morphine and Neoplasms

In vertebrates, the glucuronidation of small lipophilic agents is catalyzed by the endoplasmic reticulum UDP-glucuronosyltransferases (UGTs). This metabolic pathway leads to the formation of water-soluble metabolites originating from normal dietary processes, cellular catabolism, or exposure to drugs and xenobiotics. This classic detoxification process, which led to the discovery nearly 50 years ago of the cosubstrate UDP-glucuronic acid (19), is now known to be carried out by 15 human UGTs. Characterization of the individual gene products using cDNA expression experiments has led to the identification of over 350 individual compounds that serve as substrates for this superfamily of proteins. This data, coupled with the introduction of sophisticated RNA detection techniques designed to elucidate patterns of gene expression of the UGT superfamily in human liver and extrahepatic tissues of the gastrointestinal tract, has aided in understanding the contribution of glucuronidation toward epithelial first-pass metabolism. In addition, characterization of the UGT1A locus and genetic studies directed at understanding the role of bilirubin glucuronidation and the biochemical basis of the clinical symptoms found in unconjugated hyperbilirubinemia have uncovered the structural gene polymorphisms associated with Crigler-Najjar's and Gilbert's syndrome. The role of the UGTs in metabolism and different disease states in humans is the topic of this review.

Topics: Autoimmunity; Chromosome Mapping; Glucuronides; Glucuronosyltransferase; Humans; Hyperbilirubinemia; Neoplasms; Steroids; Terminology as Topic

Cancer diagnosis during pregnancy occurs in 1 out of 1000 pregnancies with common malignancies including breast and hematological cancers. Fetal exposure to currently utilized agents is poorly described. We directly assessed fetal exposure by screening meconium from 23 newborns whose mothers had undergone treatment for cancer during pregnancy.. Meconium was collected from newborns whose mothers were diagnosed with cancer during pregnancy and underwent chemotherapy in the second or third trimester as part of the Cancer and Pregnancy Registry. We conducted screening of 23 meconium samples for chemotherapeutics and known metabolites of chemotherapeutics by liquid chromatography-high resolution mass spectrometry (LC-HRMS). Putative identification of paclitaxel and/or its metabolites was made in 8 screened samples. In positively screened samples, we quantified paclitaxel, 3'-p-hydroxypaclitaxel, and 6α-hydroxypaclitaxel by stable isotope dilution-LC-HRMS.. Mean (standard deviation) levels of paclitaxel in positively screened samples were 399.9 (248.6) pg/mg in meconium samples from newborn born to mothers that underwent chemotherapy during pregnancy. 3'-p-hydroxypaclitaxel and 6α-hydroxypaclitaxel mean levels were 105.2 (54.6) and 113.4 (48.9) pg/mg meconium, respectively.. Intact paclitaxel, 3'-p-hydroxypaclitaxel, and 6α-hydroxypaclitaxel were detected in meconium, providing unambiguous confirmation of human fetal exposure. Variability in meconium levels between individuals may indicate a potential for reducing fetal exposure based on timing, dosing, and individual characteristics. This preliminary study may provide an approach for examining the effects of cancer diagnosis during pregnancy on other outcomes by providing a measure of direct fetal exposure.

Topics: Adult; Chromatography, High Pressure Liquid; Chromatography, Liquid; Female; Follow-Up Studies; Humans; Infant, Newborn; Longitudinal Studies; Meconium; Neoplasms; Paclitaxel; Pregnancy; Pregnancy Complications, Neoplastic; Registries; Tandem Mass Spectrometry

Zinc coproporphyrin I (ZnCP-I) is a photosensitive molecule and a major component of meconium. Here, we examined the effects of ZnCP-I as a potential photosensitizer in photodynamic therapy for tumors.. (1) Aqueous ZnCP-I was irradiated with a pulsed YAG-SHG laser (wavelength: 532 nm)/YAG-SHG dye laser (wavelength: 566 nm). (2) HeLa cells were incubated in 200 mM ZnCP-I, and accumulation of ZnCP-I in HeLa cells was evaluated with ZnCP-I-specific fluorescence over 500 nm. (3) Aqueous ZnCP-I was administered intravenously to HeLa tumor-bearing mice at a dose of 10.2 mg/kg body weight. The tumors were irradiated with a filtered halogen lamp (wavelength: 580 nm) at 100 J/cm(2) 20 min after administration.. (1) An intense near-infrared emission spectrum was observed at around 1,270 nm after irradiation. The emission intensity was proportional to the laser power between 10 and 80 mW and was completely inhibited by addition of NaN3, a singlet oxygen scavenger. (2) ZnCP-I-specific fluorescence was detected in the HeLa cell cytoplasm. (3) Irradiated tumors treated with ZnCP-I were mostly necrotized.. ZnCP-I accumulated in tumor cells, produced singlet oxygen upon irradiation, and necrotized the tumor cells. These results suggest that ZnCP-I may be an effective photosensitizer.

