vitamin-k-semiquinone-radical and Adenocarcinoma

Although there is increasing evidence that vitamins influence pancreatic adenocarcinoma biology and carcinogenesis, a comprehensive review is lacking. In this study, we performed a PubMed literature search to review the anticancer mechanisms and the preclinical and clinical studies that support the development of the bioactive vitamins A, C, D, E, and K in pancreatic cancer intervention. Preclinical studies have shown promising results for vitamin A in pancreatic cancer prevention, with clinical trials showing intriguing responses in combination with immunotherapy. For vitamin C, preclinical studies have shown slower tumor growth rates and/or increased survival when used alone or in combination with gemcitabine, with clinical trials with this combination revealing decreased primary tumor sizes and improved performance status. Preclinical studies with vitamin D analogues have shown potent antiproliferative effects and repression of migration and invasion of pancreatic cancer cells, with a clinical trial showing increased time to progression when calciferol was added to docetaxel. For vitamin E, preclinical studies have shown that δ-tocotrienol and γ-tocotrienol inhibited tumor cell growth and survival and augmented gemcitabine activity. Early-phase clinical trials with δ-tocotrienol are ongoing. Vitamin K demonstrates activation of apoptosis and inhibition of cellular growth in pancreatic tumor cells; however, there are no clinical studies available for further evaluation. Although preclinical and clinical studies are encouraging, randomized controlled trials with endpoints based on insights gained from mechanistic and preclinical studies and early-phase clinical trials are required to determine the efficacy of bioactive vitamin interventions in pancreatic cancer.

Topics: Adenocarcinoma; Apoptosis; Ascorbic Acid; Cell Proliferation; Combined Modality Therapy; Dietary Supplements; Humans; Neoplasm Invasiveness; Pancreatic Neoplasms; Survival Rate; Vitamin A; Vitamin D; Vitamin E; Vitamin K; Vitamins

Topics: Adenocarcinoma; Anticoagulants; Carcinoma, Small Cell; Clinical Trials as Topic; Colorectal Neoplasms; Heparin; Humans; Lung Neoplasms; Neoplasms; Odds Ratio; Thrombophilia; Vitamin K

The four fat-soluble vitamins A, D, E and K have been tested in experimental and human studies to assess their influence on the growth of cancer cells of different origins. Receptors for vitamin A and D have been detected on pancreatic cancer cells, and analogues of these reduced the cell number in vitro. The aim of the present study was to evaluate the effect of fat-soluble vitamins on the growth of pancreatic cancer cells.. The seven cell lines used were established from patients operated on for pancreatic adenocarcinoma. The effect of incubation with the vitamin A analogues all-trans-retinoic acid (atRA;tretinoin) and 9-cis-retinoic acid (9-cis-RA), the synthetic vitamin D analogue EB 1089, vitamin E succinate and K on the cell number was examined by the XTT method.. The vitamin A and D analogues decreased the pancreatic cancer cell number when high concentrations of 10 - 10 M were administered. A combination of retinoids and the vitamin D analogue EB 1089 did not enhance the effect. Vitamin E succinate inhibited cell growth to a small extent (maximal 26%) in 3 out of 7 cell lines, whereas vitamin K increased the pancreatic cancer cell number in 3 out of 7 cell lines.. High concentrations of vitamin A and D analogues decreased the cell number in pancreatic cancer cell lines. Vitamin E succinate and K did not have this effect. In the treatment of pancreatic cancer, further exploration of vitamin D analogues could be fruitful.

