AIM To investigate the therapeutic potential of two recombinant proteins, Survivin and luteinizing hormone-releasing hormone (LHRH) fusion protein [LHRH(6 leu)-LTB] for immunotherapy of breast cancer.METHODS Murine 4 ...AIM To investigate the therapeutic potential of two recombinant proteins, Survivin and luteinizing hormone-releasing hormone (LHRH) fusion protein [LHRH(6 leu)-LTB] for immunotherapy of breast cancer.METHODS Murine 4 T-1 breast cancer model was used to evaluate the efficacy of recombinant proteins in vivo. Twenty four Balb/c mice were divided into 4 groups of 6 mice each. Recombinant Survivin and LHRH fusion protein, alone or in combination, were administered along with immunomodulator Mycobacterium indicus pranii (MIP) in Balb/c mice. Unimmunized or control group mice were administered with phosphate buffer saline. Each group was then challenged with syngeneic 4 T-1 cells to induce the growth of breast tumor. Tumor growth was monitored to evaluate the efficacy of immune-response in preventing the growth of cancer cells.RESULTS Preventive immunization with 20 μg recombinant Survivin and MIP was effective in suppressing growth of 4 T-1 mouse model of breast cancer (P = 0.04) but 50 μg dose was ineffective in suppressing tumor growth. However, combination of Survivin and LHRH fusion protein was more effective in suppressing tumor growth (P = 0.02) as well as metastasis in vivo in comparison to LHRH fusion protein as vaccine antigen alone.CONCLUSION Recombinant Survivin and MIP suppress tumor growth significantly. Combining LHRH fusion protein with Survivin and MIP enhances tumor suppressive effects marginally which provides evidence for recombinant Survivin and LHRH fusion protein as candidates for translating the combination cancer immunotherapy approaches.展开更多
Aim： To evaluate the long-term effectiveness, side effects and compliance rates of two types of drugs （luteinizing hormone-releasing hormone [LHRH] agonist and antiandrogen） that were used individually to treat pat...Aim： To evaluate the long-term effectiveness, side effects and compliance rates of two types of drugs （luteinizing hormone-releasing hormone [LHRH] agonist and antiandrogen） that were used individually to treat patients with localized prostate cancer （T1-2） at our institution. Methods： Ninety-seven patients who were diagnosed in the period from April 1997 to January 2000 as having clinically localized prostate cancer （T1-2） received either LHRH agonist （leuprolide acetate 7.5 mg/month） monotherapy （group 1, n = 62） or antiandrogen monotherapy （group 2, n = 35; 18 received bicalutamide 50 mg q.d., 13 received nilutamide 150 mg t.i.d, and 4 received flutamide 250 mg t.i.d.）. The mean age in both groups was 76 years. Results： The mean follow-up time was （50.8 ±8.5） months in group 1 and （43.1 ± 2.2） months in group 2. Prostate-specific antigen （PSA） levels rose in only 1 of the 62 patients （1.6%） in group 1, and in 20 of the 35 patients （57.1%） in group 2. In group 2, 10 of the 20 patients （50 %） with increasing PSA levels were treated with LHRH salvage therapy, and eight （80%） responded. Hot flashes （54.8%） and lethargy （41.9%） were the most common side effects in group 1. In contrast, nipple-tenderness （40%） and light-dark adaptation （17.1%） were more often seen in group 2. Only 1 of the 62 patients （1.6%） in group 1 switched to another medication because of adverse side effects; whereas 8 of the 35 patients （22.9%） in group 2 did so. Conclusion： Unlike antiandrogen monotherapy, LHRH agonist monotherapy provided long-term durable control of localized prostate cancer （T1-2）. It can also be an effective treatment option for patients whose disease failed to respond to antiandrogen monotherapy. The limitations of our study are the lack of health outcomes analysis and a small sample size.展开更多
