Breast cancer is the leading cancer in women of reproductive age; more than a quarter of women diagnosed with breast cancer in the US are premenopausal. A common adjuvant treatment for this patient population is chemotherapy, which has been shown to cause premature menopause and infertility with serious consequences to quality of life. Luteinizing-hormone-releasing hormone (LHRH) agonists, which induce temporary ovarian function suppression (OFS), has been shown to be a useful alternative to chemotherapy in the adjuvant setting for estrogen-receptor-positive breast cancer patients. LHRH agonists have the potential to preserve fertility after treatment, thus, reducing the negative effects on a patient’s reproductive health. However, little is known about the association between a patient’s underlying degree of OFS and disease-free survival (DFS) after receiving LHRH agonists. Specifically, we are interested in whether patients with lower underlying degrees of OFS (i.e. higher estrogen production) after taking LHRH agonists are at a higher risk for late breast cancer events. In this paper, we propose a latent class joint model (LCJM) to analyze a data set from International Breast Cancer Study Group (IBCSG) Trial VIII to investigate the association between OFS and DFS. Analysis of this data set is challenging due to the fact that the main outcome of interest, OFS, is unobservable and the available surrogates for this latent variable involve masked event and cured proportions. We employ a likelihood approach and the EM algorithm to obtain parameter estimates and present results from the IBCSG data analysis.
joint modeling; latent class model; EM algorithm; masked event; cured proportion; breast cancer
Current standard adjuvant therapies for early breast cancer include tamoxifen and chemotherapy, depending on the disease prognosis and menopausal status. Luteinizing hormone-releasing hormone (LHRH) analogues offer a different approach to the management of early breast cancer in pre- and perimenopausal women. The most widely studied LHRH analogue is goserelin. It acts on the hypothalamic-pituitary axis to suppress ovarian function, decreasing luteinizing hormone and oestradiol levels to post-menopausal values. Pooled data from 228 premenopausal and perimenopausal patients with advanced breast cancer enrolled in 29 studies worldwide demonstrated an objective response rate for goserelin, 3.6 mg, of 36.4%, with a median duration of response of 44 weeks. These results fall well within the ranges of reported response rates for ovarian ablation and for tamoxifen in similar patient populations. By virtue of its mode of action, goserelin does not stimulate the ovaries and is unlikely to have detrimental effects on the endometrium. In addition, given that goserelin has no oestrogen agonist-like effects, unlike tamoxifen, there is no potential for tumour stimulation in those patients becoming resistant to treatment. Goserelin is generally well tolerated, and the main side-effects are related to ovarian suppression, which is potentially reversible. Preliminary results in premenopausal women with early breast cancer indicate that endocrine treatment with goserelin plus tamoxifen may be as effective as standard combination chemotherapy (cyclophosphamide-methotrexate-5-fluorouracil), but has significantly less acute toxicity. A number of large, randomized trials are now in progress to assess the potential role of goserelin as adjuvant therapy for early breast cancer.
Long-acting luteinizing hormone-releasing hormone (LHRH) agonists, such as goserelin, have been used for locally advanced and metastatic prostate cancer for many years and are the main forms of androgen deprivation therapy (ADT). Acting on pituitary LHRH receptors, they initially stimulate a transient rise in serum follicle-stimulating hormone (FSH) and LH. Long-term administration of an LHRH analogue will eventually lead to down regulation of LHRH receptors, thus suppressing FSH and LH secretion. This in turn suppresses testosterone production hence achieving and maintaining androgen deprivation. This case highlights the potential anomaly of a sustained elevated serum testosterone in the context of newly diagnosed locally advanced prostate cancer with a co-existing pituitary macroadenoma after administration of LHRH analogues. Alternative methods of androgen deprivation must be considered in such patients.
