ABSTRACT
BACKGROUND: The isolation of cell-free DNA (cfDNA) from the bloodstream can be used to detect and analyze somatic alterations in circulating tumor DNA (ctDNA), and multiple cfDNA-targeted sequencing panels are now commercially available for Food and Drug Administration (FDA)-approved biomarker indications to guide treatment. More recently, cfDNA fragmentation patterns have emerged as a tool to infer epigenomic and transcriptomic information. However, most of these analyses used whole-genome sequencing, which is insufficient to identify FDA-approved biomarker indications in a cost-effective manner. PATIENTS AND METHODS: We used machine learning models of fragmentation patterns at the first coding exon in standard targeted cancer gene cfDNA sequencing panels to distinguish between cancer and non-cancer patients, as well as the specific tumor type and subtype. We assessed this approach in two independent cohorts: a published cohort from GRAIL (breast, lung, and prostate cancers, non-cancer, n = 198) and an institutional cohort from the University of Wisconsin (UW; breast, lung, prostate, bladder cancers, n = 320). Each cohort was split 70%/30% into training and validation sets. RESULTS: In the UW cohort, training cross-validated accuracy was 82.1%, and accuracy in the independent validation cohort was 86.6% despite a median ctDNA fraction of only 0.06. In the GRAIL cohort, to assess how this approach performs in very low ctDNA fractions, training and independent validation were split based on ctDNA fraction. Training cross-validated accuracy was 80.6%, and accuracy in the independent validation cohort was 76.3%. In the validation cohort where the ctDNA fractions were all <0.05 and as low as 0.0003, the cancer versus non-cancer area under the curve was 0.99. CONCLUSIONS: To our knowledge, this is the first study to demonstrate that sequencing from targeted cfDNA panels can be utilized to analyze fragmentation patterns to classify cancer types, dramatically expanding the potential capabilities of existing clinically used panels at minimal additional cost.
Subject(s)
Cell-Free Nucleic Acids , Circulating Tumor DNA , Prostatic Neoplasms , Male , Humans , Circulating Tumor DNA/genetics , Mutation , Prostatic Neoplasms/genetics , Cell-Free Nucleic Acids/genetics , Gene Expression Profiling , Biomarkers, Tumor/geneticsABSTRACT
IMPORTANCE: Brain metastasis (BM) is the most common malignant intracranial neoplasm in adults with over 100,000 new cases annually in the United States and outnumbering primary brain tumors 10:1. OBSERVATIONS: The incidence of BM in adult cancer patients ranges from 10-40%, and is increasing with improved surveillance, effective systemic therapy, and an aging population. The overall prognosis of cancer patients is largely dependent on the presence or absence of brain metastasis, and therefore, a timely and accurate diagnosis is crucial for improving long-term outcomes, especially in the current era of significantly improved systemic therapy for many common cancers. BM should be suspected in any cancer patient who develops new neurological deficits or behavioral abnormalities. Gadolinium enhanced MRI is the preferred imaging technique and BM must be distinguished from other pathologies. Large, symptomatic lesion(s) in patients with good functional status are best treated with surgery and stereotactic radiosurgery (SRS). Due to neurocognitive side effects and improved overall survival of cancer patients, whole brain radiotherapy (WBRT) is reserved as salvage therapy for patients with multiple lesions or as palliation. Newer approaches including multi-lesion stereotactic surgery, targeted therapy, and immunotherapy are also being investigated to improve outcomes while preserving quality of life. CONCLUSION: With the significant advancements in the systemic treatment for cancer patients, addressing BM effectively is critical for overall survival. In addition to patient's performance status, therapeutic approach should be based on the type of primary tumor and associated molecular profile as well as the size, number, and location of metastatic lesion(s).
Subject(s)
Brain Neoplasms , Radiosurgery , Adult , Aged , Brain Neoplasms/surgery , Cranial Irradiation , Humans , Prognosis , Quality of Life , Retrospective Studies , Salvage TherapyABSTRACT
OBJECTIVES: Our principle objective was to examine the personal and professional impact of service user (SU) suicide on mental health professionals (MHPs). We also wished to explore putative demographic or clinical factors relating to SUs or MPHs that could influence the impact of SU suicide for MHPs and explore factors MHPs report as helpful in reducing distress following SU suicide. METHODS: A mixed-method questionnaire with quantitative and thematic analysis was utilised. RESULTS: Quantitative data indicated SU suicide was associated with personal and professional distress with sadness (79.5%), shock (74.5%) and surprise (68.7%) particularly evident with these phenomena lasting less than a year for more than 90% of MHPs. MHPs also reported guilt, reduced self-confidence and a fear of negative publicity. Thematic analysis indicated that some MHPs had greater expertise when addressing SU suicidal ideation and in supporting colleagues after experiencing a SU suicide. Only 17.7% of MHPs were offered formal support following SU suicide. CONCLUSION: SU suicide impacts MHPs personally and professionally in both a positive and negative fashion. A culture and clear pathway of formal support for MHPs to ascertain the most appropriate individualised support dependent on the distress they experience following SU suicide would be optimal.
