Receptors for luteinizing hormone-releasing hormone, somatostatin, prolactin, and epidermal growth factor in rat and human prostate cancers and in benign prostate hyperplasia

Using sensitive multipoint micromethods, we estimated membrane receptors for [D-Trp6]-luteinizing hormone-releasing hormone ([ D-Trp6]-LH-RH), somatostatin (SS-14), human prolactin (hPRL), and epidermal growth factor (EGF) in experimental Dunning rat prostate cancers and in samples of normal human prostate, benign prostatic hyperplasia (BPH), and human prostate cancer (PC) obtained from biopsy, after prostatectomy, or at autopsy. In the Dunning R-3327 rat prostate adenocarcinoma specimens, the receptors were characterized in untreated animals and following in vivo treatment with microcapsules of the agonist [D-Trp6]-LH-RH and the somatostatin analog RC-160. Two populations of binding sites were found for [D-Trp6]-LH-RH, one with high affinity and low capacity and another with low affinity and high capacity. Treatment with [D-Trp6]-LH-RH and RC-160 alone or with the combination of these analogs increased the binding capacity (Bmax) of the low-affinity binding sites for [D-Trp6]-LH-RH and decreased Bmax for hPRL and EGF. Therapy with [D-Trp6]-LH-RH also reduced Bmax of SS-14 binding and dissociation binding constant of high-affinity binding sites for [D-Trp6]-LH-RH, whereas administration of RC-160 or the combination treatment with both analogs increased Bmax of SS-14 binding. These findings are compatible with the view that analogs of LH-RH and SS-14 might exert some direct inhibitory effects on the Dunning prostate cancer. Among 13 human BPH samples examined, only one had receptors for [D-Trp6]-LH-RH, and seven specimens exhibited binding for prolactin. [D-Trp6]-LH-RH receptors were found in all seven samples of human PC but not in any of the eight specimens of normal human prostate. All samples of normal human prostate, BPH, and human PC exhibited binding sites for EGF but not for SS-14. Our findings on the membrane receptors in the human and rat prostate cancers raise the intriguing possibility that LH-RH, acting as a growth factor, along with EGF and prolactin, might be involved in complex interactions that contribute to the promotion of prostate cancer in man.     

Potentiation of the inhibitory effect of growth hormone-releasing hormone antagonists on PC-3 human prostate cancer by bombesin antagonists indicative of interference with both IGF and EGF pathways

BACKGROUND: In view of the involvement of various neuropeptides and growth factors in the progression of androgen-independent prostate cancer, we investigated the effects of antagonists of growth hormone-releasing hormone (GHRH) alone or in combination with an antagonist of bombesin/gastrin-releasing peptide (BN/GRP) on PC-3 human prostate cancers. METHODS: Nude mice implanted with PC-3 tumors received GHRH antagonists MZ-5-156 or JV-1-38, each at 20 microgram/day s.c. In experiment 2, treatment consisted of daily injections of JV-1-38 (20 microgram), BN/GRP antagonist RC-3940-II (10 microgram), or a combination of JV-1-38 and RC-3940-II. Serum IGF-I levels, expression of mRNA for IGF-II, and characteristics of BN/GRP and EGF receptors in tumor tissue were investigated. RESULTS: JV-1-38 induced a greater inhibition of tumor growth and suppression of IGF-II mRNA than MZ-5-156, both compounds causing a similar decrease in serum IGF-I. In experiment 2, JV-1-38 and RC-3940-II produced a comparable reduction in tumor volume (65% and 61%, respectively), but a combination of both antagonists augmented tumor inhibition to 75%. Combined treatment with JV-1-38 and RC-3940-II also led to a greater suppression of IGF-II mRNA (92%), as compared with JV-1-38 (72%) or RC-3940-II (77%). Serum IGF-I concentration was lowered only in mice treated with JV-1-38, while the downregulation of BN/GRP and EGF receptors was specific for groups receiving RC-3940-II. CONCLUSIONS: The inhibitory effects of GHRH antagonists on PC-3 human androgen-independent prostate cancer can be potentiated by concomitant use of BN/GRP antagonists. The combination of both types of analogs apparently interferes with both IGF and bombesin/EGF pathways, and might be clinically useful for the management of androgen-independent prostate cancer.     