Topics: Adenocarcinoma; Cell Count; Cell Proliferation; Dose-Response Relationship, Drug; Female; Humans; Male; Pancreatic Neoplasms; Probability; Reference Values; Sensitivity and Specificity; Tumor Cells, Cultured; Vitamin A; Vitamin D; Vitamin E; Vitamin K

Calciphylaxis is a rare disorder of small-vessel calcification and cutaneous infarction associated with chronic renal failure. Rare cases of calciphylaxis not associated with chronic renal failure have been reported with breast cancer, hyperparathyroidism, and alcoholic cirrhosis. To our knowledge, we report the first case of calciphylaxis without chronic renal failure associated with cholangiocarcinoma and the first attempt to treat calciphylaxis with vitamin K. A 56-year-old woman presented with necrotic leg ulceration. She was treated initially with low-molecular-weight heparin, with no effect. A coagulation work-up showed vitamin K deficiency. During vitamin K therapy, the patient had fulminant progression of the calciphylaxis. She died, and an autopsy showed metastatic cholangiocarcinoma. Thrombosis and protein C deficiency have been implicated in the pathophysiology of calciphylaxis. Functional protein C deficiency may be one of several factors contributing to the development of calciphylaxis. Vitamin K therapy was ineffective in our patient and may have been detrimental.

Topics: Adenocarcinoma; Anticoagulants; Bile Duct Neoplasms; Bile Ducts, Intrahepatic; Biopsy; Calciphylaxis; Cholangiocarcinoma; Fatal Outcome; Female; Heparin, Low-Molecular-Weight; Humans; Leg Ulcer; Liver Neoplasms; Lung Neoplasms; Middle Aged; Necrosis; Neoplasms, Multiple Primary; Prognosis; Sepsis; Vitamin K; Vitamin K Deficiency

The development of drug resistance of tumors is multifactorial and still poorly understood. Some cytotoxic drugs generate free radicals, and, therefore, antioxidant enzymes may contribute to drug resistance. We investigated the levels of manganese superoxide dismutase (Mn SOD), its inducibility, and its protective role against tumor necrosis factor-alpha and cytotoxic drugs (cisplatin, epirubicin, methotrexate, and vindesin) in human pleural mesothelioma (M14K) and pulmonary adenocarcinoma (A549) cells. We also studied other major antioxidant mechanisms in relation to oxidant and drug resistance of these cells. A549 cells were more resistant than M14K cells toward both oxidants (hydrogen peroxide and menadione) and all the cytotoxic drugs tested. M14K cells contained higher basal Mn SOD activity than A549 cells (28.3 +/- 3.4 vs. 1.8 +/- 0.3 U/mg protein), and Mn SOD activity was significantly induced by tumor necrosis factor-alpha only in A549 cells (+524%), but the induction did not offer any protection during subsequent oxidant or drug exposure. Mn SOD was not induced significantly in either of these cell lines by any of the cytotoxic drugs (0.007-2 microM, 48 h) tested when assessed by Northern blotting, Western blotting, or specific activity. A549 cells contained higher catalase activity than M14K cells (7.6 +/- 1.3 vs. 3.6 +/- 0.5 nmol O(2). min(-1). mg protein(-1)). They also contained twofold higher levels of glutathione and higher immunoreactivity of the heavy subunit of gamma-glutamylcysteine synthetase than M14K cells. Experiments with inhibitors of gamma-glutamylcysteine synthetase and catalase supported our conclusion that mechanisms associated with glutathione contribute to the drug resistance of these cells.

Topics: Adenocarcinoma; Antioxidants; Catalase; Glutamate-Cysteine Ligase; Glutathione; Humans; Hydrogen Peroxide; Lung Neoplasms; Mesothelioma; Oxidants; RNA, Messenger; Superoxide Dismutase; Tumor Cells, Cultured; Vitamin K

Scanning and transmission electron microscopy and fluorescence light microscopy were employed to characterize the cytotoxic effects of vitamin C (VitC), vitamin K3 (VitK3) or a VitC:VK3 combination on a human bladder carcinoma cell line (T24) following 1-h and 2-h vitamin treatment. T24 cells exposed to VitC alone exhibited membranous damage (blebs and endoplasmic extrusions, elongated microvilli). VitK3-treated cells displayed greater membrane damage and enucleation than those treated with VitC as well as cytoplasmic defects characteristic of cytoskeletal damage. VitC:VitK3-treated cells showed exaggerated membrane damage and an enucleation process in which the perikarya separate from the main cytoplasmic cell body by self-excision. Self-excisions continued for perikarya which contained an intact nucleus surrounded by damaged organelles. After further excisions of cytoplasm, the nuclei exhibited nucleolar segregation and chromatin decondensation followed by nuclear karryorhexis and karyolysis. This process of cell death induced by oxidative stress was named autoschizis because it showed both apoptotic and necrotic morphologic characteristics.