Subject(s)
Mental Health , Suicide , Health Personnel/psychology , Humans , Self Concept , Suicide/psychology , Surveys and QuestionnairesABSTRACT
BACKGROUND: In 2001, the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) program established Residual Tissue Repositories (RTR) in the Hawaii, Iowa, and Los Angeles Tumor Registries to collect discarded tissue blocks from pathologic laboratories within their catchment areas. To validate the utility of the RTR for supplementing SEER's central database, we assessed human epidermal growth factor receptor-2 (HER2) and estrogen receptor expression (ER) in a demonstration project. MATERIALS: Using a prepared set of tissue microarrays (TMAs) residing in the Hawaii Tumor Registry (HTR), we performed standard immunohistochemistry. Breast cancers in the TMA were diagnosed in 1995, followed through 2006, and linked to SEER's main database. RESULTS: The TMA included 354 cases, representing 51% of 687 breast cancers in the HTR (1995). The HTR and TMA cases were similar with respect to patient demographics and tumor characteristics. Seventy-six percent (76%, 268 of 354) of TMA cases were HER2+ and/or ER+, i.e., 28 HER2+ER-, 12 HER2+ER+, and 228 HER2-ER+. There were 67 HER2-ER- cases and 19 were unclassified. Age distributions at diagnosis were bimodal with dominant early-onset modes for HER2+ER- tumors and dominant late-onset modes for HER2-ER+ breast cancers. Epidemiologic patterns for concordant HER2+ER+ (double-positive) and HER2-ER- (double-negative) were intermediate to discordant HER2+ER- and HER2-ER+. CONCLUSION: Results showed contrasting incidence patterns for HER2+ (HER2+ER-) and ER+ (HER2-ER+) breast cancers, diagnosed in 1995. Though sample sizes were small, this demonstration project validates the potential utility of the RTR for supplementing the SEER program.
Subject(s)
Breast Neoplasms/genetics , Receptor, ErbB-2/genetics , Receptors, Estrogen/genetics , Age Distribution , Age of Onset , Breast Neoplasms/epidemiology , Breast Neoplasms/pathology , Female , Humans , Immunohistochemistry , Incidence , Middle Aged , Oligonucleotide Array Sequence Analysis , Receptors, Progesterone/analysis , Registries , Reproducibility of Results , SEER ProgramABSTRACT
BACKGROUND: Tamoxifen has been shown to promote the growth of human endometrial tumors implanted in athymic mice, and it has been associated with a twofold to threefold increase in endometrial cancer. Toremifene, a chlorinated derivative of tamoxifen, and ICI 182,780, a pure antiestrogen, are two new antiestrogens being developed for the treatment of breast cancer. The effects of these drugs on endometrial cancer are currently unknown. Our objective was to evaluate the effects of toremifene and ICI 182,780 on the growth of human endometrial cancer in athymic mice. METHODS: Athymic, ovariectomized mice were implanted with human endometrial tumors and treated with estrogen, tamoxifen, or the new antiestrogens. RESULTS: The effects of tamoxifen and toremifene on the growth of either tamoxifen-stimulated or tamoxifen-naive endometrial tumors in athymic mice were not substantially different. ICI 182,780 inhibited the growth of tamoxifen-stimulated endometrial cancer, in both the presence and the absence of estrogen. CONCLUSIONS: Toremifene and tamoxifen produce identical effects in our endometrial cancer models. Therefore, it is possible that toremifene, like tamoxifen, may be associated with an increased incidence of endometrial cancer. In contrast, ICI 182,780 inhibited tamoxifen-stimulated endometrial cancer, both in the presence and in the absence of estrogen, suggesting that this drug may be safe with regard to the endometrium, even if it is used following tamoxifen, and that it may not result in an increased incidence of endometrial cancer. Indeed, it is even possible that ICI 182,780 may prove useful as an adjuvant agent in early stage endometrial cancer.