Luteinizing hormone-releasing hormone(LHRH) is known to influence sexual behavior in many vertebrate taxa, but there have been no systematic studies on the role of LHRH in sexual behavior of turtles. We tested the hyp...Luteinizing hormone-releasing hormone(LHRH) is known to influence sexual behavior in many vertebrate taxa, but there have been no systematic studies on the role of LHRH in sexual behavior of turtles. We tested the hypotheses that exogenous LHRH analogues would induce sexual behavior of male Four-eyed turtle, Sacalia quadriocellata. We examined this by challenging males with intramuscular injections of mammalian luteinizing hormone-releasing hormone analogue(LHRH-A), human chorionic gonadotropin(HCG), or a combination of the two, and subsequently exposing them to sexually receptive females for behavioral observation. Our data show that the injection of only HCG could not, while that of only LHRH-A could, facilitate sexual behavior along with testicular recrudescence and spermatogenesis in S. quadriocellata. The injection of both LHRH-A and HCG would induce more drastic sexual behavior of the animals than that of LHRH-A alone, indicating HCG enhances the effects of LHRH-A induced sexual behavior. However, different pharmacological dosages of LHRH-A(0.5 μg, 1 μg, 2 μg per 100 g bodyweight) did not correspond to different activity levels. Though the mechanism of LHRH effect was not determined, this study may support that the sexual behavior of S. quadriocellata which occurs at the beginning of the injection despite regression of the gonads. This is the first report on the exogenous LHRH-A induced sexual behavior for this species.展开更多
Benign prostatic hyperplasia(BPH)is a pathologic condition of the prostate described as a substantial increase in its number of epithelial and stromal cells.BPH may significantly reduce the quality of life due to the ...Benign prostatic hyperplasia(BPH)is a pathologic condition of the prostate described as a substantial increase in its number of epithelial and stromal cells.BPH may significantly reduce the quality of life due to the initiation of bladder outlet obstruction and lower urinary tract syndromes.Current medical therapies mostly consist of inhibitors of 5α-reductase orα1-adrenergic blockers;their efficacy is often insufficient.Antagonistic analogs of neuropeptide hormones are novel candidates for the management of BPH.At first,antagonists of luteinizing hormone-releasing hormone(LHRH)have been introduced to the therapy aimed to reduce serum testosterone levels.However,they have also been found to produce an inhibitory activity on local LHRH receptors in the prostate as well as impotence and other related side effects.Since then,several preclinical and clinical studies reported the favorable effects of LHRH antagonists in BPH.In contrast,antagonists of growth hormone-releasing hormone(GHRH)and gastrin-releasing peptide(GRP)have been tested only in preclinical settings and produce significant reduction in prostate size in experimental models of BPH.They act at least in part,by blocking the action of respective ligands produced locally on prostates through their respective receptors in the prostate,and by inhibition of autocrine insulin-like growth factors-Ⅰ/Ⅱand epidermal growth factor production.GHRH and LHRH antagonists were also tested in combination resulting in a cumulative effect that was greater than that of each alone.This article will review the numerous studies that demonstrate the beneficial effects of antagonistic analogs of LHRH,GHRH and GRP in BPH,as well as suggesting a potential role for somatostatin analogs in experimental therapies.展开更多
本研究应用大鼠下丘脑正中隆起(ME),观察 γ-氨基丁酸(GABA)和去甲肾上腺素(NA)对下丘脑促黄体生成激素释放激素(LHRH)神经元末梢分泌作用的影响。结果发现:GABA(10^(-6)mol/L)可显著促进 ME 的 LHRH 和 NA 的释放,即 LHRH 释放量由27.3...本研究应用大鼠下丘脑正中隆起(ME),观察 γ-氨基丁酸(GABA)和去甲肾上腺素(NA)对下丘脑促黄体生成激素释放激素(LHRH)神经元末梢分泌作用的影响。结果发现:GABA(10^(-6)mol/L)可显著促进 ME 的 LHRH 和 NA 的释放,即 LHRH 释放量由27.3±2.5pg/100ul 增加至150.4±27.9pg/100μl;NA 释放量由50.9±4.2pg/100μl 增加至105.5±19.1pg/100ul,两者与对照组相比有显著差异(P<0.01)。GABA 这些作用可被受体拮抗剂荷包牡丹碱(Bicuculline)所翻转。当荷包牡丹碱和 GABA(10^(-6)mol/L)同时存在于 ME 的培灌液中,LHRH 的分泌量下降为18.2±1.9pg/100μl,而 NA 分泌量下降为43.9±3.4pg/100μl。在内源性 NA 被利血平耗竭时,LHRH 的释放量仅增加26.5%,而 GABA 能使正常大鼠 LHRH 释放量增加451.9%。本研究提示:GABA 可促进下丘脑 ME 释放 LHRH,这一作用可能通过 NA 中介。展开更多