Topics: Adenocarcinoma; Antineoplastic Agents; Ascorbic Acid; Cell Death; Drug Screening Assays, Antitumor; Drug Synergism; Humans; Microscopy, Electron, Scanning; Time Factors; Tumor Cells, Cultured; Urinary Bladder Neoplasms; Vitamin K; Vitamin K 3

6-[211At]-astato-MNDP is of a class of a high linear energy transfer endoradiotherapeutic drug, which selectively targets to an onco-APase isoenzyme expressed by certain epithelial and germ cell tumors. The therapeutic efficacy and acute toxicity of its endogenous alpha-particle emissions have been studied in a murine tumor model.. 211At was produced by the 207Bi(alpha,2n)211 At cyclotron-based nuclear reaction. High specific activity 6-[211At]-astato-MNDP was rapidly synthesized by in vacuo thermal heterogeneous isotopic exchange. The therapeutic potential of 6-[211At]-astato-MNDP and 211At- was determined in mice bearing a transplanted CMT-93 rectal carcinoma which exhibited onco-APase activity.. Significant therapeutic effects due to targeted alpha-particle emissions have been confirmed for the activity dose range, 10-750 kBq 6-[211At]-astato-MNDP. A therapeutic window has been identified, whereby cure rates of approximately 45-65% were achieved following administration of 55-300 kBq 6-[211At]-astato-MNDP. Estimated tumor absorbed radiation doses were not inconsistent with clinical response. Irreversible hematoxicity or stigmata of acute radiation damage in other critical normal tissues were not encountered. Nonspecifically internalized 211At- exerted no therapeutic effect.. Therapeutic results for 6-[211At]-astato-MNDP have confirmed the profound in vivo cytotoxicity of its targeted alpha-radiations in the CMT-93 tumor. Acute normal tissue toxicity was acceptable. A rationale for optimal fractionation of targeted 6-[211At]-astato-MNDP endoradiotherapy is discussed, and its putative role in the possible individualized management of certain human tumors has been proposed.

Topics: Adenocarcinoma; Animals; Astatine; Brachytherapy; Energy Transfer; Leukocyte Count; Male; Mice; Mice, Inbred C57BL; Neoplasms, Experimental; Rectal Neoplasms; Vitamin K; Vitamin K 3

The effects of menadione (Vit K3) administered at 20 or 40 mg.kg-1 ig 3 times a week for both 24 and 28 wk on 1,2-dimethylhydrazine (DMH)-induced mouse colon adenocarcinomas were investigated. At the 24th wk, the number of colon tumors in Vit K3 20 or 40 mg.kg-1 group (0.3 +/- 0.5 and 0.5 +/- 0.8, respectively) was less than that of DMH controls (2.1 +/- 2.5, P < 0.05), but the difference in incidence of colon tumors in these 3 groups was not significant (P > 0.05). After 28 wk, the tumor incidence of both Vit K3 groups (each 8 of 13) was lower than that of DMH controls (13 of 13, P < 0.05); the number of colon tumors of Vit K3 40 mg.kg-1 group (1.3 +/- 1.3, P < 0.05) was decreased, whereas the Vit K3 20 mg.kg-1 group (3.0 +/- 5.1, P > 0.05) was not different from the DMH controls (7.3 +/- 9.3). Determination of the nuclear DNA content of cells from DMH-induced mouse colon mucosa (24 wk) indicated that Vit K3 20 or 40 mg.kg-1 group showed lower DNA content (1.92 +/- 0.12 C and 1.91 +/- 0.10 C, respectively) decreased values of percent-over-3C and -4C and narrow distribution range. Besides, the colon mucosa of DMH-treated mice (28 wk) showed higher superoxide dismutase (SOD) activity (70 +/- 28 U/mg protein, P < 0.05) than the normal controls (30 +/- 20 U/mg protein). Vit K3 40 mg.kg-1 reduced the elevated SOD activity markedly (44 +/- 23 U/mg protein, P < 0.05).