Androgen deprivation therapy remains the mainstay of medical treatment for advanced prostate cancer. Commonly, this is achieved with medical androgen deprivation rather than surgical intervention as the permanence and psychological effects of the latter are unacceptable for most patients. Degarelix is a third generation antagonist of luteinizing hormone-releasing hormone (LHRH, also termed gonadotropin-releasing hormone) for the first-line treatment of androgen-dependent advanced prostate cancer. Degarelix acts directly on the pituitary receptors for LHRH, blocking the action of endogenous LHRH. The use of degarelix eliminates the initial undesirable surge in gonadotropin and testosterone levels, which is produced by agonists of LHRH. Degarelix is the most comprehensively studied and widely available LHRH antagonist worldwide. Clinical trials have demonstrated that degarelix has a long-term efficacy similar to the LHRH agonist leuprolide in achieving testosterone suppression in patients with prostate cancer. Degarelix, however, produces a faster suppression of testosterone and prostate-specific antigen (PSA), with no testosterone surges or microsurges, and thus prevents the risk of clinical flare in advanced disease. Recent clinical trials demonstrated that treatment with degarelix results in improved disease control when compared with an LHRH agonist in terms of superior PSA progression-free survival, suggesting that degarelix likely delays progression to castration-resistant disease and has a more significant impact on bone serum alkaline phosphatase and follicle-stimulating hormone. Degarelix is usually well tolerated, with limited toxicity and no evidence of systemic allergic reactions in clinical studies. Degarelix thus represents an important addition to the hormonal armamentarium for therapy of advanced androgen-dependent prostate cancer.
degarelix; GnRH; LHRH; metastatic prostate cancer; androgen-dependent prostate cancer; hormonal therapy
Analogues of luteinising hormone releasing hormone (LHRH) have recently been introduced as an alternative to surgical orchidectomy in prostate cancer, but there has been concern about the economic costs of long-term treatment. The paper presents a comparison of costs for LHRH analogues versus orchidectomy in patients with advanced prostate cancer. The cost for the surgical procedure was estimated using data on patients treated with orchidectomy in Stockholm County, Sweden, during 1981-86. Estimates of costs for treatment with a depot LHRH analogue was based on observed treatment times among patients with symptomatic prostate cancer in a British randomised clinical trial of medical castration versus surgical orchidectomy. The average cost for orchidectomy was estimated at 2,580 pounds i.e. 7-31% less than for treatment with a depot LHRH analogue (2,760 pounds-3,380 pounds) assuming a mean treatment time in the range 19-23 months. The most cost-effective policy for castration was found to be initial treatment with an LHRH analogue followed by deferred orchidectomy after about 2 years among long-term responders. This policy would obviate the need for surgery in about 85% of the patients and the average cost (1,900 pounds) would be about 26% lower compared to that of a policy of primary orchidectomy in all patients.
Active targeting could increase the efficacy of anticancer drugs. Methotrexate-human serum albumin (MTX-HSA) conjugates, functionalized by luteinizing hormone-releasing hormone (LHRH) as targeting moieties, with the aim of specifically targeting the cancer cells, were prepared. Owing to the high expression of LHRH receptors in many cancer cells as compared to normal cells, LHRH was used as the targeting ligand in this study. LHRH was conjugated to MTX-HSA nanoparticles via a cross-linker. Three types of LHRH targeted nanoparticles with a mean particle size between 120–138 nm were prepared. The cytotoxicity of LHRH targeted and non-targeted nanoparticles were determined on the LHRH positive and negative cell lines. The internalization of the targeted and non-targeted nanoparticles in LHRH receptor positive and negative cells was investigated using flow cytometry analysis and fluorescence microscopy. The cytotoxicity of the LHRH targeted nanoparticles on the LHRH receptor positive cells were significantly more than non-targeted nanoparticles. LHRH targeted nanoparticles were also internalized by LHRH receptor positive cells significantly more than non-targeted nanoparticles. There were no significant differences between the uptake of targeted and non-targeted nanoparticles to the LHRH receptor negative cells. The active targeting procedure using LHRH targeted MTX-HSA nanoparticles could increase the anti-tumoral activity of MTX.
