ANTIPROLIFERATIVE EFFECTS OF LUTEINIZING-HORMONE-RELEASING HORMONE AGONISTS ON THE HUMAN PROSTATIC-CANCER CELL-LINE LNCAP

被引:38
作者
LIMONTA, P
DONDI, D
MORETTI, RM
MAGGI, R
MOTTA, M
机构
[1] Department of Endocrinology, University of Milan, Milan
关键词
D O I
10.1210/jcem.75.1.1320049
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Highly potent LH-releasing hormone (LHRH) agonists have been recently introduced in therapy for the treatment of the carcinoma of the prostate, an androgen-dependent pathology. These peptides are believed to act mainly by inhibiting the pituitary-testicular axis and, consequently, by reducing testosterone levels. The recent observation that binding sites for LHRH analogs are present on prostatic tumor tissue suggests that these drugs could also act directly on the tumor. To verify this hypothesis, the effects of two potent LHRH agonists [Zoladex (Z) and Buserelin (B)] have been studied on the proliferation of the human prostatic cancer cell line LNCaP (lymph node carcinoma of the prostate). LNCaP cells were treated for 9 days with different doses of either Z or B (concentrations from 10(-12)-10(-6) m). Both analogs significantly inhibited cell proliferation at doses between 10(-9)-10(-6) M. The antiproliferative action of the two LHRH agonists was shown to be dose dependent, with IC50 values of 0.82 and 1.79 nm for Z and B, respectively. A similar treatment with B was without any significant effect on the proliferation of a mouse embryo fibroblast cell line (Swiss 3T3), which was used as a nontumoral control. The inhibitory action of both LHRH agonists (10(-8) m) on LNCaP cell proliferation was completely antagonized by the simultaneous treatment of the cells with a potent LHRH antagonist (Nal-Arg-LHRH; 10(-8) M); when given alone at the dose selected, the antagonist did not affect cell growth. These results clearly suggest that the antiproliferative effect of LHRH agonists on LNCaP cells may be mediated by specific receptors. The presence of binding sites for [I-125]B was consequently demonstrated on the membranes of LNCaP cells cultured in a medium containing charcoal-stripped fetal calf serum, i.e, in the absence of steroids. The affinity of these binding sites for the ligand was lower than that observed for the same receptors on rat pituitary membranes. To clarify the mechanism of the antiproliferative action of the LHRH agonists, the effects of both Z and B on the incorporation of [H-3]thymidine and [C-14]methionine into LNCaP cells were investigated. During a short incubation period (3 h), the two LHRH agonists rapidly inhibited [H-3]thymidine incorporation into the cells. The same treatment did not affect the incorporation of [C-14]methionine into proteins. It is concluded that 1) LHRH agonists specifically inhibit LNCaP cell proliferation in a dose-dependent manner; 2) the antiproliferative action of LHRH agonists is completely antagonized by simultaneous treatment of the cells with a potent LHRH antagonist; 3) LNCaP cells possess LHRH receptors; 4) LHRH agonists seem to interfere with thymidine (and possibly DNA) metabolism without affecting protein synthesis; and 5) it may be speculated that LHRH agonists, when used for the treatment of prostatic carcinoma, might inhibit tumor growth not only by reducing testosterone secretion (through suppression of the activity of the pituitary-testicular axis), but also by exerting a direct antiproliferative action at the level of the tumor.
引用
收藏
页码:207 / 212
页数:6
相关论文
共 39 条
[1]   GONADOTROPIN REGULATION AND CLINICAL-APPLICATIONS OF GNRH [J].
BELCHETZ, PE .
CLINICS IN ENDOCRINOLOGY AND METABOLISM, 1983, 12 (03) :619-640
[2]   LUTEINIZING-HORMONE-RELEASING HORMONE BINDS TO ENRICHED HUMAN PLACENTAL MEMBRANES AND STIMULATES INVITRO THE SYNTHESIS OF BIOACTIVE HUMAN CHORIONIC-GONADOTROPIN [J].
BELISLE, S ;
GUEVIN, JF ;
BELLABARBA, D ;
LEHOUX, JG .
JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM, 1984, 59 (01) :119-126
[3]   ANDROGEN-DEPENDENT GROWTH-REGULATION OF AND RELEASE OF SPECIFIC PROTEIN(S) BY THE ANDROGEN RECEPTOR CONTAINING HUMAN-PROSTATE TUMOR-CELL LINE LNCAP [J].
BERNS, EMJJ ;
DEBOER, W ;
MULDER, E .
PROSTATE, 1986, 9 (03) :247-259
[4]   DIRECT INHIBITORY EFFECT OF A LUTEINIZING-HORMONE-RELEASING HORMONE AGONIST ON MCF-7 HUMAN-BREAST CANCER-CELLS [J].
BLANKENSTEIN, MA ;
HENKELMAN, MS ;
KLIJN, JGM .
EUROPEAN JOURNAL OF CANCER & CLINICAL ONCOLOGY, 1985, 21 (12) :1493-1499
[5]  
BRADFORD MM, 1976, ANAL BIOCHEM, V72, P248, DOI 10.1016/0003-2697(76)90527-3
[6]   GONADOTROPIN-RELEASING-HORMONE - FROM PHYSIOLOGY TO PHARMACOLOGY [J].
CLAYTON, RN .
CLINICAL ENDOCRINOLOGY, 1987, 26 (03) :361-384
[7]  
CONN PM, 1984, FED PROC, V43, P2351
[8]   HUMAN PLACENTAL RECEPTORS FOR LUTEINIZING-HORMONE RELEASING HORMONE [J].
CURRIE, AJ ;
FRASER, HM ;
SHARPE, RM .
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 1981, 99 (01) :332-338
[9]   INHIBITION OF INTERCELLULAR JUNCTIONAL COMMUNICATION IN HUMAN-FIBROBLASTS BY TRIPHENYLMETHANE, TRIPHENYLMETHYLCHLORIDE, TETRAPHENYLBORON AND RELATED-COMPOUNDS [J].
DAVIDSON, JS ;
BAUMGARTEN, IM ;
HARLEY, EH .
BIOCHIMICA ET BIOPHYSICA ACTA, 1985, 847 (01) :1-7
[10]   SIMULTANEOUS ANALYSIS OF FAMILIES OF SIGMOIDAL CURVES - APPLICATION TO BIOASSAY, RADIOLIGAND ASSAY, AND PHYSIOLOGICAL DOSE-RESPONSE CURVES [J].
DELEAN, A ;
MUNSON, PJ ;
RODBARD, D .
AMERICAN JOURNAL OF PHYSIOLOGY, 1978, 235 (02) :E97-E102