Hormone naive advanced prostate cancer is subdivided into two disease states： biochemical recurrence and traditional M 1 （metastatic） prostate cancer and characterized by no prior hormonal therapy or androgen depri...Hormone naive advanced prostate cancer is subdivided into two disease states： biochemical recurrence and traditional M 1 （metastatic） prostate cancer and characterized by no prior hormonal therapy or androgen deprivation therapy （ADT）. In biochemical recurrence/ prostate-specific antigen （PSA） recurrence, men should be risk-stratified based on their PSA doubling time, the Gleason score and the timing of the recurrence. In general, only men who are at high risk should be considered for early/immediate ADT although this is best done using shared decision with the patient. The type of ADT to be used in biochemical recurrence ranging from oral-only peripheral blockade （peripheral androgen deprivation） to complete hormonal therapy （combined androgen blockade [CAB]） remains in debate owing to lack of randomized controlled trials （RCT）. However, there is good RCT support for use of intermittent hormonal therapy （IHT）. There is also limited research on biomarker response （PSA and testosterone decline） to predict prognosis. On the other hand, in the setting of M1 hormone naive prostate cancer, there are many more RCT＇s to inform our decisions. CAB and gonadotrophin-releasing hormone antagonists perhaps provide a slight efficacy advantage while IHT may be slightly inferior with minimal M1 disease. The PSA nadir at 7 months after starting ADT is a powerful prognostic tool for M1 patients. There is growing recognition that serum testosterone （T） control while on ADT is linked to the development of castrate-resistant prostate cancer. Especially for a M 1 patient, maintaining a serum T below 20-30 ng d1-1 prolongs the response to ADT. Novel oral agents （abiraterone and enzalutamide） may soon find use in hormone naive disease and may alter the treatment landscape. Despite over 75 years of experience with ADT, many questions remain, and the field continues to evolve.展开更多
The introduction of new cytotoxic substances as well as agents that target vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) signaling has improved clinical outcome of patients with...The introduction of new cytotoxic substances as well as agents that target vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) signaling has improved clinical outcome of patients with metastatic colorectal cancer (mCRC). In this review we summarize the most relevant clinical data on VEGF and EGFR targeting regimens in mCRC. The effects of available treatment strategies for mCRC are often temporary, with resistance and disease progression developing in most patients. Thus, new treatment strategies are urgently needed. Some GI peptides including gastrin and gastrin releasing peptide, certain growth factors such as insulin-like growth factor-I and II and neuropeptides such as growth hormone releasing hormone (GHRH) are implicated in the growth of CRC. Experimental investigations in CRC with antagonistic analogs of bombesin/gastrin-releasing peptide, GHRH, and with cytotoxic peptides that can be targeted to peptide receptors on tumors, are summarized in the second part of the review.展开更多
