Cancer Biol Ther. 2007 Feb;6(2):278-87. Epub 2007 Feb 27. Clinical and mechanistic aspects of glucocorticoid-induced chemotherapy resistance in the majority of solid tumors.
Zhang C, Wenger T, Mattern J, Ilea S, Frey C, Gutwein P, Altevogt P, Bodenmüller W, Gassler N, Schnabel PA, Dienemann H, Marmé A, Hohenfellner M, Haferkamp A, Pfitzenmaier J, Gröne HJ, Kolb A, Büchler P, Büchler M, Friess H, Rittgen W, Edler L, Debatin KM, Krammer PH, Rutz HP, Herr I.
Research Group Molecular OncoSurgery, University of Heidelberg, Im Neuenheimer Feld 365, Heidelberg 69120, Germany.
BACKGROUND: Glucocorticoids have been used widely in conjunction with cancer therapy due to their ability to induce apoptosis in hematological cells and to prevent nausea and emesis. However, recent data including ours, suggest induction of therapy-resistance by glucocorticoids in solid tumors, although it is unclear whether this happens only in few carcinomas or is a more common cell type specific phenomenon. MATERIAL AND METHODS: We performed an overall statistical analysis of our new and recent data with 157 tumor probes evaluated in vitro, ex vivo and in vivo. The effect of glucocorticoids on apoptosis, viability and cell cycle progression under diverse clinically important questions was examined. RESULTS: New in vivo results demonstrate glucocorticoid-induced chemotherapy resistance in xenografted prostate cancer. In an overall statistical analysis we found glucocorticoid-induced resistance in 89% of 157 analysed tumor samples. Resistance is common for several cytotoxic treatments and for several glucocorticoid-derivatives and due to an inhibition of apoptosis, promotion of viability and cell cycle progression. Resistance occurred at clinically achievable peak plasma levels of patients under anti-emetic glucocorticoid therapy and below, lasted for a long time, after one single dose, but was reversible upon removal of glucocorticoids. Two nonsteroidal alternative anti-emetic agents did not counteract anticancer treatment and may be sufficient to replace glucocorticoids in cotreatment of carcinoma patients. CONCLUSION: These data demonstrate the need for prospective clinical studies as well as for detailed mechanistic studies of GC-induced cell-type specific pro- and anti-apoptotic signalling.
GCs blocked the lethal signal delivered by a variety of clinically used cytotoxic drugs even if they were given several hours after induction of apoptosis.
Moreover, resistance induced by a single treatment with GCs lasted for up to 10 days before it started to decline, and resistance was noted at peak plasma concentrations found in patients and below. In contrast, alternative nonsteroidal antiemetic medicaments usesd in cancer therapy, such as a NK1 and a 5‑HT3 receptor antagonists, did not induce resistance.
Quote:
Statistical evaluation of new and our recent data demonstrates that DEX‑induced resistance in solid tumors is the rule, not the exception.
Quote:
we xenografted a human prostate cancer cell line to nude mice and measured tumor growth during a period of 15 days in untreated mice or upon treatment with paclitaxel, DEX, or paclitaxel and DEX together (Fig. 1). While paclitaxel alone resulted in a strong growth retardation, comedication of DEX induced therapy resistance, since the paclitaxel treated cells grew as fast as untreated control tumors. These results are similar to our recent in vivo studies using xenografted tumors of ovary, pancreas, colon and lung as well as 67 established cell lines and 85 freshly resected surgical specimen treated with various anticancer drugs in the presence or absence of GCs. Comedication of GCs induced therapy resistance, as evident from inhibited apoptosis and enhanced viability in 94% of the established cell lines, 85% of the primary cells and in all of a total of five examined tumor xenografts
Quote:
To demonstrate that GCs counteract the effect of various cytotoxic agents, we treated P5 cells with several clinically used anticancer agents (Fig. 4B). DEX counteracted the effect of cisplatin, etoposide, cytarabine, gemcitabine, methotrexate, 5‑fluorouracil, paclitaxel and ionizing radiation as measured by analyzing apoptosis and viability. Thus, induction of resistance is common for several GCs and different cytotoxic treatments.
Quote:
we report here, that (I) DEX‑induced therapy resistance is common for several cytotoxic treatments including cisplatin, etoposide, g‑irradiation, gemcitabine, methotrexate, 5‑fluorouracil, cytarabine and paclitaxel; (II) Resistance is due to inhibition of apoptosis, promotion of viability and cell cycle progression (III) Resistance lasts long but is reversible after removal of DEX; (IV) induction of resistance is common for several GC‑derivatives including DEX, betamethasone, hydrocortisone and prednisone; (V) nonsteroidal anti‑emetic agents used in cancer therapy such as serotonin‑receptor or NK1 receptor antagonists do not induce resistance. In addition, our data show that DEX‑mediated resistance occurs over a wide range of DEX concentrations resembling peak plasma levels found in patients,14 down to relatively low concentrations. Since lower concentrations occur in patients at later times after DEX administration, as plasma levels decline, this point leads to more concerns about safety and the question whether the level of naturally occurring GCs may interfere with cancer therapy.
Quote:
Our findings suggest that GCs are highly suspicious to induce therapy resistance of solid tumors also in clinical settings and there are indeed several hints demonstrating an negative effect of corticosteroids on tumor growth in patients.6
Quote:
In conclusion, GC‑cotreatment switches the balance between several interacting signaling pathways to death in lymphoid cells but to survival in cells derived from tissue or a solid tumor.