蛙皮素受体拮抗剂RC-3095联合吉西他滨对人胰腺癌细胞CFPAC-1生长的影响

目的:探讨蛙皮素受体拮抗剂RC-3095联合吉西他滨(gemcitabine,GEM)是否有协同拮抗人胰腺癌细胞CFPAC-1生长的作用。方法:采用CCK-8法检测不同浓度的RC-3095、GEM以及联合治疗对胰腺癌细胞体外增殖的影响;给予荷瘤裸鼠RC-3095(20μg/d)、GEM[15 mg/(kg·3 d)]以及两者联合治疗4周,观察移植瘤的体积和重量变化;采用Western印迹法检测干预后移植瘤组织中蛙皮素受体的表达变化,包括GRP-R、NMB-R和BRS-3。结果:在体外试验中,联合用药组展现出强大的肿瘤细胞增殖抑制效应。干预4周后发现,RC-3095或GEM都可显著降低移植瘤的体积和重量。联合组比任何单一用药组都能更显著地抑制CFPAC-1移植瘤的生长。Western印迹法显示,RC-3095组或GEM组均能降低移植瘤中GRP-R和BRS-3的蛋白质表达;联合用药组降低作用更明显。结论:RC-3095联合GEM能协同抑制人胰腺癌细胞CFPAC-1在体外和体内的生长发展。这种协同抑制的效果与GRP-R和(或)BRS-3表达下降有关。     

Histologic changes in the rat prostate cancer model after treatment with somatostatin analogs and D-Trp-6-LH-RH

Histopathologic changes produced during the treatment of Dunning R3327 prostate cancer with new superactive somatostatin analogs (RC-121 and RC-160) and D-Trp-6 analog of luteinizing hormone-releasing hormone agonist (D-Trp-6-LH-RH) were studied. A significant reduction of the tumor weight could be observed in all treated groups, but the greatest decrease in the tumor volume was seen in the groups receiving the combination of the somatostatin analog and D-Trp-6-LH-RH. Histologically, the treatments resulted in a loss of the tumorous glandular elements and the proliferation of the stromal cells. In the tumors treated with somatostatin analogs, the amount of connective tissue was greatly increased and was accompanied by the appearance of thick collagenous fibers. In the D-Trp-6-LH-RH treated groups, regressive changes in the epithelium were seen in addition to the proliferation of connective tissue. The greatest histologic improvement was observed in the group treated with the combination of RC-160 and D-Trp-6-LH-RH. This histopathologic evaluation clearly supports our contention that superactive analogs of somatostatin greatly potentiate the inhibitory effect of D-Trp-6-LH-RH on the growth of Dunning prostate tumors and may improve the clinical response in patients with prostate cancer.     

Inhibition of proliferation of PC-3 human prostate cancer by antagonists of growth hormone-releasing hormone: lack of correlation with the levels of serum IGF-I and expression of tumoral IGF-II and vascular endothelial growth factor

BACKGROUND: Antagonists of growth hormone-releasing hormone (GHRH) such as JV-1-38 can inhibit androgen-independent prostate cancer directly by several mechanisms and/or indirectly by suppressing growth hormone/insulin-like growth factor-I (GH/IGF-I) axis. To shed more light on the mechanisms involved, the effects of JV-1-38 on PC-3 human prostate cancer were compared with those of somatostatin analog RC-160 in vivo and in vitro. METHODS: Nude mice bearing PC-3 tumors received JV-1-38 (20 microg), RC-160 (50 microg) or a combination of JV-1-38 and RC-160. The concentration of IGF-I in serum and the expression of mRNA for IGF-II and vascular endothelial growth factor (VEGF) in tumor tissue were investigated. RESULTS: In vivo, the final volume of PC-3 tumors treated with JV-1-38 was significantly lowered by 49% (P < 0.01), whereas RC-160 exerted only 30% inhibition (NS), compared with controls. Combined use of both compounds augmented tumor inhibition to 63% (P < 0.001). Serum IGF-I levels were decreased only in mice treated with RC-160. JV-1-38 suppressed mRNA for IGF-II in PC-3 tumors by 42%, whereas RC-160 alone or in combination with JV-1-38 caused a 65% reduction. JV-1-38 and RC-160 used as single drugs decreased the expression of VEGF by 50%, and their combination caused a 63% reduction. In vitro, JV-1-38 inhibited the proliferation of PC-3 cells by 39%. This effect could be partially reversed by addition of IGF-I to the serum-free medium. RC-160 alone did not affect the PC-3 cell growth in vitro, but in combination with JV-1-38 it augmented the antiproliferative effect of the GH-RH antagonist to 72%. Exposure to JV-1-38 in vitro reduced the expression of mRNA for IGF-II in PC-3 cells by 55% but did not change VEGF mRNA levels, whereas RC-160 had no effect. CONCLUSIONS: The antiproliferative effect of JV-1-38 was not associated with the suppression of serum IGF-I and was only partially correlated with the expression of IGF-II and VEGF in PC-3 tumors, suggesting that other mechanisms play a role in the antitumor action of GHRH antagonists. Nevertheless, the stronger inhibition of tumor growth after combined treatment with JV-1-38 and RC-160 indicates that the interference with multiple local stimulatory factors leads to an enhanced inhibition of prostate cancer.     

