naloxone and Breast-Neoplasms

An 82-year-old female on hemodialysis was diagnosed with advanced breast cancer. She received 20 mg of controlled-release oral morphine per day for the relief of cancer pain. After a total dose of 30 mg was administered, she was hospitalized with disturbance of consciousness. The patient underwent hemodialysis the next day, but developed impaired consciousness and respiratory depression. On the third day of hospitalization, a continuous infusion of naloxone was started and administered for eleven days. Thereafter, she was given oxycodone during hemodialysis without any side effects. Morphine-6-glucuronide(M-6-G)can accumulate in the blood of renal failure and dialysis patients. Toxicity of M-6-G may persist even after this metabolite is removed by dialysis, causing potentially life-threatening opioid toxicity. Morphine is therefore not recommended for use in renal failure and dialysis patients. The use of fentanyl or oxycodone is recommended as an alternative opioid. It is essential that medical staff are aware that these patients have an increased risk of developing serious morphine-related toxicity.

Topics: Aged, 80 and over; Breast Neoplasms; Consciousness; Delayed-Action Preparations; Female; Humans; Morphine; Naloxone; Narcotic Antagonists; Pain; Renal Dialysis; Respiratory Insufficiency; Time Factors

Morphine is widely used for relieving cancer pain in patients with advanced cancer. However, whether morphine can suppress or promote the progression of cancer in breast cancer patients receiving morphine analgesia remains unclear. Therefore, we used an in vitro model treated with morphine and naloxone to investigate the effects of morphine on breast cancer cell line MCF-7. MCF-7 cells were cultured with different concentrations (0.01 to 10 µM) of morphine at 12th, 24th, 36th, 48th, 60th and 72nd hours. Then, cell viability was measured through the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, and cell cycle and apoptosis assays were detected by flow cytometry (FCM). In addition, cell proliferation was conducted by colony formation assay. In this study, we have found that morphine (0.01 to 10 µM) could significantly reduce the cell vitality, growth and colony formation rate of MCF-7 cells, which has a certain relationship with cell cycle progression arrested at the G0/G1 and G2/M phase and MCF-7 cells apoptosis. Moreover, naloxone along with morphine could not reverse these effects, which indicates that the inhibition of MCF-7 breast cancer cell growth and proliferation by morphine could be its independent effect, not associated with opioid receptors. Morphine can inhibit cell growth by blocking the cell cycle and promote apoptosis in MCF-7 cells. Hence, morphine may be unable to promote the progression of cancer in breast cancer patients receiving morphine analgesia.

Topics: Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Breast Neoplasms; Cell Cycle; Cell Division; Cell Growth Processes; Cell Survival; Drug Interactions; Drug Screening Assays, Antitumor; Female; Humans; MCF-7 Cells; Morphine; Naloxone; Tumor Stem Cell Assay

This study was designed to investigate the efficacy of a new vaccine against breast cancer, which was made by mixing the extract of heated 4T1 cells and naloxone, as an adjuvant.. Female BALB/c mice of 6-8 weeks old were challenged subcutaneously in the right flanks with 4T1 cells. When all animals developed a palpable tumor, immunotherapy was initiated. Mice in the experimental groups received, twice with a 1-week interval, either the extract of heated 4T1 alone or in combination with naloxone, and mice in the negative control group received phosphate-buffered saline. One week after the last immunotherapy, half of the mice were euthanized in order to determine the immune response profile. The remaining animals were kept until the time when death occurred spontaneously.. The combined-treated mice with mammary tumors showed a more favorable survival curve and slower rate of tumor development compared to the mice with tumors that received only heated 4T1 and/or negative control mice. Moreover, the combined immunization significantly amplified the respiratory burst potential and the secretion of IFN-γ, and, conversely, diminished the secretion of IL-4, IL-10, and TGF-β in the splenocyte population compared to splenocytes from other groups.. The combined naloxone and heated 4T1 cells promote beneficial outcomes in the mouse model of breast cancer.