It is found that the drugs for nourishing yin to reduce pathogenic fire can significantly down-regulate,and the drugs for tonifying the kidney to replenish essence can up-regulate mRNA expression of the hypothalamic G...It is found that the drugs for nourishing yin to reduce pathogenic fire can significantly down-regulate,and the drugs for tonifying the kidney to replenish essence can up-regulate mRNA expression of the hypothalamic GnRH,pituitary FSH,LH and osteoblastic BGP,indicating that the Chinese drugs for tonifying the kidney can regulate gene expression of the hypothalamic GnRH,pituitary FSH,LH,and osteoblastic BGP,which is possibly one of the main mechanisms of the Chinese drug for tonifying the kidney,regulating ephebic development process and improving skeletal development in sexual precocity children.展开更多
文摘AIM To investigate the therapeutic potential of two recombinant proteins, Survivin and luteinizing hormone-releasing hormone (LHRH) fusion protein [LHRH(6 leu)-LTB] for immunotherapy of breast cancer.METHODS Murine 4 T-1 breast cancer model was used to evaluate the efficacy of recombinant proteins in vivo. Twenty four Balb/c mice were divided into 4 groups of 6 mice each. Recombinant Survivin and LHRH fusion protein, alone or in combination, were administered along with immunomodulator Mycobacterium indicus pranii (MIP) in Balb/c mice. Unimmunized or control group mice were administered with phosphate buffer saline. Each group was then challenged with syngeneic 4 T-1 cells to induce the growth of breast tumor. Tumor growth was monitored to evaluate the efficacy of immune-response in preventing the growth of cancer cells.RESULTS Preventive immunization with 20 μg recombinant Survivin and MIP was effective in suppressing growth of 4 T-1 mouse model of breast cancer (P = 0.04) but 50 μg dose was ineffective in suppressing tumor growth. However, combination of Survivin and LHRH fusion protein was more effective in suppressing tumor growth (P = 0.02) as well as metastasis in vivo in comparison to LHRH fusion protein as vaccine antigen alone.CONCLUSION Recombinant Survivin and MIP suppress tumor growth significantly. Combining LHRH fusion protein with Survivin and MIP enhances tumor suppressive effects marginally which provides evidence for recombinant Survivin and LHRH fusion protein as candidates for translating the combination cancer immunotherapy approaches.
文摘Aim： To evaluate the long-term effectiveness, side effects and compliance rates of two types of drugs （luteinizing hormone-releasing hormone [LHRH] agonist and antiandrogen） that were used individually to treat patients with localized prostate cancer （T1-2） at our institution. Methods： Ninety-seven patients who were diagnosed in the period from April 1997 to January 2000 as having clinically localized prostate cancer （T1-2） received either LHRH agonist （leuprolide acetate 7.5 mg/month） monotherapy （group 1, n = 62） or antiandrogen monotherapy （group 2, n = 35; 18 received bicalutamide 50 mg q.d., 13 received nilutamide 150 mg t.i.d, and 4 received flutamide 250 mg t.i.d.）. The mean age in both groups was 76 years. Results： The mean follow-up time was （50.8 ±8.5） months in group 1 and （43.1 ± 2.2） months in group 2. Prostate-specific antigen （PSA） levels rose in only 1 of the 62 patients （1.6%） in group 1, and in 20 of the 35 patients （57.1%） in group 2. In group 2, 10 of the 20 patients （50 %） with increasing PSA levels were treated with LHRH salvage therapy, and eight （80%） responded. Hot flashes （54.8%） and lethargy （41.9%） were the most common side effects in group 1. In contrast, nipple-tenderness （40%） and light-dark adaptation （17.1%） were more often seen in group 2. Only 1 of the 62 patients （1.6%） in group 1 switched to another medication because of adverse side effects; whereas 8 of the 35 patients （22.9%） in group 2 did so. Conclusion： Unlike antiandrogen monotherapy, LHRH agonist monotherapy provided long-term durable control of localized prostate cancer （T1-2）. It can also be an effective treatment option for patients whose disease failed to respond to antiandrogen monotherapy. The limitations of our study are the lack of health outcomes analysis and a small sample size.