nanoparticles; drug targeting; conjugates; anti-cancer; human serum albumin; LHRH
Pancreatic ductal adenocarcinomas are invariably lethal and developing effective treatments that have minimal side effects is a challenge. Previous studies from our lab have shown that conjugates of cell membrane disrupting lytic peptides and luteinizing hormone releasing hormone (LHRH) target and destroy human prostate and breast cancer cells in xenografts in the nude mouse model 1, 2 which express LHRH receptors. The objectives of this study were to synthesize a bioconjugate of LHRH analog ([DLys6]-LHRH) and a dietary micro-chemical (Curcumin) and test the hypothesis that [DLys6]-LHRH-Curcumin targets and inhibits pancreatic cancer cell growth in vitro and in vivo. In in vitro studies, we determined by confocal microscopy, flow cytometry analysis and RT-PCR that MIAPaCa-2, Panc-1 and BxPC-3 pancreatic cancer cell lines express LHRH receptors. [DLys6]-LHRH-Curcumin inhibited cell proliferation of pancreatic cancer cell lines and induced apoptotic cell death (p < 0.05). Apoptosis was induced by cleavage of PARP and Caspase-3. The activity of [DLys6]-LHRH-Curcumin was equal to free Curcumin at equimolar concentrations in vitro. Unlike Curcumin itself, the [DLys6]-LHRH-Curcumin conjugate is water soluble which allows its intravenous administration. In two in vivo studies, [DLys6]-LHRH-Curcumin given intravenously caused a significant (p < 0.01) reduction in tumor weights and volumes, and free Curcumin given by gavage at an equal dose failed to cause a significant reduction in tumor weights and volumes in the nude mouse pancreatic cancer model. [DLys6]-LHRH-Curcumin treatment enhanced apoptosis compared to [DLys6]-LHRH and vehicle treated controls in tumor tissue. In conclusion, [DLys6]-LHRH-Curcumin may be useful in treating pancreatic cancer.
Pancreatic cancer; Curcumin; [DLys6]-LHRH-Curcumin; luteinizing hormone releasing hormone receptor; tumor growth inhibition
Previously, we have shown that 17β-estradiol (E2) induces an increase in firing activity and modifies the pattern of intracellular calcium ([Ca2+]i) oscillations with a latency less than 1 min in primate luteinizing hormone releasing hormone (LHRH) neurons. A recent study also indicates that E2, the nuclear membrane impermeable estrogen, estrogen- dendrimer conjugate (EDC), and the plasma membrane impermeable estrogen, E2-BSA conjugate, all similarly stimulated LHRH release within 10 min of exposure in primate LHRH neurons, indicating that the rapid action of E2 is caused by membrane signaling. The results from a series of studies further suggest that the rapid E2 action in primate LHRH neurons appears to be mediated by GPR30. Whereas the estrogen receptor antagonist, ICI 182,780, neither blocked the E2-induced LHRH release nor the E2-induced changes in [Ca2+]i oscillations, E2 application to cells treated with pertussis toxin (PTX) failed to result in these changes in primate LHRH neurons. Moreover, knockdown of GPR30 in primate LHRH neurons by transfection with human siRNA for GPR30 completely abrogated the E2-induced changes in [Ca2+]i oscillations, whereas transfection with control siRNA did not. Finally, the GPR30 agonist, G1, resulted in changes in [Ca2+]i oscillations similar to those observed with E2. In this review the authors discuss the possible role of G-protein coupled receptors in the rapid action of estrogen in neuronal cells.
GnRH neurons; rapid action of estrogen; GPR30; GPCR; primates
Ten previously untreated postmenopausal women with metastatic breast cancer, none of whom had received prior systemic therapy, were treated with the luteinising hormone releasing hormone (LHRH) analogue D-Ser(But)6, Azgly10-LHRH (ICI 118630). Two obtained an objective partial remission, one in bone metastases and one in lung metastases. One patient proved unassessable. Amongst the seven failures, incomplete pituitary gonadotrophin suppression over the relatively short treatment period with the daily injections was noted. The seven patients failing ICI 118630 received tamoxifen and two with high tumour oestrogen receptor values responded. LHRH analogues may provide a novel endocrine therapy for postmenopausal breast cancer although more data are needed. In this study, the monthly depot injection proved superior to daily injections with regard to gonadotrophin suppression, although it is not clear that this provides the mechanism of action.