Topics: Animals; Breast Neoplasms; Cell Line, Tumor; Female; Humans; Immunotherapy; Mice; Mice, Inbred BALB C; Naloxone

Topics: Aged; Analgesics, Opioid; Breast Neoplasms; Female; Humans; Liver Neoplasms; Naloxone; Narcotic Antagonists; Oxycodone; Pain

In our earlier study we have demonstrated that MCF-7 cell line expresses all three opioid receptor types, micro, delta and kappa (MOR, DOR and KOR, respectively), but predominantly MOR. Morphine, as well as endogenous MOR-selective agonists, endomorphin-1 and endomorphin-2 were shown to decrease MOR gene expression in MCF-7 cells. Opioid antagonist - naloxone -produced the opposite effect, increasing MOR gene expression. In this study we investigated and compared the influence of several opioid antagonists of alkaloid structure (beta-funaltrexamine and naloxonazine) and of peptide structure: [Dmt(1), D-1-Nal(4)]endomorphin-2, [Dmt, D-2-Nal(4)]endomorphin-1, and [Dmt, D-2-Nal(4)]endomorphin-2 on MOR up-/down-regulation and proliferation in MCF-7 cell line.. MCF-7 cells were incubated with opioids. The levels of MOR mRNA were assessed using quantitative real-time RT-PCR assay. Cell growth was measured by Mosmann tetrazolium salt assay.. It was shown that all tested opioid antagonists produced up-regulation of MOR gene expression, but the strongest effect was observed with naloxonazine. However, none of the antagonists at concentrations as high as 10(-4) M showed any antiproliferative effects on MCF-7 cells, neither in the presence or absence of beta-estradiol.. It seems that up- or down-regulation of MOR mRNA levels has no direct effect on cell proliferation.

Topics: Breast Neoplasms; Cell Division; Cell Line, Tumor; Estradiol; Humans; Naloxone; Narcotic Antagonists; Polymerase Chain Reaction; Receptors, Opioid, mu; RNA, Messenger; Up-Regulation

Urokinase plasminogen activator plays a key role in tumor-associated processes, increasing cancer cell invasion and metastasis, and is therefore used as a marker in cancer prognosis. In this study, we have determined the effect of mu-opioid receptor agonists and antagonists on the urokinase plasminogen activator secretion in MCF-7 cell line. It was shown that mu-opioid receptor agonists, such as morphine and endomorphins, greatly stimulate urokinase plasminogen activator secretion, while naloxone and MOR-selective antagonists elicit the opposite effect. The same tendency was observed also on the urokinase plasminogen activator mRNA level. However, neither agonists nor antagonists had any effect on proliferation of MCF-7 cells. The findings reported in this study may be useful in designing further experiments aimed at elucidating the role of the opioid system in cancer cells.

Topics: Analgesics, Opioid; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Female; Humans; Morphine; Naloxone; Narcotic Antagonists; Receptors, Opioid, mu; Receptors, Urokinase Plasminogen Activator; RNA, Messenger; Time Factors; Urokinase-Type Plasminogen Activator

The aim of the study was to investigate the presence of opioid receptor types in human breast adenocarcinoma MCF-7 cells and to characterize the changes in MOR expression induced by opioid agonist and antagonist treatment. We have shown that all three types of opioid receptors, but predominantly MOR, are expressed in MCF-7 cells. Selective MOR agonists, morphine, endomorphin-1, and endomorphin-2 downregulated MOR mRNA levels in a concentration- and time-dependent manner, but the effect produced by endomorphins was much stronger. Downregulation was blocked by the opioid antagonist naloxone. Naloxone alone produced a slight increase in MOR gene expression. Immunoblotting with antiserum against MOR-1 confirmed these results at the protein level. The results of our study indicate that, in MCF-7 cells, MOR gene expression is downregulated by opioid agonists and upregulated by opioid antagonists. We propose that the opioid-induced regulation of MOR mRNA expression is mediated by reduced binding of the transcription factors NFkappaB and AP-1 to the promoter region on the MOR gene.

