Q000032:analysis*; D004958:Estradiol / Q000494:pharmacology; D004961:Estramustine / Q000378:metabolism* / Q000494:pharmacology; D012739:Gonadal Steroid Hormones / Q000494:pharmacology / Q000502:physiology*; D015151:Immunoblotting; D008297:Male; D009376:Neoplasms, Hormone-Dependent / Q000737:chemistry; D009919:Orchiectomy; D011471:Prostatic Neoplasms / Q000737:chemistry*; D029584:Prostatic Secretory Proteins; D051381:Rats; D014407:Tumor Cells, Cultured
D002352:Carrier Proteins; D012739:Gonadal Steroid Hormones; D029584:Prostatic Secretory Proteins; C028321:estramustine-binding protein; D004961:Estramustine; D004958:Estradiol