Phase I trial on sms-D70 somatostatin analogue in advanced prostate and renal cell cancer.

Plasma concentrations and tolerability of a novel somatostatin analogue sms-D70 were studied in patients with metastatic hormone-resistant prostate cancer (HRPC) or metastatic renal cell cancer. To overcome the limitations of the octapeptides having affinity only to somatostatin receptor subtypes 2 and 5, HRPC expressing mainly somatostatin receptors 1 and 4, a somatostatin derivative based on the natural somatostatin having affinity to all five somatostatin receptor subtypes, was developed. The in vivo stability of this dextran-conjugated derivative, somatostatin-D70, was confirmed previously in animal studies, and the nanomolar "panaffinity" has been shown in in vitro receptor binding studies on cell lines transfected with the somatostatin receptor genes. Sms-D70 was given with subcutaneous injection once a week at dose levels of 5, 10, 20, 35, and 50 mg. For pharmacokinetic studies, sms-D70 was labeled with 131I. Fourteen patients were treated, of whom 10 had prostate and 4 renal cell cancer. The kinetic data revealed high stability with a long half-life in the blood. The drug was well tolerated, and no grade 4 (WHO) toxicity was observed. The maximal tolerated dose could not be established due to the lack of dose-limiting toxicities. Objective PSA responses were not recorded in these heavily treated patients, but subjective stabilization of pain was observed and urinary symptoms were alleviated in four patients. Three patients with metastatic HRPC received 5-10-mg intravenous injections of sms-D70 once weekly for 4-14 months on a compassionate use basis. In all cases, serum PSA values decreased more than 50% from the pretreatment level, but these results are difficult to interpret due to concomitant treatments given to these patients. In conclusion, sms-D70 was well tolerated in the treatment of metastatic prostate and renal cell cancer, but no responses were found in these heavily treated patients.

Primary radiation therapy in the treatment of localized prostatic cancer.

Prostatic carcinoma is one of the leading causes of male cancer deaths. However, the routine diagnostic and therapeutic strategies have not yet been established. Although the outcome of surgical and radiotherapeutical approaches has frequently been reported to be comparable, the profile of side effects is different. This could offer the basis for selecting the treatment of choice in individual cases. During the last decade the radiotherapeutical technique has markedly improved, in part due to the achievements in the field of computer assisted tomography planning and conformal technique; the outcome of side-effects has decreased with concurrent increase in the rate of local control. The prescribing, recording and reporting of irradiation have also recently developed, as well as the staging of the disease. Therefore we consider it timely to review progress in this subject and to emphasize the role of radiotherapy in the treatment of localized prostatic cancer.

Induction of avidin messenger ribonucleic acid in the chick oviduct by progesterone and other steroids.

Avidin gene expression was analyzed using an avidin immunoassay and RNA hybridization analysis. To ascertain whether the induction of the avidin gene by progesterone remains specific also during secondary restimulation with diethylstilbestrol, chicks were given different steroid hormones or hormone combinations. Progesterone-specific induction of avidin protein and messenger RNA (mRNA) was 15- to 30-fold over the control even after secondary restimulation with diethylstilbestrol. A functional difference between the progesterone response element and glucocorticoid response element was suggested, since dexamethasone alone did not induce avidin in vivo. In spite of progesterone specificity, a combination of progesterone with other steroids nevertheless generated a synergistic increase in the amount of avidin mRNA. This may indicate that binding of progesterone receptor to the progesterone response element may be important to alter the functional activity of other hormone response elements present on the avidin gene. The time response curve of the avidin mRNA induction by progesterone was also determined. Avidin mRNA was detectable 8 h after progesterone induction, and its amount was maximal after 16-24 h. This would indicate that the avidin gene belongs in the so-called late responder genes, which also include chicken ovalbumin, ovomucoid, and lysozyme genes.

The effect of dihydrotestosterone on the estrogen-induced cytodifferentiation of the chick oviduct.