Quote:
Most importantly, when applying these findings to the clinical situation, the protection of normal tissue by GCs may be of benefit for patients, but the protection of cells of a solid tumor may minimize the effect of cytotoxic therapy. Thus, our data suggest to replace GCs in prevention of cancer therapy‑induced emesis by nonsteroidal anti‑emetic agents, which do not induce therapy resistance.
Cancer Biol Ther. 2007 Sep;6(9):1345-54. Epub 2007 Jul 19. Cell cycle arrest by glucocorticoids may protect normal tissue and solid tumors from cancer therapy.
Mattern J, Büchler MW, Herr I.
Molecular OncoSurgery, Department of Surgery, University and German Cancer Research Center (DKFZ), Heidelberg, Germany.
Glucocorticoids have been widely used as cotreatment for patients with cancer due to potent pro-apoptotic properties in lymphoid cells, reduction of nausea and diminishing acute toxicity on normal tissue. There are now data from preclinical and, to some extent, clinical studies, demonstrating that these medicaments are highly suspicious to induce therapy resistance in the majority of malignant solid tumors-irrespective of tumor origin and the nature of specific anticancer drugs or irradiation used for treatment. Despite these huge amounts of data, the underlying mechanisms of cell type-specific signaling by these steroid hormones are just beginning to be described. This review summarizes our present understanding of a relationship between glucocorticoid-induced reversible cell cycle arrest and therapy resistance in solid tumors. We give a summary of our current knowledge of decreased proliferation rates in response to glucocorticoid pre and combination treatment which are suspicious to be involved not only in protection of normal tissues, but also in protection of solid tumors from cytotoxic effects of anticancer agents. The inhibition of cell cycle progression by pretreatment with GCs may be crucially involved in switching the balance of several interacting pathways to survival upon treatment with GCs.
GCs strongly induce apoptosis in cells of the haematological lineage. This makes these compounds of tremendous value in the treatment of leukemias, lymphomas, and multiple myeloma.34 In contrast, cells of epithelial origin, such as mammary gland, ovarian follicular cells and hepatocytes as well as the majority of human solid malignant tumor cells are protected by GCs against various stimuli for apoptosis. Tumors involved have been found to be derived from bladder, brain, breast, cervix, colon, liver, lung, kidney, ovary, pancreas, prostate, rectum and testis and also gliomas, melanomas and osteosarcomas are rendered therapy resistant by GCscortisone treatment has also been found to favor an increased metastatic spread in patients with breast carcinoma,108,110 lung carcinoma109 and renal carcinoma (compare also Table 2).6,35 These GC‑induced protective effects may become clinically relevant.
Quote:
Agosin et al.102 and Molomut et al.103 have reported an increase in the incidence of metastases in cortisone‑treated tumor‑bearing mice. These observation could be confirmed by many authors (Table 7).104‑106 However, .111 Recently, Sorensen et al.112 compared in a large population‑based follow‑up study among 59.043 individuals who received prescriptions for GCs, the observed and expected number of cases of skin cancer and non-Hodgkin lymphoma. They found an elevated risk for squamous cell carcinomas and basal cell carcinomas of the skin and also for non-Hodgkin lymphoma in patients who received prescriptions for GCs. These results further indicate that immunosuppression by GCs may be a risk for these malignancies.
2009 Oct 28. [Epub ahead of print] Estrogen Receptor, Progesterone Receptor, and Glucocorticoid Receptor Expression in Normal Breast Tissue, Breast In Situ Carcinoma, and Invasive Breast Cancer.
Buxant F, Engohan-Aloghe C, Noël JC.
*Gynecology daggerPathology, Erasme Hospital, Free University of Brussels (ULB), Belgium. Glucocorticoids (GCs) are used in cancer treatment to induce programmed cell death in transformed cells of the hematopoietic system and to lessen side effects. Moreover, GCs have been described not only as inhibitors of some chemotherapy or radiation-induced apoptosis, but also as inhibitors of cancer progression by down-regulation or up-regulation of different gene expressions. Recently, it has been suggested that GCs can attenuate estrogen responses through induction of expression and activity of the sulfotransferase. The presence or absence of glucocorticoid receptor (GR) in normal and abnormal breast tissue is thus interesting, and the aim of this study was to analyze the expression of GR during the progression of breast tissue. We tested by immunohistochemistry the expression status of estrogen receptor (ER), progesterone receptor (PR), and GR in normal breast parenchyma (n=49), ductal intraepithelial neoplasia (DIN) 1a (n=9), DIN 1b-1c (n=15), DIN 2-3 (n=21), and invasive breast carcinoma (n=39). The evaluation of GR expression was made by using the Allred score. All the normal parenchyma, DIN 1a, DIN 1b, and DIN 1c were ER-positive (ER) and PR-positive (PR). Seventeen of 21 DIN 2-3 and 30 of 39 invasive carcinomas were ER/PR. The other samples were ER-negative (ER) and PR-negative (PR). Moreover, all the ER/PR samples were GR-negative. Interestingly, we found a significant correlation between the histologic grade and the GR-negative tumors, and a percentage of positive patients presented with nuclear immunoreaction to GR, which decreases significantly with tumor histologic grade. Understanding the role of GCs in breast carcinoma is thus essential before continuing the widespread use of GCs combined with antineoplastic drugs or agents in the clinical management of women with breast cancer.
PMID: 19875955 [PubMed - as supplied by publisher]
Endocr Relat Cancer. 2009 Sep 23. [Epub ahead of print] Dexamethasone enhances cell resistance to chemotherapy through increasing adhesion to extracellular matrix in human ovarian cancer cells.
Chen YX, Wang Y, Fu CC, Diao F, Song LN, Li ZB, Yang R, Lu J.