Antagonists of growth hormone releasing hormone (GHRH) and of bombesin/gastrin releasing peptide (BN/GRP) suppress the expression of VEGF, bFGF, and receptors of the EGF/HER family in PC-3 and DU-145 human androgen-independent prostate cancers

BACKGROUND: Antagonists of growth hormone releasing hormone (GHRH) as well as antagonists of bombesin/gastrin releasing peptide (BN/GRP) inhibit the growth of various malignancies (cancers) including prostate cancer. METHODS: We investigated the effects of GHRH antagonists MZ-J-7-118 and RC-J-29-18, BN/GRP antagonists RC-3940-II and RC-3940-Et and the combination of MZ-J-7-118 and RC-3940-II on the growth of PC-3 and DU-145 human androgen independent prostate cancers xenografted s.c. into nude mice. To elucidate the mechanisms of action of these analogs, growth factors like IGF-II (insulin-like growth factor-II), vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), and epidermal growth factor receptor/human epidermal growth factor receptor (EGF-R/HER) family were measured in tumors as well as IGF-I in serum. RESULTS: Antagonists of GHRH and BN/GRP alone or in combination significantly inhibited growth of PC-3 and DU-145 tumors, the greatest inhibition of tumor volume being achieved by combination of MZ-J-7-118 (5 microg/day) and RC-3940-II (10 microg/day). BN/GRP and GHRH antagonists and their combination also decreased the expression of VEGF significantly in PC-3 and non-significantly in DU-145, as measured by radioimmunoassay for VEGF protein and RT-PCR for mRNA levels of VEGF. GHRH and BN/GRP antagonists reduced bFGF concentrations and the maximal binding capacity of EGF receptors, and their mRNA levels in PC-3 and DU-145 tumors. mRNA levels for HER-2 and -3 were also diminished in PC-3 tumors by GHRH and BN/GRP antagonists. No changes in HER-4 were found after treatment. Serum IGF-I and tumoral IGF-II levels were not affected by the analogs. CONCLUSIONS: BN/GRP and GHRH antagonists inhibit growth of PC-3 and DU-145 prostate cancers by suppressing the expression of tumoral growth factors such as VEGF and bFGF as well as the receptors for EGF and related HER-2 and -3. Additive effects on tumor inhibition (TI) in vivo, but not on VEGF, bFGF, or members of the EGF/HER receptor family, can be achieved by the joint administration of both classes of analogs.     

Effect of microcapsules of luteinizing hormone-releasing hormone antagonist SB-75 and somatostatin analog RC-160 on endocrine status and tumor growth in the Dunning R-3327H rat prostate cancer model.