Topics: Analgesics, Opioid; Breast Neoplasms; Cell Line, Tumor; Gene Expression Regulation, Neoplastic; Humans; Morphine; Naloxone; Narcotic Antagonists; NF-kappa B; Oligopeptides; Receptors, Opioid, mu; RNA, Messenger; Transcription Factor AP-1; Transcription, Genetic

Estrogen promotes the growth of breast cancer via estrogen receptors (ER). Earlier studies showed that the opioid receptor antagonist naloxone inhibits MCF-7 breast cancer growth in mice. We examined the cellular and molecular mechanism of naloxone antagonism of ERalpha activity in human MCF-7 cells. Naloxone (100 nmol/L) inhibited 17beta-estradiol (E2)-induced (10 nmol/L) MCF-7 cell proliferation by 65% and mitogen-activated protein kinase/extracellular signal-regulated kinase phosphorylation. Naloxone blocked the E2-induced activation of ERalpha, with 85% inhibition after 5 minutes and 100% recovery after 60 minutes. This assay is based on quantitation of E2-activated nuclear ERalpha binding to the immobilized coactivator peptide. A significant decrease in E2-induced ERalpha transactivation was observed in the presence of naloxone in the estrogen response element-luciferase reporter assay (P < 0.05, E2 versus E2 + naloxone). Naloxone also blocked E2-induced down-regulation of ERalpha mRNA at 30 minutes and 6 hours. Although naloxone inhibits ERalpha activity directly, it also induces a cross-talk between mu-opioid receptor (MOR) and ERalpha. Immunoprecipitates with anti-MOR antibody showed the presence of ERalpha in cells incubated with E2 in the presence of naloxone but not in cells incubated with E2 or naloxone alone. Higher amounts of ERalpha associated with MOR after 60 minutes compared with 10 minutes of incubation. Naloxone inhibited E2-bovine serum albumin-FITC binding to plasma membrane-associated ERalpha and also inhibited the direct binding of [3H]E2 to ERalpha. Thus, naloxone modulates ERalpha activity directly as well as indirectly via MOR. This study suggests that naloxone-like compounds can be developed as novel therapeutic molecules for breast cancer therapy.

Topics: Animals; Antineoplastic Agents; Breast Neoplasms; Cell Line, Tumor; Cell Nucleus; Cell Proliferation; Estradiol; Estrogen Antagonists; Estrogen Receptor alpha; Female; Humans; Mice; Mice, Nude; Naloxone; Narcotic Antagonists; Receptors, Opioid, mu; Xenograft Model Antitumor Assays

In our studies of the development of a novel class of selective estrogen receptor modulators, (+)-3-[4-(1-piperidinoethoxy)phenyl]spiro[indene-1,1'-indane]-5,5'-diol hydrochloride (1) was found to be an estrogen receptor ligand with beneficial effects in rat models for human hot flush. Moreover, 1 was found to have beneficial effects on lipid and bone metabolism while maintaining marginal effects on the uterus and breasts. These findings suggest that 1 would provide a new treatment for hot flush.

Topics: Animals; Bone Density; Breast Neoplasms; Cholesterol; Drug Evaluation, Preclinical; Estradiol; Female; Hot Flashes; Indans; Male; Morphine Dependence; Naloxone; Piperidines; Rats; Rats, Sprague-Dawley; Receptors, Estrogen; Selective Estrogen Receptor Modulators; Skin Temperature; Spiro Compounds; Stereoisomerism; Tumor Cells, Cultured; Uterus

Topics: Administration, Oral; Adult; Analgesics, Opioid; Breast Neoplasms; Chemistry, Pharmaceutical; Constipation; Female; Humans; Methadone; Naloxone; Naltrexone; Narcotic Antagonists; Pain; Quaternary Ammonium Compounds