Y Chen, Department of Pathophysiology, the Second Military Medical University, Shanghai, China. Glucocorticoids (GCs) are widely used as co-medication in therapy of solid malignant tumors to relieve some of the side effects of chemotherapy drugs. However, recent studies have shown that GCs could render cancer cells more resistant to cytotoxic drug-induced apoptosis, but the mechanism is largely unknown. In the present study, we found that the treatment of human ovarian cancer cell lines HO-8910 and SKOV3 with synthetic GCs Dexamethasone (Dex) significantly increased their adhesion to extracellular matrix (ECM) and their resistance to apoptosis induced by cytotoxic drugs cisplatin and paclitaxel. Dex also increased the protein levels of adhesion molecules integrin beta1, alpha4 and alphaV in HO-8910 cells. The neutralizing antibody against integrin beta1 prevented Dex-induced adhesion and significantly abrogated the protective effect of Dex toward cytotoxic agents. We further found that TGF-beta1 alone not only increased cell adhesion and cell survival of HO-8910 cells in the presence of cisplatin, but also has synergistic pro-adhesion and pro-survival effects with Dex. Moreover, TGF-beta1 neutralizing antibody that could block TGF-beta1-induced cell adhesion and apoptosis resistance markedly abrogated the synergistic pro-adhesion and pro-survival effects of Dex and TGF-beta1. Finally, we further demonstrated that Dex could up-regulate the expression of TGF-beta receptor type II (TbetaRII) and enhance the responsiveness of cells to TGF-beta1. In conclusion, our results indicate that increased adhesion to ECM through enhancing integrin beta1 signaling and TGF-beta1 signaling plays an important role in chemoresistance induced by GCs in ovarian cancer cells.
PMID: 19776289 [PubMed - as supplied by publisher]
Int J Oncol. 2006 Feb;28(2):551-8. Glucocorticoid-mediated inhibition of chemotherapy in ovarian carcinomas.
Zhang C, Marmé A, Wenger T, Gutwein P, Edler L, Rittgen W, Debatin KM, Altevogt P, Mattern J, Herr I.
Molecular Urooncology, German Cancer Research Center, Heidelberg, Germany.
The glucocorticoid dexamethasone is frequently used as a co-treatment in cytotoxic cancer therapy, e.g. to prevent nausea, to protect normal tissue or for other reasons. While the potent pro-apoptotic properties and supportive effects of glucocorticoids to tumour therapy in lymphoid cells are well studied, the impact on the cytotoxic treatment of ovarian carcinoma is unknown. We tested apoptosis-induction, viability, tumour growth and protein expression using established cell lines, primary cell lines freshly isolated from patient material and a xenograft on nude mice. We found a general induction of resistance toward cytotoxic therapy by DEX-co-treatment in most of the examined ovarian cancer cells treated in vitro, ex vivo or in vivo. Resistance occurred independently of cell density and was found at peak plasma levels of dexamethasone and below. Mechanistically, the dexamethasone-induced expression of survival genes may be involved in the resistance. These data show that glucocorticoid-induced resistance is common in ovarian carcinomas implicating that the use of glucocorticoids may be harmful for cancer patients.
PMID: 16391812 [PubMed - indexed for MEDLINE]
Administration of Glucocorticoids to Ovarian Cancer Patients Is Associated with Expression of the Anti-apoptotic Genes SGK1 and MKP1/DUSP1 in Ovarian Tissues
Authors' Affiliations: Departments of 1Medicine, 2Obstetrics and Gynecology, 3Pathology, 4Health Studies, and 5Ben May Department for Cancer Research, The University of Chicago, Chicago, Illinois
Requests for reprints:
Suzanne D. Conzen, MC 2115, The University of Chicago, Chicago, IL 60637. Phone: 773-834-2604; Fax: 773-834-0188; E-mail: sdconzen@uchicago.edu.
Abstract
Purpose: To prevent chemotherapy-related side effects, synthetic glucocorticoids, for example, dexamethasone, are routinely administered to patients with ovarian cancer. However, preclinical data implicate glucocorticoids in suppressing chemotherapy-mediated apoptosis in epithelial tumors. The anti-apoptotic mechanisms underlying this increased survival have been shown to require up-regulation of prosurvival genes, including serum and glucocorticoid-regulated kinase 1 (SGK1) and map kinase phosphatase 1 (MKP1)/dual specificity phosphatase 1 (DUSP1). Despite abundant preclinical data, there are no correlative studies in patients. We therefore evaluated anti-apoptotic gene expression in tumor samples from patients randomized to dexamethasone or normal saline. Experimental Design: Eighteen patients were randomized before exploratory laparotomy for suspected ovarian cancer. Dexamethasone or normal saline was administered i.v. following anesthesia. Ovarian and omental tumor samples were collected intra-operatively before and after infusion. Samples were analyzed for histology and glucocorticoid receptor expression by immunohistochemistry. SGK1 and MKP1/DUSP1 mRNA levels were determined using quantitative real-time PCR. Results: Ten patients were evaluable. At 30 min postinfusion, tumor samples from five patients receiving dexamethasone revealed an average SGK1 mRNA induction of 6.1-fold (SEM, ±2.6) compared with only 1.5-fold (SEM, ±0.4) in tumor samples from five patients receiving normal saline (P = 0.028). Average MKP1/DUSP1 mRNA expression was increased by 8.2-fold (SEM, ±2.9) following dexamethasone versus 1.1-fold (SEM, ±0.4) following normal saline (P = 0.009). All samples expressed glucocorticoid receptor. Conclusion: Glucocorticoid administration to patients is associated with rapid up-regulation of SGK1 and MKP1 expression in ovarian tumors. This finding supports the hypothesis that pharmacologic doses of glucocorticoids may decrease chemotherapy effectiveness in ovarian cancer patients through increased anti-apoptotic gene expression.
