naloxone and Adenocarcinoma

In the present study, we measured the kinetics and distribution in vivo of the selective delta-opioid antagonist 11C-methylnaltrindole (11C-MeNTI) and the mu-opioid agonist 11C-carfentanil (11C-CFN) in patients with lung carcinoma using PET.. Paired measurements of 11C-MeNTI and 11C-CFN binding were performed in biopsy-proven small-cell (n = 2), squamous (n = 2), and adenocarcinoma (n = 3) lung cancer patients. Dynamic PET scans of increasing duration (0.5-8 min) were acquired over 90 min after an intravenous bolus injection of 370 MBq of tracer. Time-activity curves for tumor and normal lung parenchyma binding were generated using the region-of-interest (ROI) method. The mean activity at equilibrium was measured, and the specific-to-nonspecific binding ratio (tumor - lung)/lung was calculated. Four of 7 patients underwent an additional static 18F-FDG PET scan for clinical indications. Three of 7 patients underwent surgery, and stained sections of tumor were inspected for inflammation, necrosis, and scar tissue.. Increased binding of 11C-MeNTI and 11C-CFN was detected in all tumor types studied. 11C-MeNTI binding in tumor and healthy lung tissue was significantly more intense than that of 11C-CFN. The average specific-to-nonspecific binding ratio across cell types for 11C-MeNTI (4.32 +/- 1.31; mean +/- SEM) was greater than that of 11C-CFN (2.42 +/- 1.17) but lower than that of 18F-FDG (7.74 +/- 0.53). Intravenous naloxone produced 50% and 44% decreases in the specific-to-nonspecific binding ratios of 11C-MeNTI and 11C-CFN, respectively.. These data provide in vivo evidence for the presence of delta- and mu-opioid receptor types in the 3 major human lung carcinomas and suggest the suitability of 11C-MeNTI and 11C-CFN as investigational probes of lung carcinoma biology.

Topics: Adenocarcinoma; Aged; Carcinoma, Non-Small-Cell Lung; Carcinoma, Small Cell; Carcinoma, Squamous Cell; Coloring Agents; Female; Humans; Inflammation; Lung Neoplasms; Male; Middle Aged; Naloxone; Narcotic Antagonists; Necrosis; Radionuclide Imaging; Radiopharmaceuticals; Receptors, Opioid, delta; Receptors, Opioid, mu; Tissue Distribution

Gemcitabine is the standard of care for advanced pancreatic neoplasia, and exerts its effect through inhibition of DNA synthesis. However, gemcitabine has limited survival benefits. Opioid growth factor (OGF) is an autocrine-produced peptide that interacts with the nuclear receptor, OGFr, to inhibit cell proliferation but is not cytotoxic or apoptotic. The present study was designed to examine whether a combination of chemotherapy with gemcitabine and biotherapy with OGF is more effective than either agent alone in inhibiting pancreatic cancer growth in vitro and in vivo. The combination of OGF (10(-6) M) and gemcitabine (10(-8) M) reduced MIA PaCa-2 cell number from control levels by 46% within 48 h, and resulted in a growth inhibition greater than that of the individual compounds. OGF in combination with 5-fluorouracil also depressed cell growth more than either agent alone. The action of OGF, but not gemcitabine, was mediated by a naloxone-sensitive receptor, and was completely reversible. OGF, but no other endogenous or exogenous opioids, altered pancreatic cancer growth in tissue culture. The combination of OGF and gemcitabine also repressed the growth of another pancreatic cancer cell line, PANC-1. MIA PaCa-2 cells transplanted into athymic mice received 10 mg/kg OGF daily, 120 mg/kg gemcitabine every 3 days; 10 mg/kg OGF daily and 120 mg/kg gemcitabine every 3rd day, or 0.1 ml of sterile saline daily. Tumor incidence, and latency times to tumor appearance, of mice receiving combined therapy with OGF and gemcitabine, were significantly decreased from those of the control, OGF, and gemcitabine groups. Tumor volumes in the OGF, gemcitabine, and OGF/gemcitabine groups were markedly decreased from controls beginning on days 14, 12, and 8, respectively, after tumor cell inoculation. Tumor weight and tumor volume were reduced from control levels by 36-85% in the OGF and/or gemcitabine groups on day 45 (date of termination), and the group of mice exposed to a combination of OGF and gemcitabine had decreases in tumor size of 70% and 63% from the OGF or the gemcitabine alone groups, respectively. This preclinical evidence shows that combined chemotherapy (e.g. gemcitabine) and biotherapy (OGF) provides an enhanced therapeutic benefit for pancreatic cancer.

