Pathophysiologic and Endocrine Aspects
Transcription
Pathophysiologic and Endocrine Aspects
The Journal of International Medical Research 1990; 18 (suppl I): 8 - 10 Pathophysiologic and Endocrine Aspects G. Sica Institute of Histology and General Embryology, Catholic University of s. Cuore, Rome, Italy Androgens regulate development and functional maturation of the prostate. A lack of androgens at puberty impairs normal prostate growth and causes regression and atrophy of the gland in adults. Orchidectomy or indirect androgen suppression by hypophysectomy or administration of oestrogens reduces prostatic weight and secretion. As far as prostatic cancer is concerned, significant improvement occurs in the clinical conditions of patients affected by advanced neoplasia subjected to castration or oestrogen administration. Recently, other endocrine manipulations have been proposed, but the response to these treatments strictly depends on the composition of the neoplastic population. Prostatic cancer consists of cells that are sensitive to or dependent on hormones and others that are hormone-independent. Biological activity of hormones, particularly androgens, is mediated via intracellular receptors, which are not easy to measure in prostatic tissue. Androgen receptor level can be modulated in prostatic cancer cells by natural interferon-f3, opening new perspectives in the therapy of prostatic cancer. Les androgenes assurent Ie develcppement et la regulation de la maturation fonctionnelle de la prostate. Un deficit en androgenes au moment de la puberte affecte Ie developpement normal de la prostate et, it l'age mur, est synonyme de regression et d'atrophie. Une orchidectomie ou une suppression indirecte des androgenes par hypophysectomie ou par administration d'oestrogenes reduit l'acttvite de la prostate; ces therapies ont done ete les traitements de choix du cancer prostatique metastatique, Plus recemment, it a He propose d'autres manipulations endocrines. Le cancer prostatique consiste en cellules qui sont sensibles ou dependantes des androgenes et en d'autres qui sont independantes des androgenes et ainsi plus ditliciles it traiter. Des recepteurs d'androgenes cytosoliques et nucleaires ont ainsi ete etu- Address for correspondence: Professor G. Sica, Instituto Di Istologia, Universita Cattolica, Largo F Vito 1,00168 Rome, Italy. 8 © Copyright 1990 by Cambridge Medical Publications Ltd Downloaded from imr.sagepub.com at SAGE Publications on June 20, 2016 Pathophysiologic and endocrine aspects dies en faisant appel a des Iigandes synthetiques dans Ie cadre d'un dosage d'echange. Le rapport entre les taux de recepteurs et la reponse a la therapie et I'identification des groupes chez qui une reponse a ete obtenue feront I'objet d'un debat, Le niveau des recepteurs peut etre modifie in vitro par I'interferon-B a une dose de 100 a 1000 UI/ml dans les cellules PC-3 derivees du cancer prostatique humain. L'auteur de Particle discute I'efflcacite de Pinterferon-B dans Ie traitement du cancer prostatique. Gli androgeni regolano 10 sviluppo e la maturazione funzionale della prostata. La carenza di androgeni in eta puberale ostacola il normale sviluppo della ghiandola e ne causa, nell'adulto, una riduzione ponderale associata ad atrofia degli elementi secernenti. L'orchiectomia 0 la soppressione androgenica prodotta in via indiretta mediante ipofisectomia 0 somministrazione di estrogeni riduce il peso e l'attivita secretoria della prostata. Per quanta concerne il carcinoma della prostata, Ie condizioni cliniche di pazienti affetti da neoplasia in fase avanzata traggono notevole giovamento dalla castrazione 0 dalla somministrazione di estrogeni. Recentemente, altri tipi di trattamento endocrino sono stati proposti, ma la risposta esempre condizionata dalla composizione della popolazione neoplastica. Essa infatti e data da cellule ormono-sensibili, da cellule del tutto dipendenti dagli ormoni e da cellule svincolate dal controllo ormonale. L'attlvita biologica degli ormoni, nella fattispecie degli androgeni, e mediata da recettori intracellulari, che, nel tessuto prostatico, sono difficilmente dosabili. II livello dei recettori per gli androgeni PUQ essere modulato in Iinee cellulari di cancro della prostata dal beta interferone naturale. Questa possibilita apre nuove prospettive nel trattamento del carcinoma prostatico. KEY WORDS: Prostatic cancer; pathophysiology; hormonal effects; interferon-S rr'he prostate comprises a conglomerate ~ of between 30 and 50 glands, which are surrounded by interstitial tissue containing muscle, and elastic and collagen fibres. These fibres provide