Cancer Biol Ther. 2006 Aug;5(8):933-40. Epub 2006 Aug 2. Dexamethasone decreases xenograft response to Paclitaxel through inhibition of tumor cell apoptosis.
Pang D, Kocherginsky M, Krausz T, Kim SY, Conzen SD.
Department of Medicine and Committee on Cancer Biology, University of Chicago, Chicago, Illinois 60637, USA.
Comment in:
Glucocorticoid receptor (GR) activation has recently been implicated in the initiation of anti-apoptotic signaling pathways in epithelial cell lines grown in culture. However, the evidence that GR-mediated inhibition of tumor cell apoptosis is the mechanism that diminishes chemotherapy effectiveness in vivo is limited. We therefore initiated a breast cancer xenograft study to examine whether or not pretreatment with glucocorticoids (GCs) decreases tumor response to chemotherapy by inhibiting tumor cell apoptosis. Here we report a significant decrease in paclitaxel-induced apoptosis in xenografts from mice pretreated with dexamethasone (Dex). A significant difference in apoptosis in xenografts from Dex/paclitaxel versus paclitaxel treated animals was seen eight days following initiation of chemotherapy. Nine days later, mice treated with Dex/paclitaxel had significantly larger tumors compared with those that received paclitaxel alone (p = 0.032). Dex pretreatment did not significantly affect tumor cell proliferation rates. Taken together, these results demonstrate that systemic Dex administration results in significantly reduced breast cancer xenograft apoptosis in the context of chemotherapy treatment. We also found that systemic Dex treatment results in upregulation of the anti-apoptotic gene MKP-1 and downregulation of pro-apoptotic Bid and TRAIL genes in tumor cells six hours following Dex treatment. These in vivo gene expression changes correlated with significant inhibition of chemotherapy-induced apoptosis. Interestingly, the decreased chemotherapeutic response of Dex-pretreated tumors persisted for several weeks following treatment. These data suggest that GR-mediated transcriptional regulation of pro- and anti-apoptotic genes contributes to the mechanism through which GCs decrease paclitaxel-induced apoptosis.
PMID: 16775428 [PubMed - indexed for MEDLINE]
J Biol Chem. 2005 Feb 11;280(6):4117-24. Epub 2004 Dec 7. Glucocorticoid receptor-induced MAPK phosphatase-1 (MPK-1) expression inhibits paclitaxel-associated MAPK activation and contributes to breast cancer cell survival.
Wu W, Pew T, Zou M, Pang D, Conzen SD.
Department of Medicine and the Committee on Cancer Biology, University of Chicago, Chicago, Illinois 60637, USA.
Glucocorticoid receptor (GR) activation has recently been shown to inhibit apoptosis in breast epithelial cells. We have previously described a group of genes that is rapidly up-regulated in these cells following dexamethasone (Dex) treatment. In an effort to dissect the mechanisms of GR-mediated breast epithelial cell survival, we now examine the molecular events downstream of GR activation. Here we show that GR activation leads to both the rapid induction of MAPK phosphatase-1 (MKP-1) mRNA and its sustained expression. Induction of the MKP-1 protein in the MCF10A-Myc and MDA-MB-231 breast epithelial cell lines was also seen. Paclitaxel treatment resulted in MAPK activation and apoptosis of MDA-MB-231 breast cancer cells, and both processes were inhibited by Dex pretreatment. Furthermore, induction of MKP-1 correlated with the inhibition of extracellular signal-regulated kinase (ERK1/2) and c-Jun N-terminal kinase (JNK) activity, whereas p38 activity was minimally affected. Blocking Dex-induced MKP-1 induction using small interfering RNA increased ERK1/2 and JNK phosphorylation and decreased cell survival. ERK1/2 and JNK inactivation was associated with Ets-like transcription factor-1 (ELK-1) dephosphorylation. To explore the gene expression changes that occur downstream of ELK-1 dephosphorylation, we used a combination of temporal gene expression data and promoter element analyses. This approach revealed a previously unrecognized transcriptional target of ELK-1, the human tissue plasminogen activator (tPA). We verified the predicted ELK-1--> tPA transcriptional regulatory relationship using a luciferase reporter assay. We conclude that GR-mediated MAPK inactivation contributes to cell survival and that the potential transcriptional targets of this inhibition can be identified from large scale gene array analysis.
Autophagy. 2009 Nov 18;5(8). [Epub ahead of print] Autophagy as the main means of cytotoxicity by glucocorticoids in hematological malignancies.
Grandér D, Kharaziha P, Laane E, Pokrovskaja K, Panaretakis T.
Department of Oncology/Pathology, Cancer Centre Karolinska (CCK) R8:03, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.
Glucocorticoids are fundamental drugs used in the treatment of lymphoid malignancies with apoptotic cell death as the hitherto proposed mechanism of action. We have recently shown that dexamethasone induces autophagy in lymphoid leukemia cells and in this particular setting this cell death modality is a prerequisite for the efficient killing of the leukemic cells by dexamethasone.(1) Hence, inhibition of autophagy by siRNA-mediated silencing of Beclin 1, as well as chemical inhibition of type III PtdIns3K, inhibits apoptosis, demonstrating an important role of autophagy in dexamethasone-induced cell death. In this brief report, we review these findings and introduce the multiple myeloma cells as a novel system to study autophagy in response to dexamethasone.