Topics: Adenocarcinoma; Animals; Antimetabolites, Antineoplastic; Apoptosis; Caspase 3; Caspases; Cell Line, Tumor; Cell Proliferation; Deoxycytidine; Drug Therapy, Combination; Enkephalin, Methionine; Fluorouracil; Gemcitabine; Growth Substances; Humans; Male; Mice; Mice, Nude; Naloxone; Narcotics; Pancreatic Neoplasms; Receptors, Opioid; Tumor Burden; Xenograft Model Antitumor Assays

Opioid growth factor (OGF) is a native endogenous opioid peptide ([Met5]-enkephalin) that interacts with the OGF receptor (OGFr), and serves as a tonically active negative growth factor in neoplasia. To inquire whether OGF modulates anchorage-independent growth, HT-29 human colon cancer cells were grown in soft agar and subjected to this peptide. In contrast to controls, HT-29 cells exposed to OGF had 57% fewer colonies, and these colonies were reduced in area by 75%. The changes induced by OGF were abolished by concomitant treatment with naloxone, indicating a receptor-mediated mechanism for peptide activity. Continuous blockade of opioid-receptor interactions with the potent and long-acting opioid antagonist, naltrexone (NTX), revealed an increase of 81 and 49% in the number and area, respectively, of colonies compared to control levels. These data suggest that OGF is tonically active in neoplastic cells growing in soft agar medium. HT-29 cells studied under anchorage-independent conditions were not influenced in growth by a variety of natural and synthetic opioids, including those selective for micro, delta, and kappa opioid receptors. Similar effects on anchorage-independent growth by OGF and NTX observed for HT-29 cells were recorded in pancreatic adenocarcinoma cells (Mia PaCa-2, Panc-1) and squamous cell carcinoma of the head and neck (CAL-27). These results using anchorage-independent conditions are consistent with previous data showing that OGF can markedly influence tumor growth in xenografts, and suggest that clonogenic assays can be utilized as indicators of tumorigenicity when tumor transplantation experiments are restricted.

Topics: Adenocarcinoma; Carcinoma, Squamous Cell; Cell Adhesion; Cell Division; Colonic Neoplasms; Colony-Forming Units Assay; Enkephalin, Methionine; Head and Neck Neoplasms; Humans; Naloxone; Naltrexone; Narcotic Antagonists; Pancreatic Neoplasms; Receptors, Opioid; Transplantation, Heterologous; Tumor Cells, Cultured

The effect of the opioid receptor agonist methionine enkephalin (Met-enkephalin) and the opioid receptor antagonist naloxone on colonic carcinogenesis induced by azoxymethane was investigated in Wistar rats. Rats received ten weekly injections of 7.4 mg/kg of body weight of azoxymethane and injections of Met-enkephalin (50 micrograms/kg of body weight), naloxone (2 mg/kg of body weight), or Met-enkephalin (50 micrograms/kg of body weight) plus naloxone (2 mg/kg of body weight) once every 2 days. In wk 40, the group treated with Met-enkephalin had a significantly increased incidence of colonic tumors. A combination of Met-enkephalin and naloxone attenuated the enhancing effect by Met-enkephalin on the development of colonic tumors. Administration of naloxone alone had no influence on colonic tumorigenesis. During and after administration of the carcinogen, the bromodeoxyuridine-labeling indices of the colon mucosa and/or cancers were significantly increased in rats treated with Met-enkephalin. However, a combination of Met-enkephalin and naloxone significantly decreased the labeling indices of the colon mucosa and/or cancers. These findings indicate that Met-enkephalin enhanced colon carcinogenesis and that naloxone attenuated this enhancement. Because naloxone is an opioid receptor antagonist, these findings also indicate that the enhancing effect of Met-enkephalin on colon carcinogenesis may be mediated through opioid receptors.

Topics: Adenocarcinoma; Animals; Azoxymethane; Colon; Colonic Neoplasms; Drug Administration Schedule; Drug Synergism; Enkephalin, Methionine; Male; Naloxone; Rats; Rats, Inbred Strains

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: Adenocarcinoma; Colonic Neoplasms; Half-Life; Humans; Infusion Pumps; Injections, Epidural; Male; Middle Aged; Morphine; Naloxone; Palliative Care; Rectal Neoplasms; Respiration

Topics: 9,10-Dimethyl-1,2-benzanthracene; Adenocarcinoma; Animals; Endorphins; Female; Mammary Neoplasms, Experimental; Naloxone; Naltrexone; Rats