The androgenic effects on the estrogen-induced cytodifferentiation of the chick oviduct epithelium were investigated. Dihydrotestosterone was shown to have an effect on the organization of stromal cells. Since these cells contained androgen receptor (AR), it is reasonable to assume an involvement of androgens in the differentiation and functioning of these cells through a direct action. Immunohistochemical analysis revealed a wide distribution of AR. AR was shown to be expressed in both the endothelial and smooth muscle cells of blood vessels. In the immature oviduct AR was located in the epithelial, mesenchymal and mesothelial cells. In the differentiating oviduct, whether induced by exogenous estrogen or normally by endogenous hormones, AR was also expressed by the tubular gland cells. Dihydrotestosterone alone had no effect on the morphology of the immature oviduct, suggesting the involvement of the determinants of differentiation in the action of androgen together with estrogen.

Chick oviduct differentiation. The effect of estrogen and progesterone on the expression of progesterone receptor.

Progesterone receptor (PR) is a marker of estrogen action. Its cellular appearance during estrogen (20 mg/kg i.m.)-induced differentiation of the immature chick oviduct was therefore studied by immunohistochemistry. PR was located in the epithelial, mesothelial, submucosal stromal and smooth muscle cells. Progesterone (20 mg/kg i.m.) caused an obvious decrease in PR immunoreactivity without inducing synthesis of progesterone-dependent avidin. Thus mere receptor occupation by ligand is not sufficient for this induction. This paper reports that the expression of PR in the mucosal stromal cell differs from that in other cell types. In the mucosal stromal cell PR was inducible, i.e., not shown without the action of estrogen. The formation of tubular glands did not commence before mucosal stromal cells expressed PR. It would seem that the mucosal stromal cells have a crucial role in mediating epithelial differentiation. The onset of differentiation was preceded by vascularization and invasion of mononuclear cells in the submucosa. It was conspicuous that the smooth muscle cells of arteries also contained PR.

Progesterone-induced avidin as a marker of cytodifferentiation in the oviduct: comparison to ovalbumin.

Immunohistochemical analysis of avidin and ovalbumin expression in the normally developing chick oviduct was compared to those changes induced by exogenous estrogen. Oviduct maturation was found to occur in two consecutive phases: slow proliferation and rapid differentiation. Mitosis was induced in the epithelium by estrogen, whereas it was inhibited by progesterone. Endogenous progesterone may retard the proliferation and prevent the differentiation, an effect that is overridden by increased estrogen concentration at the beginning of differentiation. Short secondary stimulation was shown to closely mimic normal maturation. When chicks treated with diethylstilbestrol (DES) for 1 month were allowed to mature, there were marked alterations in oviduct histology and laying behavior. The tubular glands were found to form from the surface epithelium as budlike invaginations, and these cells also contained avidin and ovalbumin. Ovalbumin production was stable in tubular glands. In contrast, the intensity of avidin staining was variable between gland cells even in the same sections. It was conspicuous that the number of avidin-expressing gland cells diminished markedly when estrogen treatment was prolonged over 1 week. After 2-week stimulation with DES, avidin was expressed predominantly by cells of the basal layer of pseudostratified surface epithelium, and ovalbumin mainly by tubular glands and cells of the luminal layer of surface epithelium. Neither of these proteins was expressed by goblet cells. Expression of progesterone receptor, characterized by two antibodies (polyclonal IgG-RB and monoclonal PR6), did not explain the heterogeneity of expression of avidin and ovalbumin, but probably reflects various differentiation stages of epithelial cells.

Ontogeny of the estrogen receptor in the chick oviduct.

The distribution of estrogen receptor (ER) in the chick oviduct was studied immunohistochemically with monoclonal antibody H222, known to recognize chick ER [1]. The ontogeny of ER appeared to be very dependent on cellular differentiation. In the undifferentiated oviduct ER was located in the epithelial, mesothelial, stromal and smooth muscle cells. During differentiation ER disappeared from the surface epithelium, mesothelium, stromal and smooth muscle cells. At the onset of differentiation the protodifferentiated gland cells invaginated into the underlying stroma; these cells expressed ER. In the fully differentiated chick oviduct ER was located only in the tubular gland cells, which correlates with the known transcriptional activity of estrogen-induced ovalbumin-gene. However, we have reported estrogen dependency of PR also in ER-negative stromal cells, the mechanism being so far unknown. It is possible that there are mechanisms other than ER regulating the expression of PR. Estrogen-induced differentiation did not differ from normal maturation in regard to the distribution of ER. Since stromal, epithelial, mesothelial and smooth muscle cells were ER-negative in the mature oviduct, the concentration of ER, i.e. ER binding sites/cell is underestimated when whole tissue homogenates are used.