Pheochromocytoma is a rare but potentially lethal chromaffin cell tumor with currently no effective treatment. Peptide hormone receptors are frequently overexpressed on endocrine tumor cells and can be specifically targeted by various anti-tumor peptide analogs. The present study carried out on mouse pheochromocytoma cells (MPC) and a more aggressive mouse tumor tissue-derived (MTT) cell line revealed that these cells are characterized by pronounced expression of the somatostatin receptor 2 (sst2), growth hormone-releasing hormone (GHRH) receptor and the luteinizing hormone-releasing hormone (LHRH) receptor. We further demonstrated significant anti-tumor effects mediated by cytotoxic somatostatin analogs, AN-162 and AN-238, by LHRH antagonist, Cetrorelix, by the cytotoxic LHRH analog, AN-152, and by recently developed GHRH antagonist, MIA-602, on MPC and for AN-152 and MIA-602 on MTT cells. Studies of novel anti-tumor compounds on these mouse cell lines serve as an important basis for mouse models of metastatic pheochromocytoma, which we are currently establishing.
pheochromocytoma; peptide analogs; targeted tumor therapy
The cyclic production of estrogen and progesterone by the premenopausal ovary accounts for the steep rise in breast cancer risk in premenopausal women. These hormones are breast cell mitogens. By reducing exposure to these ovarian hormones, agonists of luteinizing hormone-releasing hormone (LHRH) given to suppress ovarian function may prove useful in cancer prevention. To prevent deleterious effects of hypoestrogenemia, the addition of low-dose hormone replacement to the LHRH agonist appears necessary. Pilot data with such an approach indicates it is feasible and reduces mammographic densities.
breast cancer prevention; gonadotropin-releasing hormone agnonists; hormonal carcinogenesis; luteinizing hormone-releasing hormone agonists
Uveal melanoma is the most common primary intraocular malignancy in adults, with a very high mortality rate due to frequent liver metastases. Consequently, the therapy of uveal melanoma remains a major clinical challenge and new treatment approaches are needed. For improving diagnosis and designing a rational and effective therapy, it is essential to elucidate molecular characteristics of this malignancy. The aim of this study therefore was to evaluate as a potential therapeutic target the expression of luteinizing hormone-releasing hormone (LHRH) receptor in human uveal melanoma. The expression of LHRH ligand and LHRH receptor transcript forms was studied in 39 human uveal melanoma specimens by RT-PCR using gene specific primers. The binding charachteristics of receptors for LHRH on 10 samples were determined by ligand competition assays. The presence of LHRH receptor protein was further evaluated by immunohistochemistry. The expression of mRNA for type I LHRH receptor was detected in 18 of 39 (46%) of tissue specimens. mRNA for LHRH-I ligand could be detected in 27 of 39 (69%) of the samples. Seven of 10 samples investigated showed high affinity LHRH-I receptors. The specific presence of full length LHRH receptor protein was further confirmed by immunohistochemistry. A high percentage of uveal melanomas express mRNA and protein for type-I LHRH receptors. Our results support the merit of further investigation of LHRH receptors in human ophthalmological tumors. Since diverse analogs of LHRH are in clinical trials or are already used for the treatment of various cancers, these analogs could be considered for the LHRH receptor-based treatment of uveal melanoma.