Inhibitory effects of sustained delivery systems (microcapsules) of the modern antagonist of luteinizing hormone-releasing hormone [Ac-D-Nal(2)1, D-Phe(4Cl)2, D-Pal(3)3, D-Cit6, D-Ala10]LH-RH (SB-75) or the potent somatostatin analog D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Trp-NH2 (RC-160) were investigated in the Dunning R-3327H rat prostate cancer model. In the first experiment, the treatment was started 4 months after tumor transplantation, when the tumors measured approximately 2 cm3. Tumor volumes and weights were significantly reduced by SB-75 microcapsules releasing 48 micrograms/day or RC-160 microcapsules releasing 38 micrograms/day given alone, as compared with the control. The combination of these two analogs showed a synergistic effect. In the second experiment, the treatment was started 7 months after tumor transplantation, when the tumors were well developed and measured about 16 cm3. In addition to a significant reduction in volume, weight, and growth rate of tumors, histological signs of tumor regression were found in the groups treated with SB-75 microcapsules releasing 72 micrograms/day given alone or in combination with RC-160 microcapsules releasing 76 micrograms/day, but not with RC-160 alone. No synergistic effect of the combination therapy was found in the second experiment. Serum testosterone levels decreased to undetectable levels and LH levels were also diminished within 2 weeks by administration of SB-75 alone or in combination with RC-160. In both experiments, the weights of testes, ventral prostate, and seminal vesicles were greatly reduced by administration of SB-75 alone or in combination with RC-160. Our results suggest that the combined therapy with microcapsules of SB-75 and RC-160, started soon after the diagnosis of prostate cancer is made, could improve therapeutic response.     

Endogenous phosphorylation in Dunning prostate tumors of rats treated with LH-RH analogues

We investigated phosphorylation in Dunning R-3327H prostate tumor tissue of untreated rats, and rats treated with the agonist D-Trp6-LH-RH and antagonist N-Ac-D-p-Cl-Phe1,2,D-Trp3,D-Arg6,D-Ala10-LH-RH. The total phosphorylation was significantly higher in Dunning tumors than in normal ventral and dorsal prostate. Incorporation of 32P into tumor tissue of rats treated with D-Trp6-LH-RH was significantly lower than in tumors from untreated animals. The tumor regression produced by LH-RH agonist appeared to be linked with changes in the pattern of tumor protein phosphorylation. Although inhibition of tumor growth also occurred after administration of the LH-RH antagonist, no significant changes in phosphorylation were observed. The dissimilarity of effects of the agonists and the antagonists on protein phosphorylation in rat prostate tumors may be related to the differences in the mechanisms of action of these two types of LH-RH analogues.     

Characterization of high-affinity receptors for bombesin/gastrin releasing peptide on the human prostate cancer cell lines PC-3 and DU-145: Internalization of receptor bound 125I-(Tyr4) bombesin by tumor cells

Specific receptors for bombesin/gastrin releasing peptide (GRP) on the androgen-independent human prostate cancer cell lines PC-3 and DU-145 were characterized. No specific binding of ¹²⁵I-[Tyr⁴]-bombesin to the androgen-dependent human prostate cancer cell line LNCaP was detectable. The binding of ¹²⁵I-[Tyr⁴]-bombesin to PC-3 and DU-145 cells was found to be time- and temperature-dependent, saturable, and reversible. Scatchard analysis revealed a single class of binding sites with high affinity (K_d 9.8 × 10^?11 M for PC-3, and 9.1 × 10-¹¹ M for DU-145 cells at 25°C) and with a binding capacity of 44,000 binding sites/cell and 19,000 binding sites/cell, respectively. Bound ¹²⁵I-[Tyr⁴]-bombesin was rapidly internalized by PC-3 cells. The nonhydrolyzable GTP analog GTP-gamma-S caused a dose-dependent inhibition of ¹²⁵I-[Tyr⁴]-bombesin binding to PC-3 and DU-145 cells, indicating that a G-protein (guanine nucleotide-binding protein) couples the bombesin receptor to intracellular effector systems. Bombesin and GRP(14-27) inhibited the binding of ¹²⁵I-[Tyr⁴]-bombesin to both cell lines in a dose-dependent manner with inhibition constants (K_i of 0.5 nM and 0.4 nM, respectively. Both cell lines express the bombesin/GRP preferring bombesin receptor subtype, since, in displacement studies, neuromedin B was more than 200 times less potent than bombesin and GRP(14-27) in inhibiting the binding of ¹²⁵I-[Tyr⁴]-bombesin. Two synthetic bombesin/GRP antagonists, RC-3095 and RC-3110, powerfully inhibited the specific binding of ¹²⁵I-[Tyr⁴]-bombesin with K_i 0.92 nM and 0.26 nM on PC-3 cells, and 3.3 nM and 0.89 nM on DU-145 cells, respectively. These findings indicate that the PC-3 and DU-145 human prostate cancer cell lines possess specific high-affinity receptors for bombesin/GRP, and are suitable models for the evaluation of the antineoplastic activity of new bombesin/GRP antagonists in the treatment of androgen-independent prostate cancer. © 1994 Wiley-Liss, Inc.     