Subject(s)
Endometrial Neoplasms/chemically induced , Estradiol/analogs & derivatives , Estrogen Antagonists/adverse effects , Tamoxifen/adverse effects , Toremifene/adverse effects , Animals , Antineoplastic Agents, Hormonal/adverse effects , Breast Neoplasms/drug therapy , Disease Models, Animal , Estradiol/adverse effects , Female , Fulvestrant , Mice , Mice, Nude , OvariectomyABSTRACT
PURPOSE: Arzoxifene (Arzox) is a novel benzothiophene analogue with selective estrogen receptor modulator activity similar to raloxifene. Arzox is being developed as a treatment for breast cancer and has a predominantly antiestrogenic effect on the rodent uterus. Our objectives were to verify whether the novel selective estrogen receptor modulator, Arzox, can be a good first-line agent and also be effective at controlling the growth of endometrial cancer after exposure to tamoxifen (Tam). EXPERIMENTAL DESIGN: We compared the effects of Tam and Arzox on the growth of estrogen responsive ECC-1 endometrial cancer cells in vitro, and we determined their antitumor effects on ECC-1 and EnCa101 endometrial carcinoma growth in athymic mice. RESULTS: We observed that estrogen receptor protein expression is down-regulated by Arzox to the same extent as raloxifene, whereas 4-hydroxytamoxifen, the active metabolite of Tam, does not affect estrogen receptor protein levels. Tam and Arzox inhibit the growth of Tam-naïve ECC-1 tumors in athymic mice. However when Tam-stimulated or estrogen-stimulated (which had been treated with Tam previously) EnCa101 endometrial tumors were treated with Tam or Arzox, we observed a stimulatory effect of both compounds in these models. CONCLUSIONS: The results indicate that Arzox may be a good first-line agent, but it may be ineffective at controlling the growth of endometrial cancer after exposure to Tam. Our data suggest that Arzox stimulates endometrial tumor growth to at least the same extent as Tam, thereby suggesting a limited role as a second-line agent for the patient on Tam who develops occult endometrial cancer.
Subject(s)
Endometrial Neoplasms/drug therapy , Estrogen Antagonists/therapeutic use , Piperidines/therapeutic use , Tamoxifen/analogs & derivatives , Thiophenes/therapeutic use , Animals , Cell Division/drug effects , Down-Regulation/drug effects , Endometrial Neoplasms/pathology , Female , Humans , Mice , Mice, Nude , Receptors, Estrogen/genetics , Tamoxifen/therapeutic use , Transplantation, Heterologous , Tumor Cells, CulturedABSTRACT
MCF-7 cells are used routinely to study tamoxifen-stimulated drug resistance in vivo. However, unlike MCF-7 cells, T47D cells express mutant p53 protein and lose the estrogen receptor (ER) during long-term estrogen deprivation in vitro [Pink et al., Br. J. Cancer, 74: 1227-1236, 1996 (erratum, Br. J. Cancer, 75: 1557, 1997)]. As a result, T47D tumors may respond differently from MCF-7 tumors to long-term tamoxifen treatment. Ovariectomized athymic mice were given injections bilaterally with T47D cells (5 x 10(5)) into the mammary fat pads. A rapidly growing estradiol responsive tumor (T47D:E2) was established and 0.5 mg of tamoxifen given daily blocked estrogen-stimulated growth. In subsequent experiments, low doses of tamoxifen (0.17 mg or 0.5 mg) did not produce tamoxifen-stimulated tumors at 14 weeks, whereas high-dose tamoxifen (1.5 mg) consistently produced tamoxifen-stimulated tumors (T47D:Tam; 17 tumors/20 sites) at 8 weeks. In contrast, 1.5 mg of tamoxifen produced tamoxifen-stimulated MCF-7 tumors (MCF-7: Tam2) at a slower rate (20 weeks) and less consistently (14 tumors/26 sites). When the T47D:Tam tumor was passaged, it grew maximally with either 1.5 mg of tamoxifen or a 1-cm estradiol (premenopausal levels) capsule, and similar results were obtained with MCF-7:Tam2 tumors. Interestingly, when T47D:Tam tumors were treated with the 0.5 mg of tamoxifen, tumors grew only to 50% maximum. All of the tumors originating from MCF-7 and T47D cells expressed ER at similar levels; therefore, tamoxifen did not select for an ER-negative tumor. In conclusion, we have shown that tamoxifen-stimulated T47D p53 mutant tumors can be developed rapidly with high-dose therapy (1.5 mg daily). The results from this model provide new opportunities to investigate the rapid development of drug resistance to adjuvant tamoxifen in patients with mutant p53 breast tumors.
Subject(s)
Estrogen Receptor Modulators/pharmacology , Genes, p53 , Mammary Neoplasms, Experimental/drug therapy , Tamoxifen/pharmacology , Animals , Drug Resistance, Neoplasm , Endothelial Growth Factors/analysis , Estrogen Receptor alpha , Female , Humans , Lymphokines/analysis , Mammary Neoplasms, Experimental/pathology , Mice , Mice, Nude , Neoplasm Transplantation , Receptors, Estrogen/analysis , Transplantation, Heterologous , Vascular Endothelial Growth Factor A , Vascular Endothelial Growth FactorsABSTRACT
PURPOSE: Cross-resistance is the primary issue facing the evaluation of new antiestrogens to treat metastatic breast cancer because they may be tested, initially, in populations of patients that have failed long-term adjuvant tamoxifen (Tam) therapy. EXPERIMENTAL DESIGN: We have tested the benzothiophene derivatives, arzoxifene (Arzox; LY353381) and LY117018 in two models of Tam-stimulated tumor growth derived from either MCF-7 (M. M. Gottardis and V. C. Jordan, Cancer Res., 48: 5183-5187, 1988) or T47D (J. MacGregor Schafer et al., Clin. Cancer Res., 6: 4373-4380, 2000) breast cancer cells. RESULTS: Using the MCF-7:Tam model, we found that both Arzox and LY117018 (1.5 mg/day) resulted in tumor growth and, therefore, were partially cross-resistant with Tam. Next, using the T47D:17beta-estradiol (E(2)) model, we compared the antiestrogenic/antitumor properties of Arzox and LY117018 and determined that neither Arzox nor LY117018 caused T47D:E(2) tumor growth after 21 weeks. In addition, we determined that long-term treatment does not result in failure and subsequent development of transplantable Arzox- or LY117018-stimulated tumors. To establish whether Arzox and LY117018 are cross-resistant in T47D:Tam tumors, mice were treated with Arzox or LY117018 (1.5 mg/day), and, again, we found that neither resulted in the growth of transplantable tumors. Lastly, we showed that Arzox and LY117018 were only partially able to compete with postmenopausal E(2) (0.3 cm silastic capsule) in T47D:Tam tumors. However, when T47D:E(2) tumors were treated for 7 days instead of 5 days, both Arzox and LY117018 were more effective. CONCLUSIONS: Arzox is not cross-resistant with Tam in the T47D athymic mouse model but does exhibit cross-resistance in the MCF-7 model.