A sterically stabilized, mitoxantrone-loaded liposome, tailored to target luteinizing hormone-releasing hormone (LHRH) receptor overexpressing cells, was developed to promote the efficiency of intracellular delivery of mitoxantrone through receptor-mediated endocytosis. Liposomes were prepared by lipid film hydration and an ultrasound dispersion process. Thiolated gonadorelin with affinity for the LHRH receptor was chemically coupled to N-[(3-maleimide-1-oxopropyl) aminopropyl polyethylene glycol-carbamyl] distearoyl-l-phosphatidyl-ethanolamine via a thioether bond and subsequently inserted into polyethylene glycol-grafted liposomes. The liposome was characterized in terms of its size, ligand density, drug loading, and leakage properties. The targeting nature and antitumor effects of the liposomes were evaluated in vitro using cultured MCF-7 breast cancer cells. A protein assay of ligand coupling to the liposomal surface indicated that more than 60% of the LHRH peptides were inserted into the liposome bilayer. Up to 1.0 mg/mL of stable liposomal mitoxantrone loading was achieved, with approximately 98% of this being entrapped within the liposomes. In vitro cell culture studies revealed that the gonadorelin-modified liposomes bound to their target cells had significantly higher affinity and better antitumor efficiency than generic drug-loaded liposomes. These events were presumed to occur through specific interactions of the LHRH with its cognate receptors on the cell surface. It was concluded that the targeting properties of the delivery system would potentially improve the therapeutic benefits of mitoxantrone, as compared with nontargeted liposomes.
mitoxantrone; liposome; luteinizing hormone-releasing hormone receptor; tumor targeting
Superparamagnetic iron oxide nanoparticles (SPIONs) bound directly to luteinizing hormone releasing hormone (LHRH) have shown high efficiency for intracellular uptake to breast cancer cells, MDA-MB-435S.luc. We demonstrate in this communication that inclusion of a small spacer molecule such as glutaric acid (Glu) in between SPION and LHRH increases further receptor mediated intracellular uptake. LHRH-bound SPIONs with and without the spacer molecule were nontoxic.
Glutaric acid; luteinizing hormone releasing hormone; superparamagnetic iron oxide nanoparticles; MDA-MB-435S.luc.; intracellular uptake
The prostate secretes enzymes and nutrients to promote sperm motility. Recent reports suggest that the prostate may also secrete testosterone, which is believed to be a fuel for prostate tumour growth. The aim of this study was to determine if a difference in serum testosterone levels exists between men on luteinizing hormone releasing-hormone (LHRH) agonists who have undergone radical prostatectomy, radiation or hormone therapy as primary prostate cancer treatment.
Serum testosterone levels were evaluated in 165 consecutive prostate cancer patients using LHRH analogues for >3 months. We excluded patients receiving either radiation or chemotherapy at time of time of testosterone measurement. Patients were classified based on primary treatment: (1) radical prostatectomy; (2) radiation; or (3) primary hormone therapy. We used one-way ANOVA to compare testosterone levels. Pearson correlation was used to correlate testosterone with prostate-specific antigen (PSA) and time on LHRH agonists. Multivariable linear regression was used to predict serum testosterone levels.
The median (interquartile range) serum testosterone levels were 1.4 (1–1.9), 1.3 (1–1.625) and 1.25 (0.9–1.525) nmol/L for radical prostatectomy, radiation and primary hormone therapy groups, respectively. There was no statistically significant difference in testosterone levels between the groups (p = 0.3). No correlation was found between testosterone and PSA levels or time on LHRH (r = 0.02 and r = 0.01), respectively. Multivariable linear regression showed that none of the clinical variables were predictors of serum testosterone levels.
Our study suggests that primary treatment does not affect serum testosterone levels among men using LHRH analogues.
Irreversible chemical programming of monoclonal aldolase antibody (mAb) 38C2 has been accomplished with β-lactam equipped mono- and bifunctional targeting modules, including a cyclic-RGD peptide linked to either the peptide (D-Lys6)-LHRH or another cyclic RGD unit and a small-molecule integrin inhibitor SCS-873 conjugated to (D-Lys6)LHRH. We also prepared monofunctional targeting modules containing either cyclic RGD or (D-Lys6)-LHRH peptides. Binding of the chemically programmed antibodies to integrin receptors α(v)β(3) and α(v)β(5) and to the luteinizing hormone releasing hormone receptor were evaluated. The bifunctional and bivalent c-RGD/LHRH and SCS-783/LHRH, the monofunctional and tetravalent c-RGD/c-RGD, and the monofunctional bivalent c-RGD chemically programmed antibodies bound specifically to the isolated integrin receptor proteins as well as to integrins expressed on human melanoma M21 cells. c-RGD/LHRH, SCS-783/LHRH, and LHRH chemically programmed antibodies bound specifically to the LHRH receptors expressed on human ovarian cancer cells. This approach provides an efficient, versatile, and economically viable route to high-valency therapeutic antibodies that target defined combinations of specific receptors. Additionally, this approach should be applicable to chemically programmed vaccines.