基金supported by the National Natural Science Foundation of China(30910103916)the Key Project of the Science and Technology Program of Hainan,China(06122)
文摘Luteinizing hormone-releasing hormone(LHRH) is known to influence sexual behavior in many vertebrate taxa, but there have been no systematic studies on the role of LHRH in sexual behavior of turtles. We tested the hypotheses that exogenous LHRH analogues would induce sexual behavior of male Four-eyed turtle, Sacalia quadriocellata. We examined this by challenging males with intramuscular injections of mammalian luteinizing hormone-releasing hormone analogue(LHRH-A), human chorionic gonadotropin(HCG), or a combination of the two, and subsequently exposing them to sexually receptive females for behavioral observation. Our data show that the injection of only HCG could not, while that of only LHRH-A could, facilitate sexual behavior along with testicular recrudescence and spermatogenesis in S. quadriocellata. The injection of both LHRH-A and HCG would induce more drastic sexual behavior of the animals than that of LHRH-A alone, indicating HCG enhances the effects of LHRH-A induced sexual behavior. However, different pharmacological dosages of LHRH-A(0.5 μg, 1 μg, 2 μg per 100 g bodyweight) did not correspond to different activity levels. Though the mechanism of LHRH effect was not determined, this study may support that the sexual behavior of S. quadriocellata which occurs at the beginning of the injection despite regression of the gonads. This is the first report on the exogenous LHRH-A induced sexual behavior for this species.
基金Supported by The Medical Research Service of the Veterans Affairs Department,Departments of Pathology and Medicine,Division of Hematology/Oncology,Sylvester Comprehensive Cancer Center,University of Miami,Miller School of Medicine,the South Florida Veterans Affairs Foundation for Research and Education(all to Schally AV)the L Austin Weeks Endowment for Urologic Research(to Block NL)+2 种基金in part by a grant from the Urology Care Foundation Research Scholars Program and the American Urological Association(AUA)Southeastern Section(to Rick FG)by a stipend program of the Department of Medicine,Dresdenby the Helmholtz Alliance ICEMED(Imaging and Curing Environmental Metabolic Diseases)through the Initiative and Networking Fund of the Helmholtz Association(to Popovics P)
文摘Benign prostatic hyperplasia(BPH)is a pathologic condition of the prostate described as a substantial increase in its number of epithelial and stromal cells.BPH may significantly reduce the quality of life due to the initiation of bladder outlet obstruction and lower urinary tract syndromes.Current medical therapies mostly consist of inhibitors of 5α-reductase orα1-adrenergic blockers;their efficacy is often insufficient.Antagonistic analogs of neuropeptide hormones are novel candidates for the management of BPH.At first,antagonists of luteinizing hormone-releasing hormone(LHRH)have been introduced to the therapy aimed to reduce serum testosterone levels.However,they have also been found to produce an inhibitory activity on local LHRH receptors in the prostate as well as impotence and other related side effects.Since then,several preclinical and clinical studies reported the favorable effects of LHRH antagonists in BPH.In contrast,antagonists of growth hormone-releasing hormone(GHRH)and gastrin-releasing peptide(GRP)have been tested only in preclinical settings and produce significant reduction in prostate size in experimental models of BPH.They act at least in part,by blocking the action of respective ligands produced locally on prostates through their respective receptors in the prostate,and by inhibition of autocrine insulin-like growth factors-Ⅰ/Ⅱand epidermal growth factor production.GHRH and LHRH antagonists were also tested in combination resulting in a cumulative effect that was greater than that of each alone.This article will review the numerous studies that demonstrate the beneficial effects of antagonistic analogs of LHRH,GHRH and GRP in BPH,as well as suggesting a potential role for somatostatin analogs in experimental therapies.