Subject(s)
Breast Neoplasms/drug therapy , Piperidines/pharmacology , Pyrrolidines/pharmacology , Selective Estrogen Receptor Modulators/pharmacology , Tamoxifen/therapeutic use , Thiophenes/pharmacology , Animals , Breast Neoplasms/pathology , Drug Resistance, Neoplasm , Estradiol/therapeutic use , Female , Humans , Mice , Mice, Nude , Time Factors , Treatment Outcome , Tumor Cells, Cultured , Xenograft Model Antitumor AssaysABSTRACT
The estrogen receptor (ER)-positive MCF-7 breast cancer cell line can be transplanted into athymic mice and grown into tumors with estradiol (E2) support. Tamoxifen (TAM) blocks E2-stimulated tumor growth; however, continuous TAM treatment results in transplantable tumors within a year that will grow with either E2 or TAM (M. M. Gottardis and V. C. Jordan, Cancer Res., 48: 5183-5187, 1988). Although this model may represent the development of TAM resistance for the treatment of advanced breast cancer, no laboratory model exists to study the exposure of breast cancer to 5 years of adjuvant TAM therapy. We have addressed this issue and report the development and characterization of two tumor lines, MCF-7TAM and MT2, which have been serially transplanted into TAM-treated athymic mice for >5 years. The MCF-7TAM tumor rapidly regresses in response to E2 and then about 50% of tumors regrow in response to E2. Interestingly, tumor regression does not occur if TAM treatment is stopped, probably because E2 levels are too low in ovariectomized athymic mice. The development of the antitumor effect of E2 was documented for MT2 tumors over a 1-year period; TAM-stimulated tumor growth was retained, but E2 caused progressively less of a stimulatory effect. Most importantly, E2-stimulated tumors that regrew after initial tumor regression in both MCF-7TAM and MT2 lines were again responsive to TAM to block E2-stimulated growth. Unlike MCF-7 tumors, the MT2 tumor line contains a single point mutation, Asp351Tyr, in the ER, which was retained after the development of E2-stimulated regrowth. The mutation is associated with increased estrogen-like actions for the TAM-ER complex (A. S. Levenson et al., Br. J. Cancer, 77: 1812-1819, 1998), but we conclude that the mutant ER is not required for TAM resistance. On the basis of the new breast cancer models presented, we propose a cyclic sensitivity to TAM that may have important clinical implications: (a) it is possible that a woman's own estrogen may produce an antitumor effect on the presensitized micrometastatic disease after 5 years of TAM. Long-term antitumor action occurs because the drug is stopped, but resistance accumulates and tumors start to grow if adjuvant therapy is continued; and (b) although in the clinic TAM-resistant tumors respond to second-line therapies that cause estrogen withdrawal, e.g., pure antiestrogens or aromatase inhibitors, estrogen therapy may also be effective and return the tumor to TAM responsiveness. In this way, a hormone-responsive tumor may be controlled longer in the patient with advanced disease.