Four male transsexual subjects were given a superactive luteinizing hormone-releasing hormone (LHRH) analogue, D-tryptophan-6-LHRH at daily doses of 100 micrograms for 3--6 mo. A decrease in beard growth, acne, and erectile potency was noted; the latter was documented objectively with the recordings of nocturnal penile tumescence episodes. Plasma testosterone and dihydrotestosterone levels fell to castrate values; basal prolactin and luteinizing hormone levels showed a small decline, whereas the acutely releasable luteinizing hormone was significantly suppressed. A rise of plasma testosterone from castrate to normal levels was demonstrable with the use of human chorionic gonadotropin. Discontinuation of treatment led to a normalization of erectile potency and plasma testosterone. The suppression of Leydig cell function by D-tryptophan-6-LHRH might have wide application in reproductive biology and in endocrine-dependent neoplasia (where it could replace surgical castration).
Chemically disordered face centered cubic (fcc) FePt nanoparticles (NPs) show the controlled release of Fe in low pH solution. The released Fe catalyzes H2O2 decomposition into reactive oxygen species within cells, causing fast oxidation and deterioration of cellular membrane. Functionalized with luteinizing hormone-releasing hormone (LHRH) peptide via phospholipid, the fcc-FePt NPs can bind preferentially to the human ovarian cancer cell line (A2780) that over-expresses LHRH receptors, and exhibit high toxicity to these tumor cells. In contrast, the fcc-FePt NPs pre-etched in the low pH (4.8) buffer solution show non-appreciable cytotoxicity. The work demonstrates that fcc-FePt NPs may function as a new type of agent for controlled cancer therapy.
Advanced or recurrent endometrial cancer (EC) no longer amenable to surgery or radiotherapy is a life-threatening disease with limited therapeutic options left. Eighty percent of ECs express receptors for luteinizing hormone–releasing hormone (LHRH), which can be targeted by AEZS-108 (zoptarelin doxorubicin acetate). This phase 2 trial was performed to assess the efficacy and safety of AEZS-108 in this group of patients.
Patients had FIGO (Fédération Internationale de Gynécologie et d’Obstétrique) III or IV or recurrent EC, LHRH receptor–positive tumor status, and at least had 1 measurable lesion (Response Evaluation Criteria in Solid Tumors). Prior anthracycline therapy was not allowed. Patients received AEZS-108 as a 2-hour infusion on day 1 of a 21-day cycle. The treatment was continued for a maximum of 6 to 8 cycles. The primary end point was the response rate determined by the Response Evaluation Criteria in Solid Tumors.
From April 2008 to November 2009, 44 patients were included in the study at 8 centers in Germany (AGO) and 3 centers in Bulgaria. Forty-three of these patients were eligible. Two (5%) patients had a complete remission, and 8 (18%) achieved a partial remission. Stable disease for at least 6 weeks was observed in 44%. The median time to progression was 7 months, and the median overall survival was 15 months. The most frequently reported grade 3 or 4 adverse effects were neutropenia (12%) and leucopenia (9%).
AEZS-108, an LHRH-agonist coupled to doxorubicin, has significant activity and low toxicity in women with advanced or recurrent LHRH receptor–positive EC, supporting the principle of receptor-mediated targeted chemotherapy.