PMID: 19855186 [PubMed - as supplied by publisher]
Ann N Y Acad Sci. 2009 Oct;1179(1Glucocorticoids and Mood Clinical Manifestations, Risk Factors, and Molecular Mechanisms):86-105. Cytokines and Glucocorticoid Receptor Signaling.
Pace TW, Miller AH.
Department of Psychiatry and Behavioral Sciences, Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia, USA. Data suggest that the activation of immune responses and the release of inflammatory cytokines may play a role in the pathophysiology of major depression. One mechanism by which cytokines may contribute to depression is through their effects on the glucocorticoid receptor (GR). Altered GR function in depression has been demonstrated by neuroendocrine challenge tests that reliably reveal reduced GR sensitivity as manifested by nonsuppression of cortisol following dexamethasone administration in vivo and lack of immune suppression following administration of glucocorticoids in vitro. Relevant to the GR, cytokines have been shown to decrease GR expression, block translocation of the GR from cytoplasm to nucleus, and disrupt GR-DNA binding through nuclear protein-protein interactions. In addition, cytokines have been shown to increase the expression of the relatively inert GR beta isoform. Specific cytokine signaling molecules that have been shown to be involved in the disruption of GR activity include p38 mitogen-activated protein kinase, which is associated with reduced GR translocation, and signal transducer and activator of transcription (STAT)5, which binds to GR in the nucleus. Nuclear factor-kappaB (NF-kappaB) also has been shown to lead to GR suppression through mutually inhibitory GR-NF-kappaB nuclear interactions. Interestingly, several antidepressants have been shown to enhance GR function, as has activation of protein kinase A (PKA). Antidepressants and PKA activation have also been found to inhibit inflammatory cytokines and their signaling pathways, suggesting that drugs that target both inflammatory responses and the GR may have special efficacy in the treatment of depression.
PMID: 19906234 [PubMed - as supplied by publisher]
Patient thread on psychological effects of Decadron: LINK
Ondansetron (trade name Zofran in most countries) was the first 5-HT3 antagonist, developed by Glaxo around 1984. Its efficacy was first established in 1987, in animal models,[18][19] and it was extensively studied over the following years.[20] Ondansetron was approved by the U.S. Food and Drug Administration in 1991, and has since become available in several other countries, including the UK, Ireland, Australia, Canada, France and Brazil. As of 2008, ondansetron and granisetron are the only 5-HT3 antagonists available as a generic drug in the United States. Ondansetron may be given several times daily, depending on the severity of symptoms.
Tropisetron (trade name Navoban) was also first described in 1984.[21] It is available in several countries, such as the UK, Australia and France, but not in the United States. The effects of tropisetron last up to 24 hours, so it only requires once-daily administration.
Granisetron (trade name Kytril) was developed around 1988.[22] It is available in the U.S., UK, Australia and other countries. Clinical trials suggest that it is more effective than other 5-HT3 antagonists in preventing delayed CINV (nausea and vomiting that occur more than 24 hours after the first dose of chemotherapy).[23] It is taken once daily.
Dolasetron (U.S. trade name Anzemet) was first mentioned in the literature in 1989.[24] It is a prodrug, and most of its effects are due to its active metabolite, hydrodolasetron, which is formed in the liver by the enzymecarbonyl reductase. Dolasetron was approved by the FDA in 1997, and is also administered once daily.
Palonosetron (trade name Aloxi) is the newest 5-HT3 antagonist to become available in the U.S. market. It is an isoquinoline derivative, and is effective in preventing delayed CINV.[25] Palonosetron was approved by the FDA in 2003,[26] initially for intravenous use. An oral formulation was approved on August 22, 2008 for prevention of acute CINV alone, as a large clinical trial did not show oral administration to be as effective as IV use against delayed CINV.[27]
Ramosetron (trade name Nasea) is only available in Japan and certain Southeast Asian countries as of 2008.[28] It has higher affinity for the 5-HT3 receptor than the older 5-HT3 antagonists, and maintains its effects over two days; it is therefore significantly more effective for delayed CINV.[29] In animal studies, ramosetron was also effective against irritable bowel syndrome-like symptoms.[30]
Alosetron and cilansetron—the latter being developed by Solvay—are not antiemetics; instead, they are indicated in the treatment of a subset of irritable bowel syndrome where diarrhea is the dominant symptom. Alosetron was withdrawn from the U.S. market in 2000 due to unacceptably frequent severe side effects, and is only available through a restrictive program to patients who meet certain requirements.[31]
Certain prokinetic drugs such as cisapride, renzapride and metoclopramide, although not 5-HT3 antagonists proper, possess some weak antagonist effect at the 5-HT3 receptor. Galanolactone, a diterpenoid found in ginger, is a 5-HT3 antagonist and is believed to at least partially mediate the anti-emetic activity of this plant.[32][33]Mirtazapine (trade name Remeron) is a tetracyclic antidepressant with 5-HT3 antagonist effects and strong anti-emetic properties. Studies show mirtazapine as equally effective in treating chemotherapy-related nausea and vomiting as standard treatments; it is also cheaper and has fewer side effects than typical anti-emetics, and its antidepressant qualities may be an added benefit for cancer populations.[34] Mirtazapine has also been used in the treatment of the motility disorder gastroparesis due to its anti-emetic effects.[35]Olanzapine (trade name Zyprexa), an atypical antipsychotic with anti-emetic properties similar to those of mirtazapine, also shows promise in treating chemotherapy-induced nausea and vomiting.[34]
Dopamine antagonists act in the brain and are used to treat nausea and vomiting associated with neoplastic disease, radiation sickness, opioids, cytotoxic drugs and general anaesthetics.