Subject(s)
Antineoplastic Agents, Hormonal/adverse effects , Estradiol/therapeutic use , Mammary Neoplasms, Experimental/drug therapy , Tamoxifen/adverse effects , Animals , Antineoplastic Agents, Hormonal/therapeutic use , Cell Division/drug effects , Dose-Response Relationship, Drug , Female , Humans , Mammary Neoplasms, Experimental/chemically induced , Mammary Neoplasms, Experimental/pathology , Mice , Mice, Inbred BALB C , Mice, Nude , Mutation , Neoplasm Transplantation , Receptors, Estrogen/genetics , Tamoxifen/therapeutic use , Time Factors , Transplantation, Heterologous , Tumor Cells, CulturedABSTRACT
The triphenylethylene antiestrogens, idoxifene (Idox) and toremifene (Tor), are structurally related analogues of tamoxifen (Tam) and were developed to improve the therapeutic index for advanced breast cancer patients. However, the issue of cross-resistance with Tam for these new agents is critical for clinical testing because the majority of breast cancer patients have already received or failed adjuvant Tam. The goal of this study was to determine the effectiveness of Idox as an antitumor agent in three models of Tam-stimulated breast cancer in athymic mice and compare the results with the actions of Tor and ICI 182,780 in a Tam-stimulated MCF-7 tumor model. We first compared the activities of Tam and Idox in the 17beta-estradiol (E2)-stimulated MCF-7 tumor line MT2:E2. Tam and Idox reduced E2-stimulated growth by 65-70% (week 9: P = 0.0009 for Tam, P = 0.0005 for Idox versus E2 alone). However, Tam (1.5 mg daily) and Idox (1.0 mg daily) both produced T47D breast tumors in athymic mice during 23 weeks of treatment (12 tumors/22 sites and 15 tumors/18 sites, respectively). Tam and Idox stimulated tumor growth equally in two different Tam-stimulated MCF-7 models and in a T47D model. Tor was completely cross-resistant with Tam in the MCF-7 tumor model, which implied that neither Idox nor Tor would be effective as a second-line endocrine therapy after Tam failure and may offer no therapeutic advantages over Tam as adjuvant therapies. In contrast, ICI 182,780, a pure antiestrogen currently being tested as a treatment for breast cancer after Tam failure, had no growth-stimulatory effect on the MCF-7 Tam-stimulated breast tumor line. This agent may provide an advantage as an adjuvant therapy and increase the time to treatment failure.
Subject(s)
Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Breast Neoplasms/drug therapy , Drug Resistance, Neoplasm , Estradiol/analogs & derivatives , Estradiol/pharmacology , Estrogen Antagonists/chemistry , Estrogen Receptor Modulators/pharmacology , Mammary Neoplasms, Experimental/drug therapy , Stilbenes/chemistry , Tamoxifen/analogs & derivatives , Tamoxifen/therapeutic use , Animals , Antineoplastic Agents, Hormonal/pharmacology , Estradiol/metabolism , Female , Fulvestrant , Humans , Mice , Mice, Inbred BALB C , Mice, Nude , Neoplasm Transplantation , Tamoxifen/pharmacology , Time Factors , Toremifene/pharmacology , Tumor Cells, CulturedABSTRACT
The ras family of proto-oncogenes are upstream mediators of several essential cellular signal transduction pathways involved in cell proliferation and survival. Point mutations of ras oncogenes result in constitutively active Ras and have been shown to be oncogenic. However, ras activation can occur in the absence of ras mutations secondary to upstream receptor activation. The first important step in Ras activation is farnesylation by farnesyl transferase, and inhibitors of this enzyme have been demonstrated to inhibit Ras signaling, and have anti-tumor effects. However, it is now clear that farnesyl transferase inhibitors (FTIs) have activity independent of Ras, most likely due to effects on prenylated proteins downstream of Ras, which explains their activity in several malignancies, including breast cancer, where ras mutations are rare. Several FTIs are in clinical development for the treatment of solid tumors. Preclinical evidence suggests that FTIs can inhibit breast cancers in vitro and in vivo, and a phase II trial of the FTI, R115777, in patients with advanced breast cancer produced encouraging results. Based on prior successful outcomes with agents targeting the estrogen and epidermal growth factor receptor pathways in breast cancer, the FTIs, used alone or more likely with other agents, may be the next exciting targeted therapy in breast cancer.
Subject(s)
Alkyl and Aryl Transferases/antagonists & inhibitors , Antineoplastic Agents/pharmacology , Breast Neoplasms/drug therapy , Enzyme Inhibitors/pharmacology , Alkyl and Aryl Transferases/metabolism , Animals , Breast Neoplasms/enzymology , Farnesyltranstransferase , Female , HumansABSTRACT
Tamoxifen, a selective estrogen receptor modulator (SERM), is the treatment of choice for all stages of hormone-responsive breast cancer and has been shown to prevent breast cancer in high-risk women. Despite acting as an antiestrogen on the breast, tamoxifen has partial estrogenic effects on other target tissues. These partial estrogen agonistic actions produce beneficial effects on bones and the lipid profile in postmenopausal women. However, tamoxifen is associated with an increase in endometrial cancer. Additionally, its antiestrogenic effects in the central nervous system result in hot flashes in postmenopausal women. Raloxifene is another SERM approved for the prevention of osteoporosis in postmenopausal women. Like tamoxifen, raloxifene appears to prevent breast cancer in high-risk women and has not, to date, been noted to increase the incidence of endometrial cancer. The Study of Tamoxifen and Raloxifene will compare the effects of the two agents on breast cancer prevention and endometrial cancer risk. A number of new agents are being developed for breast cancer treatment and prevention and osteoporosis prevention. These include other SERMs, selective estrogen receptor downregulators (SERDs), and aromatase inhibitors. It is hoped that one of these new agents will be the ideal agent, acting as an antiestrogen on breast and endometrium while having estrogenic effects on bones, the lipid profile, and the central nervous system. Semin Oncol 28:260-273.