Endometrial cancer; Targeted therapy; LHRH receptor; Clinical trial; Phase 2
We previously reported the eradication of human epidermal growth factor receptor 2 (HER2)– amplified human xenografts in mice by inhibition of the HER2 pathway with lapatinib and trastuzumab to block all homo- and heterodimer signaling as well as by blockade of estrogen receptor (ER) when expressed. In this clinical trial, we sought to translate these findings to patients using targeted therapy without chemotherapy.
Patients and Methods
Women with stages II to III HER2-positive breast cancers were eligible. They received trastuzumab once per week (4 mg/kg loading, then 2 mg/kg) and lapatinib 1000 mg once per day for 12 weeks. Women with ER-positive tumors also received letrozole (plus a luteinizing hormone–releasing hormone [LHRH] agonist if premenopausal). Pathologic response was assessed by ER status. Biopsies were obtained at baseline, weeks 2 and 8, and time of surgery.
Sixty-six patients were enrolled, and 64 were eligible and evaluable for response. Median tumor size was 6 cm (range, 1.5 to 30 cm). Adverse events were mainly grades 1 to 2 (GI, 63%; skin, 46%). Grade 3 metabolic, GI, and liver (18%; 12 patients) and grade 4 liver toxicities (one patient) were also observed. Overall, in-breast pathologic complete response (pCR; ypT0-is) was 27% (ER positive, 21%; ER negative, 36%). The rate of low-volume residual disease (ypT1a-b) was 22% (ER positive, 33%; ER negative, 4%).
In patients with locally advanced HER2-positive breast cancer, our approach of targeted therapy only resulted in a high pCR rate without chemotherapy. Our data support the hypothesis that selected patients with HER2-positive tumors may not need chemotherapy, and more-complete blockade of HER receptors and ER is an effective strategy worthy of further study.
Thanks to the recent advances in reproductive medicine, more and more young women with breast cancer may be offered the possibility of preserving their fertility. Fertility can be endangered by chemotherapy, by treatment duration and by patient's age at diagnosis. The currently available means to preserve a young woman's fertility are pharmacological protection with gonadotrophin-releasing hormone analogues during chemotherapy, and ovarian tissue or oocyte/embryo freezing before treatment. New future venues, including in vitro maturation, will improve the feasibility and efficacy of the fertility preservation methods in breast cancer patients.
Breast cancer; Chemotherapy; Ovarian failure; Oocytes; Fertility preservation; Cryopreservation
We sought to compare the rate of return of testosterone levels and sexual function in men with prostate cancer receiving longer acting, 3-month preparation of luteinizing hormone-releasing hormone agonist (L-LHRH-A) versus shorter acting, 1-month preparation of luteinizing hormone-releasing hormone agonist (S-LHRH-A).
Methods and Materials:
Men with low to intermediate risk localized prostate cancer were randomized to either L-LHRH-A (2–3 month duration LHRH-A) or S-LHRH-A (6-1 month duration LHRH-A) of androgen suppression therapy (AST) and prostate brachytherapy using iodine-125 radioisotopes. Serum total testosterone levels and PSA were recorded every 2 months for 2 years.
A planned target sample size of 100 was not achieved due to insufficient accrual. A total of 55 patients were randomized and 46 were used for analysis. The median time to recovery of testosterone to baseline levels (calculated from end of AST) was 8 and 4 months in the L-LHRH-A and S-LHRH-A arms, respectively (p = 0.268). The median time to testosterone recovery to lower limit of reference range was 4 and 2 months respectively (p = 0.087).
This randomized study, which failed to reach accrual target, showed a trend towards more rapid recovery of testosterone levels using shorter acting LHRH-A. Another randomized study would be required to validate these findings. Currently, there is insufficient evidence to recommend the use of shorter acting LHRH-A as a means of providing more rapid recovery of testosterone levels.