We report a case of respiratory depression after intracerebroventricular morphine administration of a dose inadvertently 10 times greater than the typical daily dose. At the time of the respiratory dysfunction, the concentrations of morphine and its metabolites in cerebrospinal fluid (CSF) and plasma samples were determined. On comparison of these results with previous clinical studies in which there was no respiratory depression, no relationship was found between the occurrence of respiratory depression and the concentration of morphine or its metabolites in the CSF. The occurrence and characteristics of respiratory depression may be related to the concentrations of morphine and its metabolites in bulbar tissue.

Topics: Adenocarcinoma; Bone Neoplasms; Breast Neoplasms; Female; Humans; Injections, Intraventricular; Medication Errors; Middle Aged; Morphine; Naloxone; Pain; Respiratory Tract Diseases

Topics: Breast Neoplasms; Female; Gastrointestinal Hormones; Humans; Naloxone

The role of enkephalins, endorphins and other neuropeptides produced by the nervous system in the alteration of immune responsiveness is generally unknown. The present studies were undertaken to investigate the role of these neuropeptides in the modulation of cytotoxicity induced by LPS activated macrophages obtained from normal donors as well as breast cancer and Hodgkins disease patients. When the macrophages from normal donors were pretreated with these neuropeptides for 1 hr prior to co-culturing with target cells, macrophage mediated cytotoxicity was enhanced with 10(-6) M and 10(-8) M of [met]-enkephalin, 10(-6) M of [leu]-enkephalin and 10(-6) M and 10(-12) M of alpha-endorphin. However, when the macrophages were co-cultured with target cells in the presence of the neuropeptides, it was observed that 10(-6) M and 10(-12) M of alpha-endorphin enhanced cytotoxicity whereas no enhancement in cytotoxicity was observed when [met]-enkephalin or [leu]-enkephalin were added to the cultures. In fact, it appears that 10(-10) M of [met]-enkephalin and 10(-12) M of [leu]-enkephalin actually suppressed macrophage mediated cytotoxicity. When the opioid antagonist Naloxone was incubated with the neuropeptides in the presence of the macrophages the enhancement of macrophage killing produced by [met]-enkephalin, [leu]-enkephalin or alpha-endorphin was suppressed. When the breast cancer patients' macrophages were pretreated with these neuropeptides, enhancement in cytotoxicity was observed at 10(-10) M of [met]-enkephalin, and [leu]-enkephalin and at 10(-8) M and 10(-12) M of alpha-endorphin.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: alpha-Endorphin; Breast Neoplasms; Cell Line; Cytotoxicity, Immunologic; Endorphins; Enkephalin, Leucine; Enkephalin, Methionine; Hodgkin Disease; Humans; Macrophages; Naloxone; Neoplasms; Neuropeptides

The effects of administration of opiates and naloxone on the activities of PFK, 6PGDH and alpha-GPDH and alpha-GPDH/6PGDH ratios in human breast carcinomas were investigated in patients awaiting mastectomy. Injection of naloxone or fentanyl into an antecubital vein resulted in a statistically significant reduction in the activity of alpha-GPDH. Fentanyl was also effective in reducing the activity of 6PGDH. Injection of morphine into a branch of the internal mammary artery during mastectomy failed to induce changes in the activities of any of the enzymes but injection of naloxone resulted in a significant rise in the activity of 6PGDH. It is postulated that these alterations in the activities might not be associated with the binding of these drugs to opiate receptor proteins in the carcinoma. Furthermore opiate agonists or antagonists might not produce the required changes in the activities of any of the enzymes.

Topics: Breast Neoplasms; Female; Glycerolphosphate Dehydrogenase; Humans; Naloxone; Narcotics; Phosphofructokinase-1; Phosphogluconate Dehydrogenase; Receptors, Opioid