Subject(s)
Breast Neoplasms/drug therapy , Neoplasms, Hormone-Dependent/drug therapy , Raloxifene Hydrochloride/therapeutic use , Selective Estrogen Receptor Modulators/therapeutic use , Tamoxifen/therapeutic use , Aromatase Inhibitors , Breast Neoplasms/prevention & control , Estrogen Antagonists/chemistry , Estrogen Antagonists/pharmacology , Estrogen Antagonists/therapeutic use , Female , Humans , Neoplasms, Hormone-Dependent/prevention & control , Raloxifene Hydrochloride/chemistry , Raloxifene Hydrochloride/pharmacology , Tamoxifen/analogs & derivatives , Tamoxifen/chemistry , Tamoxifen/pharmacologyABSTRACT
The new antiestrogen toremifene (TOR) is currently on the market for the treatment of advanced breast cancer in postmenopausal women. TOR is known to exhibit a similar efficacy profile as tamoxifen (TAM) in the treatment of advanced breast cancer and there are studies to suggest that the beneficial side effects of TAM on bone and blood lipids are also achieved with TOR. However, the data concerning the action of TOR on the endometrium is sorely lacking. In light of the estrogenic effect of TAM on the uterus and the 2-3-fold increased incidence in endometrial carcinoma detected in patients receiving TAM therapy, it is imperative to investigate the effect of TOR on endometrial carcinoma. We compared the actions of TAM and TOR on the EnCa101 human endometrial tumor model and find that both antiestrogens have similar growth stimulatory effects. To investigate a potential mechanism of antiestrogen-stimulated endometrial tumor growth, we have examined known activators of the AP-1 signal transduction pathway, the protein kinase C (PKC) family of isozymes, in the EnCa101 human endometrial tumor model. We find that increased PKC isozyme expression correlates with hormone-independent breast cancer as well as antiestrogen-stimulated endometrial cancer.
Subject(s)
Antineoplastic Agents, Hormonal/pharmacology , Endometrial Neoplasms/pathology , Estrogen Antagonists/pharmacology , Tamoxifen/pharmacology , Toremifene/pharmacology , Breast Neoplasms/enzymology , Breast Neoplasms/pathology , Carcinoma/enzymology , Carcinoma/pathology , Cell Division/drug effects , Endometrial Neoplasms/enzymology , Female , Humans , Protein Kinase C/analysis , Tumor Cells, CulturedABSTRACT
We compared the effects of CO2 applied continuously and during expiration on laryngeal-receptor activity in paralyzed, artificially ventilated and nonparalyzed, spontaneously breathing cats by using an isolated larynx, artificially ventilated to approximate a normal respiratory cycle. The majority of quiescent negative-pressure and all cold receptors were excited by 5 and 9% CO2 applied both continuously and during expiration. In general, quiescent positive-pressure, tonic negative-pressure, and tonic positive-pressure receptors were inhibited by 5 and 9% CO2 applied continuously and during expiration. There were no significant differences between responses to 5 and 9% CO2 or to continuous and expired CO2 or between paralyzed and nonparalyzed preparations. In conclusion, laryngeal receptors respond to changes in CO2 concentration occurring during a normal respiratory cycle. Because laryngeal-receptor stimulation exerts reflex effects on ventilation and upper airway muscle activity, these results suggest that airway CO2 plays a role in reflex regulation of breathing and upper airway patency.
Subject(s)
Carbon Dioxide/metabolism , Larynx/physiology , Anesthesia , Animals , Cats , Cold Temperature , Female , Laryngeal Nerves/physiology , Male , Nerve Fibers/physiology , Respiratory Mechanics/physiology , Trachea/physiologyABSTRACT
We examined the changes in isolated pulmonary artery (PA) wall tension on switching from control conditions (pH 7.38 +/- 0.01, PCO2 32.9 +/- 0.4 Torr) to isohydric hypercapnia (pH change 0.00 +/- 0.01, PCO2 change 24.9 +/- 1.1 Torr) or normocapnic acidosis (pH change -0.28 +/- 0.01, PCO2 change -0.3 +/- 0.04 Torr) and the role of the endothelium in these responses. In rat PA, submaximally contracted with phenylephrine, isohydric hypercapnia did not cause a significant change in mean (+/- SE) tension [3.0 +/- 1.8% maximal phenylephrine-induced tension (Po)]. Endothelial removal did not alter this response. In aortic preparations, isohydric hypercapnia caused significant (P < 0.01) relaxation (-27.4 +/- 3.2% Po), which was largely endothelium dependent. Normocapnic acidosis caused relaxation of PA (-20.2 +/- 2.6% Po), which was less (P < 0.01) than that observed in aortic preparations (-35.7 +/- 3.4% Po). Endothelial removal left the pulmonary response unchanged while increasing (P < 0.01) the aortic relaxation (-53.1 +/- 4.4% Po). These data show that isohydric hypercapnia does not alter PA tone. Reduction of PA tone in normocapnic acidosis is endothelium independent and substantially less than that of systemic vessels.