Inhibition of prostate tumors by agonistic and antagonistic analogs of LH-RH

We have compared the effects of chronic administration of D-Trp6-LH-RH, a superactive agonist of LH-RH, and a potent antagonist, (NAc-p-Cl-D-Phe1,2,D-Trp3,D-Arg6,D-Ala10)LH-RH, on male Copenhagen F-1 rats bearing the Dunning R-3327H prostate adenocarcinoma. Treatment with 25 micrograms of D-Trp6-LH-RH bid for 21 days decreased the weights of the ventral prostate, testes, and adrenals, but had no effect on the weight of the anterior pituitary gland. Administration of similar doses of the antagonist reduced the weight of the ventral prostate, anterior pituitary gland, and adrenals, but did not change the weight of the testes. Both the agonist and antagonist greatly and significantly reduced tumor weight and volume as compared to controls. Serum LH, prolactin, and testosterone levels in Copenhagen F-1 rats bearing Dunning tumors were significantly decreased after treatment with D-Trp6-LH-RH as well as the antagonist. The inhibition of rat prostate tumors achieved with D-Trp6-LH-RH and the antagonistic analog raised the possibility that these compounds could be used clinically in the treatment of prostate carcinoma and other endocrine-dependent neoplasias. The antagonistic analogs have not yet been tried clinically on a chronic basis. However, the data accumulated so far from clinical trials in men with prostate carcinoma suggest that D-Trp6-LH-RH and other LH-RH agonists can be used for an effective therapy which avoids the side effects of estrogen and the pyschological impact of castration.     

Suppression of the growth and invasiveness of human prostate cancer cells in vitro by neuropeptide antagonist substance P analogues

Neuropeptides may be essential to the growth and progress of prostate cancer, particularly during androgen-independent cell development. To determine whether neuropeptide antagonists substance P analogues can be used as therapeutic agents in the treatment of prostate cancer, their effects on the growth and invasiveness of established human prostate cancer cell lines were examined. The effects of [d-Arg(1), d-phe(5), d-Trp(7,9), Leu(11)]substance P and [Arg(6), d-Trp(7,9), MePhe(8)]substance P(6-11) on two androgen-independent cell lines (PC-3 and DU-145) and an androgen-dependent cell line (LNCaP) were studied. The cytotoxicity of substance P analogues was assessed based on their effects on DNA synthesis and cell proliferation by [(3)H]thymidine incorporation and cell growth assays, respectively. Inhibition of the invasiveness of prostate cancer cells was estimated based on the extent of cell penetration of reconstituted basement membrane. Substance P analogues inhibited DNA synthesis and cell proliferation of prostate cancer cells dose dependently but complete recovery was achieved by the addition of bombesin or substance P. [d-Arg(1), d-phe, d-Trp(7,9), Leu(11)]substance P inhibited the invasiveness of PC-3 cells. Neuropeptide antagonists substance P analogues have been found useful as therapeutic agents for prostate cancer. Their action occurs primarily through the inhibition of Ca(2+) mobilizing neuropeptides such as bombesin and substance P.     

Differential effects of LHRH and somatostatin analogs on human breast cancer.

We have been interested in the possible direct effects of luteinizing hormone releasing hormone (LHRH) and somatostatin (SS) analogs on the growth of human mammary tumor cells. Four recently synthesized peptide hormones including the LHRH agonists D-Trp6-LHRH and zoladex, LHRH antagonists SB30 and SB75, and the somatostatin analog RC 160 were analyzed for their effects on DNA synthesis of MCF-7 breast cancer cells in culture. At 48 hr, D-Trp6-LHRH and SB30 did not show significant effects (dose range, 10(-12)-10(-6) M). However, the combination of these two peptides at 10(-10) M produced significant inhibition of 3[H]thymidine incorporation (50% control). At 72 hr in the absence of estradiol-stimulated growth, D-Trp6-LHRH showed inhibition at 10(-12) and 10(-10) M (P less than 0.005 and 0.001). At higher concentrations, no significant inhibition was noted. In contrast to D-Trp6, SB30 (antagonist) showed no inhibition but significant stimulation of DNA synthesis at 10(-6) and 10(-4) M. In the presence of added estradiol (10(-9) M), complete reversal of D-Trp6-LHRH analog inhibition is noted. In contrast, there is persistent stimulation by SB30 (P less than 0.001). At 96 hr, D-Trp6-LHRH continued to show maximal inhibition of 70% in the absence of estradiol. SB30 stimulated DNA synthesis 100% at 10(-6) M. At 72 hr, the SS analog RC 160 demonstrated significant inhibition (53%) that was similar to D-Trp6 and SB75 peptides.(ABSTRACT TRUNCATED AT 250 WORDS)     