Metoclopramide (Reglan) also acts on the GI tract as a pro-kinetic, and is thus useful in gastrointestinal disease; however, it is poor in cytotoxic or post-op vomiting.
Antihistamines (H1 histamine receptor antagonists), effective in many conditions, including motion sickness, morning sickness in pregnancy, and to combat opiate nausea.
Nabilone (Cesamet) - Put back on the market in late 2006. In the U.S., it is a Schedule II substance.
Sativex is an oral spray containing THC and CBD. It is currently legal in Canada and a few countries in Europe but not in legal the U.S.[citation needed]
Zolpidem has been reported to be a newer antiemetic used for patients that have been unresponsive to other first-line typical antiemetics.[citation needed]
http://kytril.com/
Kytril is Granisetron available as IV, tablets or liquid.
SANCUSO is the first and only patch (Granisetron) for the prevention of chemotherapy-induced nausea and vomiting in patients receiving moderately and/or highly emetogenic chemotherapy regimens (MEC and/or HEC) of up to 5 consecutive days' duration.1 Preventing CINV can make a positive impact on a patient's emotional and physical recovery
Read more about the occurrence of CINV, patient fear, and problems with adherence to CINV medication below.
The SANCUSOpatch delivers 34.3 mg of granisetron, a selective 5-HT3 receptor antagonist, at a rate of 3.1 mg per day through the skin and into the bloodstream.1. It’s an optimal choice for patients at risk for CINV, and those who would benefit from 5 continuous days of coverage. SANCUSO starts working before chemotherapy begins
One key to successful CINV prevention is to address the situation before it even begins and to offer continuous CINV prevention at a steady state during and after each round of chemotherapy.
SANCUSO is applied a minimum of 24 to 48 hours before chemotherapy and provides up to 5 days of continuous coverage for the prevention of chemotherapy-induced nausea and vomiting.1 Coverage prior to symptoms on a long-term basis can relieve your patients' anxieties and help them stay positive about their treatment overall.
Masui. 1996 Sep;45(9):1096-9. Treatment of postoperative nausea and vomiting with ondansetron in patients administered anti-neoplastic agents
[Article in Japanese] Morimoto Y, Nakamura M, Tamura T, Kunii T, Shimizu K, Miyauchi Y.
Department of Anesthesiology and Critical Care, Tokuyama Central Hospital.
The antiemetic effect of ondansetron (a 5-HT3 antagonist) was evaluated in patients treated with intraperitoneally administered anti-neoplastic agents (cisplatin and mitomycin-C) during surgery for ovarian cancer. Anesthesia was induced with intravenous thiopental 5 mg x kg-1 and maintained with nitrous oxide 66% in oxygen and isoflurane. After surgery, 6 patients received a single intravenous dose of ondansetron 4 mg (group O), 6 others did not receive ondansetron (group C). Both groups received an intravenous dose of methyl-prednisolone 500 mg. An intravenous dose of metoclopramide 10 mg was provided in case of continued vomiting or at the patient's request as a rescue antiemetic. The incidence of vomiting was 13% in group O and 87% in group C (P < 0.05). Nausea scores (range 1-4) were significantly lower in group O as compared with group C at 4 h and 8 h after surgery. Total dose of metoclopramide was 20 +/- 13 mg (mean +/- SD) in group C and 2 +/- 4 mg in group O. Administration of anti-neoplastic agents during surgery caused severe nausea and vomiting after surgery and ondansetron prevented the occurrence of nausea and vomiting almost completely. We conclude that ondansetron is an effective antiemetic for preventing postoperative nausea and vomiting in patients administered anti-neoplastic agents.
Efficacy and safety of casopitant mesylate, a neurokinin 1 (NK1)-receptor antagonist, in prevention of chemotherapy-induced nausea and vomiting in patients receiving cisplatin-based highly emetogenic chemotherapy: a randomised, double-blind, placebo-controlled trial
Emend is available as a capsule you can swallow in either 80 mg or 125 mg doses. How It Works
Aprepitant prevents and controls nausea and vomiting by blocking the effects of a chemical in the brain. That chemical is called P/neurokinin 1 (NK1) receptor antagonist.
note: may interfere with Tamoxifen/CYP450 pathway
Why It Is Used
Aprepitant is used to prevent and control nausea and vomiting caused by chemotherapy. It is always used in combination with serotonin antagonists (such as ondansetron) and dexamethasone.
Aprepitant is not approved for the treatment of chronic nausea or vomiting. It is most often used when the other drugs used to treat nausea and vomiting have not worked well enough. How Well It Works
Aprepitant, when combined with ondansetron and dexamethasone as part of a 3-day regimen, prevents both acute and delayed nausea and vomiting caused by chemotherapy. Side Effects
Side effects can occur with aprepitant and may include:
Dehydration.
Dizziness.
Diarrhea.
Hiccups.
Weakness and fatigue.
See Drug Reference for a full list of side effects. (Drug Reference is not available in all systems.) What To Think About
Aprepitant should be used only under the supervision of a medical oncologist or hematologist. It is approved for use only in combination with ondansetron and dexamethasone for the treatment of nausea and vomiting caused by chemotherapy. It also may do a better job than other drugs at controlling nausea and vomiting that occurs more than 1 day after treatment.
Aprepitant interacts with many other drugs. Be sure that your doctor knows all the prescription and over-the-counter drugs you are taking.
Blood-thinning drugs, such as warfarin, may not work as well when you take aprepitant. If you are taking a blood thinner, you will need frequent blood tests to make sure that your dose is high enough.