文摘本研究应用大鼠下丘脑正中隆起(ME),观察 γ-氨基丁酸(GABA)和去甲肾上腺素(NA)对下丘脑促黄体生成激素释放激素(LHRH)神经元末梢分泌作用的影响。结果发现:GABA(10^(-6)mol/L)可显著促进 ME 的 LHRH 和 NA 的释放,即 LHRH 释放量由27.3±2.5pg/100ul 增加至150.4±27.9pg/100μl;NA 释放量由50.9±4.2pg/100μl 增加至105.5±19.1pg/100ul,两者与对照组相比有显著差异(P<0.01)。GABA 这些作用可被受体拮抗剂荷包牡丹碱(Bicuculline)所翻转。当荷包牡丹碱和 GABA(10^(-6)mol/L)同时存在于 ME 的培灌液中,LHRH 的分泌量下降为18.2±1.9pg/100μl,而 NA 分泌量下降为43.9±3.4pg/100μl。在内源性 NA 被利血平耗竭时,LHRH 的释放量仅增加26.5%,而 GABA 能使正常大鼠 LHRH 释放量增加451.9%。本研究提示:GABA 可促进下丘脑 ME 释放 LHRH,这一作用可能通过 NA 中介。
文摘Hormone naive advanced prostate cancer is subdivided into two disease states： biochemical recurrence and traditional M 1 （metastatic） prostate cancer and characterized by no prior hormonal therapy or androgen deprivation therapy （ADT）. In biochemical recurrence/ prostate-specific antigen （PSA） recurrence, men should be risk-stratified based on their PSA doubling time, the Gleason score and the timing of the recurrence. In general, only men who are at high risk should be considered for early/immediate ADT although this is best done using shared decision with the patient. The type of ADT to be used in biochemical recurrence ranging from oral-only peripheral blockade （peripheral androgen deprivation） to complete hormonal therapy （combined androgen blockade [CAB]） remains in debate owing to lack of randomized controlled trials （RCT）. However, there is good RCT support for use of intermittent hormonal therapy （IHT）. There is also limited research on biomarker response （PSA and testosterone decline） to predict prognosis. On the other hand, in the setting of M1 hormone naive prostate cancer, there are many more RCT＇s to inform our decisions. CAB and gonadotrophin-releasing hormone antagonists perhaps provide a slight efficacy advantage while IHT may be slightly inferior with minimal M1 disease. The PSA nadir at 7 months after starting ADT is a powerful prognostic tool for M1 patients. There is growing recognition that serum testosterone （T） control while on ADT is linked to the development of castrate-resistant prostate cancer. Especially for a M 1 patient, maintaining a serum T below 20-30 ng d1-1 prolongs the response to ADT. Novel oral agents （abiraterone and enzalutamide） may soon find use in hormone naive disease and may alter the treatment landscape. Despite over 75 years of experience with ADT, many questions remain, and the field continues to evolve.
文摘The introduction of new cytotoxic substances as well as agents that target vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) signaling has improved clinical outcome of patients with metastatic colorectal cancer (mCRC). In this review we summarize the most relevant clinical data on VEGF and EGFR targeting regimens in mCRC. The effects of available treatment strategies for mCRC are often temporary, with resistance and disease progression developing in most patients. Thus, new treatment strategies are urgently needed. Some GI peptides including gastrin and gastrin releasing peptide, certain growth factors such as insulin-like growth factor-I and II and neuropeptides such as growth hormone releasing hormone (GHRH) are implicated in the growth of CRC. Experimental investigations in CRC with antagonistic analogs of bombesin/gastrin-releasing peptide, GHRH, and with cytotoxic peptides that can be targeted to peptide receptors on tumors, are summarized in the second part of the review.
文摘It is found that the drugs for nourishing yin to reduce pathogenic fire can significantly down-regulate,and the drugs for tonifying the kidney to replenish essence can up-regulate mRNA expression of the hypothalamic GnRH,pituitary FSH,LH and osteoblastic BGP,indicating that the Chinese drugs for tonifying the kidney can regulate gene expression of the hypothalamic GnRH,pituitary FSH,LH,and osteoblastic BGP,which is possibly one of the main mechanisms of the Chinese drug for tonifying the kidney,regulating ephebic development process and improving skeletal development in sexual precocity children.