Investigation of the combination of the agonist D-Trp-6-LH-RH and the antiandrogen flutamide in the treatment of Dunning R-3327H prostate cancer model

The therapy for the treatment of prostate cancer and other sex-steroid-dependent tumors based on agonists of LH-RH has been made more practical and efficacious by the development of a long-acting formulation of microcapsules of D-Trp-6-LH-RH for controlled release. Antiandrogens, which neutralize the effect of endogenous androgens, have been used also in the management of prostate cancer in man. The effects of a simultaneous administration of the antiandrogen flutamide and microcapsules of the agonist D-Trp-6-LH-RH were studied in the Dunning R-3327H rat prostate adenocarcinoma model to determine whether the combination of these two drugs might inhibit tumor growth more effectively than single agents. Microcapsules of D-Trp-6-LH-RH, calculated to release a controlled dose of 25 micrograms/day for a period of 30 days were injected intramuscularly once a month. Flutamide was administered SC at a daily dose of 25 mg/kg. The therapy was started 100 days after the tumor transplantation and continued for 60 days. Tumor weights and volumes were significantly reduced in rats treated with microcapsules or flutamide alone, but the former drug inhibited tumor growth more than the latter. The combined treatment of flutamide and microcapsules significantly decreased tumor weight and volume, but did not exert a synergistic effect on tumor growth, the reduction being smaller for the combination than for the microcapsules alone. There was a significant elevation of serum testosterone, LH, and prolactin in rats treated with flutamide. On the other hand, in rats given microcapsules of D-Trp-6-LH-RH, testosterone fell to castration levels within 7 days and remained at nondetectable values, serum LH and prolactin levels being also suppressed in this group. The combined administration of microcapsules and flutamide also significantly decreased serum testosterone to nondetectable levels by day 7 and suppressed serum LH and prolactin. Our findings raise doubts of whether the daily administration of the combination of LH-RH agonist with an antiandrogen offers an advantage over the use of microcapsules of an agonist like D-Trp-6-LH-RH alone in the treatment of prostatic carcinoma.     

Somatostatin analogues inhibit angiogenesis in the chick chorioallantoic membrane.

The mechanism responsible for alterations in tumor growth following administration of somatostatin analogues is unknown. Somatostatin analogues, SMS 201-995 and RC-160, have demonstrated the potential to inhibit both tumor growth and vascularity, in vivo and in vitro. We hypothesized that SMS and RC-160 inhibit angiogenesis and this inhibition may alter tumor growth. To test this hypothesis, 2 mm methylcellulose disks containing concentrations of SMS 201-995 and RC-160 at 0, 0.5, 2.5, or 50 micrograms per disk, were implanted on the chorioallantoic membrane (CAM) of 6- to 7-day-old shell-less chick embryos. Inhibition of blood vessel growth in the region of the disk was visually assessed 24-36 hr following disk implantation and graded (0-4) based on the radius of the zone of inhibition from the center of the disk. The overall incidence of inhibition for the somatostatin analogues at concentrations of 0.5, 2.5, and 50 micrograms per disk was 13, 56, and 61% for SMS and 27, 49, and 68% for RC-160, respectively. Overall incidence of inhibition for the positive (inhibitory) control was 70.5% and those for buffer (negative) controls were 3-14%. Somatostatin analogues were associated in a dose-related fashion with both a greater percentage of inhibition of blood vessel growth and an increased grade of inhibition. Inhibition of angiogenesis may be a mechanism responsible for the tumor regression observed in vivo following SMS or RC-160 therapy.     