Aprepitant decreases the effectiveness of birth control pills. If you are taking birth control pills, your doctor will help you choose another method of birth control.
Study: Ginger can help reduce nausea after chemotherapy
By Liz Szabo, USA TODAY Ginger capsules can relieve the nausea caused by chemotherapy, a new study shows.
Up to 70% of patients become nauseated after chemo, according to a study of 644 people released Thursday, in advance of the annual meeting of the American Society of Clinical Oncology, which begins in two weeks in Orlando.
Although drugs such as Kytril can prevent vomiting, they don't always relieve nausea, says author Julie Ryan, assistant professor of dermatology and radiation oncology at the University of Rochester Medical Center. Ginger, however, reduced patients' nausea levels by half, according to the study, funded by the National Cancer Institute. On a scale of one to seven — in which seven represents the worst nausea — chemo patients given placebos rated their nausea as a 5 or 6, or very nauseous.
Those given ginger, however, rated their nausea level as only 2 or 3, Ryan says. Patients took ginger three days before and three days after getting chemo, Ryan says. Patients took three capsules, twice a day. The most effective doses were 1 gram and 0.5 gram a day, which are equal to half a teaspoon or one-quarter of a teaspoon of ground ginger. All patients also got standard drugs to prevent vomiting, Ryan says.
Significantly, ginger caused no side effects.
Doctors were careful to monitor patients' platelet levels, because some earlier research suggested that ginger might act like a blood thinner, Ryan says.
"That's why we're so excited. This is something that people have access to, that won't harm them," says Ryan, who notes that ginger capsules are commonly sold in health food stores.
Although ginger has been used as a folk remedy for nausea for centuries, this is the first time that it has been so rigorously tested for chemo patients, says Richard Schilsky, oncology society president, who wasn't involved in the study. He describes the trial's results as "conclusive."
Several studies have shown that ginger can relieve morning sickness during pregnancy, says Linda Lee, director of the Johns Hopkins Integrative Medicine & Digestive Center. Doctors don't yet understand exactly why it works.
Lee notes that the Food and Drug Administration doesn't regulate supplements such as ginger the same way as it regulates drugs.
"One of the challenges about recommending a ginger supplement is that not all brands are created equal," Lee says. "One study looked at several ginger supplements on the market, only to find a few of them did not contain gingerol, one of the active compounds in ginger."
And Schilsky notes that, because researchers didn't test powdered or fresh ginger, they don't know if these types of ginger are as effective as capsules.
"How do you translate ginger in a capsule to the ginger in your spice rack?" Schilsky asks. "Can you drink a six pack of ginger ale?"
Douglas Blayney, incoming president of the oncology society, says cancer patients should resist the temptation to indulge in too much ginger soda or cookies, however. Some studies show that cancer patients who gain weight are more likely to relapse.
Studies show up to two-thirds of cancer patients try herbal remedies or other alternative therapies.
Cancer researchers are increasingly interested in testing these approaches.
In 2007, researchers at the cancer society meeting showed that ginseng could help relieve cancer patients' fatigue.
After eight weeks of treatment in that study, roughly 27% of those who took the two highest ginseng doses rated their fatigue as "moderately" or "very much" better, she says. Only 10% of those who took placebos or the lowest ginseng dose improved that much.
And while alternative therapies can relieve some treatment-related symptoms, researchers haven't shown the these folk remedies actually treat cancer. At the 2007 meeting, researchers found that shark cartilage had no effect on lung cancer.
Masui. 1996 Sep;45(9):1096-9. Treatment of postoperative nausea and vomiting with ondansetron in patients administered anti-neoplastic agents
[Article in Japanese] Morimoto Y, Nakamura M, Tamura T, Kunii T, Shimizu K, Miyauchi Y.
Department of Anesthesiology and Critical Care, Tokuyama Central Hospital.
The antiemetic effect of ondansetron (a 5-HT3 antagonist) was evaluated in patients treated with intraperitoneally administered anti-neoplastic agents (cisplatin and mitomycin-C) during surgery for ovarian cancer. Anesthesia was induced with intravenous thiopental 5 mg x kg-1 and maintained with nitrous oxide 66% in oxygen and isoflurane. After surgery, 6 patients received a single intravenous dose of ondansetron 4 mg (group O), 6 others did not receive ondansetron (group C). Both groups received an intravenous dose of methyl-prednisolone 500 mg. An intravenous dose of metoclopramide 10 mg was provided in case of continued vomiting or at the patient's request as a rescue antiemetic. The incidence of vomiting was 13% in group O and 87% in group C (P < 0.05). Nausea scores (range 1-4) were significantly lower in group O as compared with group C at 4 h and 8 h after surgery. Total dose of metoclopramide was 20 +/- 13 mg (mean +/- SD) in group C and 2 +/- 4 mg in group O. Administration of anti-neoplastic agents during surgery caused severe nausea and vomiting after surgery and ondansetron prevented the occurrence of nausea and vomiting almost completely. We conclude that ondansetron is an effective antiemetic for preventing postoperative nausea and vomiting in patients administered anti-neoplastic agents.
PMID: 8905945 [PubMed - indexed for MEDLINE]
Study: Ginger can help reduce nausea after chemotherapy
By Liz Szabo, USA TODAY Ginger capsules can relieve the nausea caused by chemotherapy, a new study shows.
Up to 70% of patients become nauseated after chemo, according to a study of 644 people released Thursday, in advance of the annual meeting of the American Society of Clinical Oncology, which begins in two weeks in Orlando.