Topics: Animals; Antineoplastic Agents; Biological Transport; Coproporphyrins; Female; Free Radical Scavengers; HeLa Cells; Humans; Lasers, Dye; Lasers, Solid-State; Meconium; Mice; Mice, Inbred BALB C; Mice, Nude; Necrosis; Neoplasms; Oxidants; Photochemotherapy; Photosensitizing Agents; Singlet Oxygen; Xenograft Model Antitumor Assays; Zinc

Topics: Air; Amniotic Fluid; Animals; Asphyxia Neonatorum; Cardiomyopathies; Contraindications; Disease Susceptibility; Dose-Response Relationship, Drug; Europe; Humans; Hypoxia; Infant, Newborn; Kidney Diseases; Meconium; Models, Animal; Muscle Hypotonia; Neoplasms; Oxygen; Oxygen Inhalation Therapy; Practice Guidelines as Topic; Resuscitation; United States

A hybridoma producing monoclonal antibody (H11) directed to lactoneotetraosylceramide (paragloboside) has been established from spleen cells of a mouse immunized with paragloboside. The monoclonal antibody H11 (immunoglobulin M type) was selected from five clones showing different reactivities with paragloboside. The monoclonal antibody was highly specific to paragloboside and lacked reactivity with other glycolipids including glucosylceramide, lactosylceramide, globotriaosylceramide, globotetraosylceramide, gangliotriaosylceramide, gangliotetraosylceramide, and GalNAc beta 1-4[NeuAc alpha 2-3]Gal beta 1-4Glc beta 1-1Cer. However, the monoclonal antibody (H11) was found to bind to lactosamine-containing glycolipids at their terminals, such as i- and I-type glycolipids as well as paragloboside. A two-step sandwich radioimmunoassay method for paragloboside antigen in serum was established by using the monoclonal antibody. The mean paragloboside antigen concentration in the sera from 20 normal individuals was 25.3 ng/ml. If the cutoff value was set at 80.9 ng/ml [25.3 + 2 x 27.8 (SD)], only 1 of 20 healthy controls had an elevated paragloboside value in the serum, whereas sera from 9 of 12 (75.0%) hepatoma, 4 of 10 (40%) pancreatic cancer, 16 of 40 (40.0%) stomach cancer, and 6 of 10 (60%) lung cancer patients had elevated paragloboside values. Sera from 3 of 8 hepatitis patients and 7 of 10 liver cirrhosis patients were estimated to be positive but sera from 16 patients with benign disease had paragloboside levels lower than the cutoff value. A larger amount of the antigen was found in liver metastases from colorectal carcinoma compared to the normal counterpart. The antigen was also detected in the medium of various human cancer cells and meconium. However, the antigen in the sera, medium, meconium, and cancer tissue seemed to be associated with glycoprotein or lipoprotein, because most of the antigen activity was eluted in the void volume fraction on high-performance liquid chromatography with a gel filtration column.

Topics: Antibodies, Monoclonal; Antibody Specificity; Culture Media; Globosides; Glycosphingolipids; Humans; Meconium; Neoplasms; Radioimmunoassay; Tumor Cells, Cultured

Rabbit antisera to an organospecific intestinal antigen are obtained. This antigen has beta 2-electromobility, is thermolabile, is not extracted by perchloric acid and phenol and immunologically differs from CEA. The antigen is found in bottom zone of colonic crypt and in carcinomas of colon and rectum.

Topics: Animals; Antigens, Neoplasm; Epitopes; Fetus; Humans; Immunization; Immunologic Techniques; Intestines; Meconium; Neoplasms; Rabbits

We have isolated carcinoembryonic antigen (CEA)-related antigens from meconium and compared them with those in adult feces. Two CEA-related antigens were detected in meconium [nonspecific cross-reacting antigen 2 (NCA-2) and meconium nonspecific cross-reacting antigen] while four CEA-related antigens were found in adult feces [normal fecal antigen 1, normal fecal antigen 2 (NFA-2), normal fecal cross-reacting antigen, and fecal nonspecific cross-reacting antigen, respectively]. By conventional anti-CEA antisera, NCA-2 in meconium, NFA-2 in adult feces, and CEA in tumor tissues were indistinguishable from each other, but they could be distinguished by specific antibody preparations against a determinant unique to CEA (CEA-distinctive determinant) or to NFA-2 (NFA-2-distinctive determinant). Neither the CEA-distinctive determinant nor the NFA-2-distinctive determinant was detected on the NCA-2 molecule. No antigenic determinants unique to NCA-2 have been detected with the anti-NCA-2 antisera which we have prepared thus far. The molecular weight of purified NCA-2 was estimated to be 150,000 to 170,000 as compared to 160,000 to 170,000 for NFA-2 and 170,000 to 180,000 for CEA. NCA-2 had amino acid and carbohydrate compositions similar to those of CEA and NFA-2. All NFA-2 preparations and about one-half of the CEA preparations were sensitive to Pronase E digestion, which released two antigen fragments from these molecules, but NCA-2-preparations were resistant to such digestion.

Topics: Amino Acids; Antibody Specificity; Antigens, Neoplasm; Carbohydrates; Carcinoembryonic Antigen; Cell Adhesion Molecules; Cross Reactions; Epitopes; Feces; Glycoproteins; Humans; Immunodiffusion; Immunoelectrophoresis; Meconium; Molecular Weight; Neoplasms; Pronase

Topics: Carcinoembryonic Antigen; Colitis, Ulcerative; Colon; Colonic Neoplasms; Crohn Disease; Epitopes; Humans; Immunity, Cellular; Intestines; Isoelectric Focusing; Meconium; Neoplasms; Radioimmunoassay