Response of patients with advanced prostatic cancer to administration of somatostatin analog RC-160 (vapreotide) at the time of relapse

BACKGROUND: The aim of this study was to evaluate the effects of administration of the somatostatin analog RC-160 (vapreotide) at the time of relapse in patients with androgen independent prostate cancer. METHODS: Our study included 13 patients with biopsy-proven prostate cancer, stage D3. Eight patients had been treated with a depot formulation of the agonist D-Trp-6-LH-RH, with a median remission time of 68 (range 48-102 months). Five patients were initially treated by surgical orchiectomy, but relapsed after a median time of 33 months (range 17-91 months). A new remission period with a median duration of 10 months (range 2-29 months) was induced with Ketoconazole in the orchiectomy group. At the relapse time, all the patients received 1 mg of vapreotide t.i.d., by subcutaneous route, in addition to D-Trp-6-LH-RH, or Ketoconazole in the orchiectomy group. RESULTS: Eight of 13 patients demonstrated clinical improvement after 3 months of therapy with vapreotide, six showing a decrease in serum prostate specific antigen (PSA) from 234.5 +/- 308.5 to 68.2 +/- 60.5 ng/ml (mean decline 71 +/- 8%; P < 0.05). Two additional patients presented a fall in serum prostatic acid phosphatase (PAP). Responding patients showed a decrease in the bone pain score from 2.62 +/- 0.48 to 0.37 +/- 0.69 and an increase in the Karnofsky performance status from 72.3 +/- 4.21 to 83.6 +/- 23.2 (P < 0.05). In accord with the ECOG criteria, two patients had a complete response; four had partial response, and two had a stable response. Four patients did not respond and one was not evaluable. Two patients died in remission, one at 16 months due to myocardial infarction and the other at 24 months due to pneumonia. Three patients relapsed at 5, 17, and 19 months respectively. Three patients who have been followed-up for more than 3 years continued in remission (79, 45, and 45 months) respectively. Vapreotide was well tolerated, only three patients having transitory mild diarrhea. CONCLUSIONS: Our results indicate that therapy with the somatostatin analog vapreotide at the time of relapse can induce objective clinical responses in some patients with prostate cancer who are refractory to androgen ablation induced by LH-RH analogs or orchiectomy.     

Effect of the neuropeptides bombesin and calcitonin on the growth of prostate cell lines, PC-3, DU 145, and LNCaP

Neuroendocrine cells are present in normal and tumoral prostate tissue, the neuropeptides secreted by this cells have a biological functions that have not been fully elucidated. The presence of neuroendocrine cells in prostatic carcinoma have been shown to increase tumor progression. We characterized the in vitro proliferative influence of bombesin and calcitonin in androgen-insensitive, PC-3 and DU-145, and androgen-sensitive, LNCaP, cell lines of human prostate cancers. The influence of these neuropeptides on proliferation were assessed using the colorimetric XTT assay and by cells counts with a hemocytometer. The growth of PC-3 and DU-145 cell lines is stimulated by bombesin and calcitonin but exerted any stimulatory effect on the proliferation of the LNCaP cell line. This indicate that bombesin and calcitonin can modulate proliferation of androgen-insensitive human prostate cell lines "in vitro" and may be potential paracrine growth promoters in stablished androgen irresponsive human prostatic carcinoma cells.     

Inhibition of two-step urinary bladder carcinogenesis by the somatostatin analogue RC-160

Summary Fisher 344 female rats were exposed for 4 weeks to the initiator carcinogen N-butyl-N-(4-hydroxybutyl)-nitrosamine (BBN) 0.05% in the drinking water and thereafter to the promoter carcinogen mitomycin C (0.08 mg per animal per week) intravesically for 12 weeks. High incidence of urinary bladder transitional cell cancers was observed (17 in situ and 17 invasive carcinomas among 40 rats). When the somatostatin analogue RC-160 (d-Phe-Cys-Tyr-d-Trp-Lys-Val-Cys-Trp-NH₂) was administered s.c. at the dose of 50 g per animal per day during 6-week period of promotion with mitomycin C, the incidence of urinary bladder cancer was dramatically reduced. Only 1 in situ carcinoma was observed among 20 rats and only preblastomatous lesions (dysplasias and papillomas) occurred. This effect could indicate that RC-160 interferes with the process of promotion by induction of enhanced apoptosis (programmed cell death) of the dysplastic urothelial cells. RC-160 could be tried therapeutically for the hormonal prevention of malignant transformation of preneoplastic lesions in the urinary bladder.