Prostate cancer is the second leading cause of cancer deaths among men. For patients with hormone-refractory disease, few treatments are available once the tumor has metastasized beyond the prostate. In the present study, two conjugated lytic peptide sequences (named JCHLHRH and JC21LHRH) were designed to target luteinizing hormone-releasing hormone receptors (LHRH-R). Our results indicate that human prostate cancer cell lines were sensitive to both LHRH-conjugated and non-conjugated lytic peptides, with IC50 concentrations for LNCaP cells, 4.4 and 9.1 µM; for DU-145 cells, 4.8 and 5.7 µM; and for PC-3 cells, 4.4 and 8.2 µM, respectively. JCHLHRH and JC21LHRH were nontoxic to normal primary human prostate epithelial cells or to bone marrow stromal cells in co-culture. There were morphological changes in PC-3 cells after 3 hr of exposure to either peptide; after 6 hr, there were significant reductions in cell numbers. Exposure of PC-3 cells for 24 hr to either JCHLHRH or JC21LHRH blocked their growth over 3 days. Since JCHLHRH and JC21LHRH have specificity for and anti-proliferative activity against tumor cells, and low toxicity for normal prostate cells, these peptides could serve as a new type of therapy for prostate cancer.
Lytic Peptides; Prostate Cancer; Luteinizing Hormone-Releasing Hormone; Luteinizing Hormone-Releasing Hormone Receptors; Chemotherapy
Mammalian puberty requires complex interactions between glial and neuronal regulatory systems within the hypothalamus that results in the timely increase in the secretion of luteinizing hormone releasing hormone (LHRH). Assessing the molecules required for the development of coordinated communication networks between glia and LHRH neuron terminals in the basal hypothalamus, as well as identifying substances capable of affecting cell-cell communication are important. One such pathway involves growth factors of the epidermal growth factor (EGF) family that bind to specific erbB receptors. Activation of this receptor results in the release of prostaglandin-E2 (PGE2) from adjacent glial cells, which then acts on the nearby LHRH nerve terminals to elicit release of the peptide. Another pathway involves novel genes which synthesize adhesion/signaling proteins responsible for the structural integrity of bi-directional glial-neuronal communication. In this review, we will discuss the influence of these glial-neuronal communication pathways on the prepubertal LHRH secretory system, and furthermore, discuss the actions and interactions of alcohol on these two signaling processes.
alcohol; puberty; transforming growth factor-α; glia; RPTPβ
To conduct a phase I study determining the safety, pharmacokinetics and preliminary efficacy of EP-100, a novel anticancer drug consisting of natural luteinizing-hormone-releasing hormone (LHRH) ligand linked to a cationic membrane-disrupting peptide.
Patients with advanced, solid tumors, positive for LHRH receptor by immunohistochemistry (IHC), received EP-100 weekly or twice weekly for 3 of 4 weeks in a 28 day cycle. A modified Fibonacci 3 + 3 dose-escalation schema was used. Initial cohorts received EP-100 once weekly (cohorts 1–7, 0.6–7.8 mg/m2, n = 21). Later cohorts received doses twice weekly (cohorts 7–11, 7.8–40 mg/m2, n = 16).
LHRH-receptor expression was confirmed by IHC in 52 of 89 consented patients; 37 patients received at least 1 dose. Cohorts receiving doses of 5.2 mg/m2 and above achieved therapeutic levels from in vitro studies Clearance was rapid (mean half-life 7.1 ± 3.8 to 15.9 ± 3.6 min). The maximum-tolerated dose was not reached at the highest dose evaluated (40 mg/m2 twice weekly). Grade 2 increase in alanine aminotransferase/serum aspartate aminotransferase in one patient resolved, did not recur upon re-treatment, and was not observed in other patients. The only drug-related adverse event was transient infusion-related dermatologic reactions (10 patients). No complete or partial tumor responses were observed; seven patients had stable disease of 16 weeks.
EP-100 was well tolerated in patients with advanced, LHRH-receptor-expressing solid tumors. The recommended phase 2 dose is 40 mg/m2 twice weekly for 3 of 4 weeks per cycle.
Electronic supplementary material
The online version of this article (doi:10.1007/s00280-014-2424-x) contains supplementary material, which is available to authorized users.
LHRH receptor; EP-100; Cytolytic peptide; Cytolytic peptide conjugate; Advanced/metastatic solid tumors