support and firmness for the epithelial component. The prostate depends on the combined action of various hormones for growth, with the most important role being played by androgens, which regulate development and functional maturation of the prostate. If androgens are not produced at puberty normal development of the prostate is impaired, whereas if androgen deprivation takes place in adult life the prostate undergoes regression and atrophy, leading to a reduction in secretion. Androgen suppression induced by orchidectomy or indirectly brought about by hypophysectomy or the administration of oestrogens results in a reduction in the weight of the prostate, with a loss of metabolic and functional activity. Since Huggins and Hodges showed in 1941 that prostatic cancer was affected by androgens.t-" androgen withdrawal has become the treatment of choice in the majority of cases for metastatic prostatic cancer.' In addition to orchidectomy and 9 Downloaded from imr.sagepub.com at SAGE Publications on June 20, 2016 G. Sica the administration of oestrogens, in patricular diethylstilboestrol, other endocrine manipulations, including the administration of anti-androgens, progestogens, antioestrogens and luteinizing hormone releasing hormone analogues, have been proposed as alternatives for the treatment of prostatic cancer." Combined therapies and hormonal associations have been suggested more recently, the aim of therapy being to obtain a more efficient and less toxic treatment. When considering the hormone sensitivity of prostatic cancer, it is important to note that the neoplastic cell population is composed of androgen-dependent, androgen-insensitive and androgen-independent cells. This heterogeneity may explain the different responses of cancer to endocrine therapy. At present, the most urgent need is for a treatment for hormone-insensitive prostatic cancers. It is generally accepted that the biological activity of steroidal hormones is medi. ated via intracellular proteins (receptors) present in the target tissues; therefore, attempts have been made to develop a method to predict the responsiveness of prostatic cancer to endocrine manipulations, with particular emphasis on the measurement of androgen receptors. Many obstacles, however, have delayed the development of a reliable assay for the determination of androgen receptors in human prostatic tissue. Some problems have been resolved using synthetic ligands, these ligands being employed in an exchange assay under conditions that minimize degradation of the androgen receptor. The receptors are mainly located in the nucleus; therefore, for the determination in prostatic tissue, receptors in both the nucleus and cytoplasm must be assayed. At present, the relationship between androgen receptor concentrations in prostatic cancer and response to therapy is not clear and the ability of androgen receptors to identify response groups is under discussion.' An interesting approach to the modulation of hormone sensitivity in prostatic cancer, at least in vitro, is represented by the possibility of using natural interferon-S to enhance androgen receptors. It has been demonstrated that interferon-B at concentrations ranging from 100 to 1000 IU/ml can increase androgen receptor concentrations in PC-3 cells derived from a human prostatic cancer when evaluated by a whole cell assay. Further investigations need to be undertaken to establish the dose and the modalities of interferon-B treatment, which could be used in vivo to achieve-the same receptor enchancement as observed in vitro. Information derived from these studies, therefore, provides new perspectives in the treatment of prostatic cancer, particularly in those tumours which are receptor-negative. REFERENCES 1. Huggins C: Studies on prostatic cancer. II. The effects of castration on advanced carcinoma of the prostate gland. Arch Surg 1941; 43: 209 - 223. 2. Huggins C, Hodges CV: Studies on prostatic cancer. II. The effects of castration, estrogen and androgen injections on serum. Cancer Res 1941; 1: 293. 3. VACURG: Treatment and survival of patients with cancer of the prostate. Surg Gynecol Obst 1967; 124: 1011. 4. Bono AV, Pozzi E, Robutelli della Cuna G, et al; Prostatic cancer - survey of hormonal treatment in Europe. J lnt Med Res 1990; 18 (suppll): 11 25. 5. Barrack ER, Tindall OJ: A critical evaluation of the use of androgen receptor assays to predict the androgen responsiveness of prostatic cancer. In: Current Concepts and Approaches to the study of Prostatic Cancer. New York: Alan R. Liss, 1987; 155 -187. 10 Downloaded from imr.sagepub.com at SAGE Publications on June 20, 2016