Subject(s)
Pulmonary Artery/physiology , Vasoconstriction/physiology , Acetylcholine/pharmacology , Acidosis/physiopathology , Animals , Carbon Dioxide/blood , Endothelium, Vascular/drug effects , Endothelium, Vascular/physiology , Endothelium, Vascular/physiopathology , Enzyme Inhibitors/pharmacology , Hydrogen-Ion Concentration , Hypercapnia/physiopathology , In Vitro Techniques , Male , Muscle, Smooth, Vascular/drug effects , Muscle, Smooth, Vascular/physiology , Muscle, Smooth, Vascular/physiopathology , NG-Nitroarginine Methyl Ester/pharmacology , Nitric Oxide Synthase/antagonists & inhibitors , Phenylephrine/pharmacology , Pulmonary Artery/drug effects , Pulmonary Artery/physiopathology , Rats , Rats, Sprague-Dawley , Vasoconstriction/drug effectsABSTRACT
In anaesthetized, paralysed and artificially ventilated cats triple-barrelled ion-selective microelectrodes (ISMs) were inserted into the right carotid body in order to measure extracellular activities of K+ ([K+]o) and Ca2+ ([Ca2+]o) simultaneously. In 3 experiments a method involving iron deposition located the tips of the ISMs in the cellular islands of the organ. A thin cannula inserted into the right carotid artery (i.c.) via the lingual artery was used to infuse Ringer-Locke solutions (0.1-0.5 ml/min) containing either sodium cyanide (NaCN), acetylcholine (ACh) or dopamine (DA). Analysis of the effects of administration of NaCN (20-100 micrograms/min i.c.) showed that during this procedure [K+]o increased and [Ca2+]o decreased by mean values (+/- S.D.) of 0.99 +/- 0.82 and 0.22 +/- 0.06 mM respectively. During administration of ACh (20-50 micrograms/min i.c.) [K+]o increased and [Ca2+]o decreased respectively by mean values (+/- S.D.) of 3.18 +/- 3.0 and 0.31 +/- 0.14 mM. Decreases in [K+]o and [Ca2+]o by mean values (+/- S.D.) of 1.53 +/- 1.64 and 0.34 +/- 0.33 mM respectively were associated with administration of DA (20-50 micrograms/min i.c.). The predominant influences exerted by NaCN and ACh on chemoreceptor activity were excitatory whereas administration of DA caused either inhibition, excitation or a combination of these two effects. Stimulation of the sympathetic supply to the carotid body was associated with either increases, decreases or no reaction of chemosensory activity, [K+]o and [Ca2+]o. The changes in [K+]o associated with the various procedures may reflect the state of polarization within the chemoreceptor complex. Decreases in [Ca2+]o usually accompanied the performance of all procedures and may have resulted from an increased influx of this ion from the interstitial fluids into the cells for the purpose of provoking neurotransmitter release. However, the time course of the changes in [K+]o and [Ca2+]o were considerably slower in onset and recovery than the associated alterations in chemoreceptor activity. Therefore, it is unlikely that these ion changes are directly related to chemoreception but rather represent recovery processes after chemoreceptor modulation. It should be noted that the response times of the ISMs used in this study were too slow to register any rapid changes in [K+]o or [Ca2+]o associated with altered chemoreceptor activity.
Subject(s)
Acetylcholine/pharmacology , Carotid Body/physiology , Chemoreceptor Cells/physiology , Chlorides/metabolism , Cyanides/pharmacology , Dopamine/pharmacology , Extracellular Space/metabolism , Potassium/metabolism , Sodium Cyanide/pharmacology , Animals , Carotid Body/drug effects , Cats , Chemoreceptor Cells/drug effects , Efferent Pathways/physiology , Electric Stimulation , Female , Male , Sympathetic Nervous System/physiologyABSTRACT
The purpose of the study was to determine the effects of early plasmin-mediated digests of rat fibrinogen on the vascular tone of rat pulmonary artery in order to compare with reported vasoactive effects of high levels of isolated human peptides in various rat vascular beds. Isometric tension was monitored in isolated rings of rat pulmonary artery precontracted with phenylephrine (4 x 10(-8) mol). Fibrinogen degradation products (FgDPs) were produced by digestion of rat fibrinogen with plasmin to 1, 2, 3 and 60 minutes whereupon the digestion was stopped by addition of Trasylol. These FgDPs were added to the tissue bath to achieve final concentrations of 6.7, 13.3, 26.7 and 53.3 micrograms/mL i.e. values similar to those found in vivo during thrombolytic therapy for myocardial infarction. Results were expressed as a percentage of a maximal contraction elicited in each ring in response to phenylephrine (10(-5) M). The early FgDP fractions, at these pathophysiological concentrations, did not induce significant change in isometric tension in the isolated pulmonary arterial rings (P > 0.05, ANOVA).