Although drugs such as Kytril can prevent vomiting, they don't always relieve nausea, says author Julie Ryan, assistant professor of dermatology and radiation oncology at the University of Rochester Medical Center. Ginger, however, reduced patients' nausea levels by half, according to the study, funded by the National Cancer Institute. On a scale of one to seven — in which seven represents the worst nausea — chemo patients given placebos rated their nausea as a 5 or 6, or very nauseous.
Those given ginger, however, rated their nausea level as only 2 or 3, Ryan says. Patients took ginger three days before and three days after getting chemo, Ryan says. Patients took three capsules, twice a day. The most effective doses were 1 gram and 0.5 gram a day, which are equal to half a teaspoon or one-quarter of a teaspoon of ground ginger. All patients also got standard drugs to prevent vomiting, Ryan says.
Significantly, ginger caused no side effects.
Doctors were careful to monitor patients' platelet levels, because some earlier research suggested that ginger might act like a blood thinner, Ryan says.
"That's why we're so excited. This is something that people have access to, that won't harm them," says Ryan, who notes that ginger capsules are commonly sold in health food stores.
Although ginger has been used as a folk remedy for nausea for centuries, this is the first time that it has been so rigorously tested for chemo patients, says Richard Schilsky, oncology society president, who wasn't involved in the study. He describes the trial's results as "conclusive."
Several studies have shown that ginger can relieve morning sickness during pregnancy, says Linda Lee, director of the Johns Hopkins Integrative Medicine & Digestive Center. Doctors don't yet understand exactly why it works.
Lee notes that the Food and Drug Administration doesn't regulate supplements such as ginger the same way as it regulates drugs.
"One of the challenges about recommending a ginger supplement is that not all brands are created equal," Lee says. "One study looked at several ginger supplements on the market, only to find a few of them did not contain gingerol, one of the active compounds in ginger."
And Schilsky notes that, because researchers didn't test powdered or fresh ginger, they don't know if these types of ginger are as effective as capsules.
"How do you translate ginger in a capsule to the ginger in your spice rack?" Schilsky asks. "Can you drink a six pack of ginger ale?"
Douglas Blayney, incoming president of the oncology society, says cancer patients should resist the temptation to indulge in too much ginger soda or cookies, however. Some studies show that cancer patients who gain weight are more likely to relapse.
Studies show up to two-thirds of cancer patients try herbal remedies or other alternative therapies.
Cancer researchers are increasingly interested in testing these approaches.
In 2007, researchers at the cancer society meeting showed that ginseng could help relieve cancer patients' fatigue.
After eight weeks of treatment in that study, roughly 27% of those who took the two highest ginseng doses rated their fatigue as "moderately" or "very much" better, she says. Only 10% of those who took placebos or the lowest ginseng dose improved that much.
And while alternative therapies can relieve some treatment-related symptoms, researchers haven't shown the these folk remedies actually treat cancer. At the 2007 meeting, researchers found that shark cartilage had no effect on lung cancer.
Emend is available as a capsule you can swallow in either 80 mg or 125 mg doses. How It Works
Aprepitant prevents and controls nausea and vomiting by blocking the effects of a chemical in the brain. That chemical is called P/neurokinin 1 (NK1) receptor antagonist. Why It Is Used
Aprepitant is used to prevent and control nausea and vomiting caused by chemotherapy. It is always used in combination with serotonin antagonists (such as ondansetron) and dexamethasone.
Aprepitant is not approved for the treatment of chronic nausea or vomiting. It is most often used when the other drugs used to treat nausea and vomiting have not worked well enough. How Well It Works
Aprepitant, when combined with ondansetron and dexamethasone as part of a 3-day regimen, prevents both acute and delayed nausea and vomiting caused by chemotherapy. Side Effects
Side effects can occur with aprepitant and may include:
Dehydration.
Dizziness.
Diarrhea.
Hiccups.
Weakness and fatigue.
See Drug Reference for a full list of side effects. (Drug Reference is not available in all systems.) What To Think About
Aprepitant should be used only under the supervision of a medical oncologist or hematologist. It is approved for use only in combination with ondansetron and dexamethasone for the treatment of nausea and vomiting caused by chemotherapy. It also may do a better job than other drugs at controlling nausea and vomiting that occurs more than 1 day after treatment.
Aprepitant interacts with many other drugs. Be sure that your doctor knows all the prescription and over-the-counter drugs you are taking.
Blood-thinning drugs, such as warfarin, may not work as well when you take aprepitant. If you are taking a blood thinner, you will need frequent blood tests to make sure that your dose is high enough.
Aprepitant decreases the effectiveness of birth control pills. If you are taking birth control pills, your doctor will help you choose another method of birth control.
Well, Rich, I hated those damn 'roids, and now I know with good reason...
__________________
Smile On!
Laurel
Dx'd w/multifocal DCIS/IDS 3/08
7mm invasive component
Partial mast. 5/08
Stage 1b, ER 80%, PR 90%, HER-2 6.9 on FISH
0/5 nodes
4 AC, 4 TH finished 9/08
Herceptin every 3 weeks. Finished 7/09
Tamoxifen 10/08. Switched to Femara 8/09
Bilat SPM w/reconstruction 10/08
Clinical Trial w/Clondronate 12/08
Stopped Clondronate--too hard on my gizzard!
Switched back to Tamoxifen due to tendon pain from Femara
15 Years NED
I think I just might hang around awhile....
Doesn’t u think these poor Indians are suffering from inferiority complex. Frustrated minds really afraid of Islam...Look at the face of this soldier LOLz, a pet dog of So-called Indian liberalism...
Linear Mode