Subject(s)
Fibrin Fibrinogen Degradation Products/pharmacology , Isometric Contraction/drug effects , Muscle, Smooth, Vascular/physiology , Pulmonary Artery/physiology , Animals , Fibrinolysin , In Vitro Techniques , Muscle, Smooth, Vascular/drug effects , Phenylephrine/pharmacology , Pulmonary Artery/cytology , Pulmonary Artery/drug effects , Rats , Rats, Sprague-Dawley , Vasoconstrictor Agents/pharmacologyABSTRACT
Tamoxifen (Nolvadex), a selective estrogen-receptor modulator, or SERM, is currently the endocrine therapy of choice for all stages of hormone-responsive breast cancer. Only tamoxifen has been approved by the US Food and Drug Administration to reduce the incidence of breast cancer in high-risk women. Despite tamoxifen's antiestrogenic effects in breast tissue, it exhibits paradoxical estrogenic effects in other tissues in the body. These effects result in the maintenance of bone mineral density, but a three- to fourfold increase in endometrial cancer in postmenopausal women. Additionally, tamoxifen can result in troublesome hot flashes and serious thromboembolic events. For this reason, current research is focusing on new agents that may maintain the beneficial effects of tamoxifen while reducing its adverse effects. Raloxifene (Evista) is another SERM, approved for the prevention of osteoporosis in postmenopausal women and now being compared with tamoxifen in an ongoing breast cancer prevention trial. Like tamoxifen, raloxifene is associated with hot flashes and thromboembolic events, but its association with the risk of endometrial cancer is unknown. A number of new SERMs are in preclinical or clinical development in an attempt to improve upon the safety profile of tamoxifen. Additionally, selective aromatase inhibitors are being examined in the early breast cancer setting.
Subject(s)
Breast Neoplasms/drug therapy , Estrogen Antagonists/therapeutic use , Neoplasms, Hormone-Dependent/drug therapy , Selective Estrogen Receptor Modulators/therapeutic use , Tamoxifen/therapeutic use , Breast Neoplasms/prevention & control , Clinical Trials as Topic , Endometrial Neoplasms/chemically induced , Estrogen Antagonists/adverse effects , Female , Humans , Middle Aged , Neoplasms, Hormone-Dependent/prevention & control , Pilot Projects , Raloxifene Hydrochloride/adverse effects , Raloxifene Hydrochloride/therapeutic use , Tamoxifen/adverse effects , Venous Thrombosis/chemically inducedABSTRACT
Laboratory models for breast and endometrial cancer have had an enormous impact on the clinical development of antiestrogens. Results from the DMBA-induced rat mammary cancer model has provided the scientific principles required to evaluate long-term adjuvant tamoxifen therapy. Similarly, the athymic mouse model allowed the identification of clinically relevant mechanisms of drug resistance to tamoxifen and a model system to test new agents for cross resistance. Additionally, the endometrial cancer model has allowed the identification of agents that cause a slight increase in the risk of endometrial cancer long before the data would have be available from clinical studies. However, it should be stressed that this model is really only relevant for agents to be tested as preventives in normal women. The risks of developing endometrial cancer during tamoxifen therapy are slight compared with the survival benefit in controlling breast cancer.Finally the discovery of the carcinogenic potential of tamoxifen in the rat liver, 20 years after it was first introduced into clinical practice, raises an interesting issue. If the studies of liver carcinogenicity had been completed and published in the early 1970's there would be no tamoxifen and tens of thousands of women with breast cancer would have died prematurely. In fact there would have been no incentive to develop new agents as alternatives to tamoxifen or following tamoxifen failure. Most importantly, we would not have any knowledge about the target-site or selective actions of antiestrogens. All the current interest in selective estrogen receptor modulators (SERMs) is based on the huge clinical data base obtained by studying tamoxifen. The success of tamoxifen as an agent that preserves bone density, lowers cholesterol and prevents contralateral breast cancer(43) has become a classic example of a multimechanistic drug. These concepts have acted as a catalyst to develop new agents for new applications. The laboratory studies of raloxifene(44-46)) provided the scientific rationale for the use of raloxifene as a preventive for osteoporosis(47)) but with the goal of preventing breast cancer in post-menopausal women(48,49)) (Fig 5). It is clear that the close collaboration between laboratory and clinical research has revolutionized the prospects for women's health care in the 21st century.
ABSTRACT
Carotid bodies of cats were perfused with saline solutions and their oxygen usages ([Formula: see text]) calculated using the Fick equation. In the initial stages of perfusion, the values of[Formula: see text] were similar to those reported for blood perfused carotid bodies. As perfusion continued, carotid body[Formula: see text] decreased sharply and these decreases were not prevented by adding plasma to the perfusates. Blood perfusion in the interval between cell-free perfusion periods stimulated[Formula: see text]. It is concluded that the process of cell-free perfusion is unable to maintain the high levels of oxidative metabolism associated with blood perfused carotid bodies.