Topics: Adenocarcinoma; Animals; Antineoplastic Agents; Colonic Neoplasms; Dimethylhydrazines; DNA, Neoplasm; Female; Intestinal Mucosa; Mice; Mice, Inbred ICR; Superoxide Dismutase; Vitamin K; Vitamin K 3

Menadione-catalyzed H2O2 production by viable cells is proportional to viable cell number. The correlations between the viable cell number and the concentration of H2O2 produced are determined with the rapid chemiluminescent assay (S. Yamashoji, T. Ikeda, and K. Yamashoji, 1989, Anal. Biochem. 181, 149-152). This chemiluminescent assay of viable cells requires only 10 min and is much faster than NR (neutral red) inclusion and MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) reduction assays, which require 3-5 h. When viable cells are incubated with antitumor drugs, detergents, mycotoxins, and glycoalkaloids for 24-48 h, a decrease in menadione-catalyzed H2O2 production in a dose- or incubation time-dependent manner is observed. In general, the 50% inhibition concentration determined by the chemiluminescent assay is lower than that determined by NR inclusion and MTT reduction assays, and the order of relative cytotoxic effects of agents is the same among these assays. Furthermore, clear cytotoxic effects are observed by the chemiluminescent assay after 1 h exposure of trypsinized cells to toxic compounds. Therefore, the chemiluminescent assay is expected to be more useful for the rapid detection of cytotoxic compounds than NR inclusion and MTT reduction assays.

Topics: 3T3 Cells; Adenocarcinoma; Animals; Antineoplastic Agents; Cell Count; Cell Line; Cell Survival; Coloring Agents; Humans; Hydrogen Peroxide; Indicators and Reagents; Luminescent Measurements; Male; Mice; Prostatic Neoplasms; Tetrazolium Salts; Thiazoles; Tomatine; Tumor Cells, Cultured; Vitamin K

During the course of measuring superoxide dismutase (SOD) activity in rat breast tissue, interferences in the nitroblue tetrazolium (NBT) and cytochrome c assay systems were noted. These interferences inhibit accurate measurement of SOD activity in breast tissues, necessitating the development of a new NBT-based assay that includes compounds capable of inhibiting tissue specific interferences. The most effective compounds were metal chelators that were also electron transport chain inhibitors. Bathocuproine sulfonate (BCS) was the most effective of these compounds. The inclusion of BCS in the NBT assay system was shown to make the accurate measurement of SOD activity in tissues with interferences possible.

Topics: Adenocarcinoma; Animals; Colorimetry; Cytochrome c Group; Female; Iron; Liver; Mammary Glands, Animal; Mice; Mitochondria, Liver; Nitroblue Tetrazolium; Pregnancy; Rats; Rats, Inbred Strains; Superoxide Dismutase; Uric Acid; Vitamin K; Xanthine Oxidase

The effects of sodium ascorbate (vitamin C) and 2-methyl-1,4-naphthoquinone (vitamin K3) administered separately or in combination on the in vitro cultured human neoplastic cell lines MCF-7 (breast carcinoma), KB (oral epidermoid carcinoma), and AN3-CA (endometrial adenocarcinoma) have been examined. When given separately, vitamin C or K3 had a growth inhibiting action only at high concentrations (5.10(3) mumol/1 and 10(5) nmol/l, respectively). Combined administration of both vitamins demonstrated a synergistic inhibition of cell growth at 10 to 50 times lower concentrations. At this level separately given vitamins are not toxic. The sensitivity to this treatment was somewhat different in the three cell lines, being slightly higher for KB line. This tumor cell growth inhibitory effect was completely suppressed by the addition of catalase to the culture medium containing vitamins C and K3, suggesting an excessive production of hydrogen peroxide as being implied in mechanisms responsible for the above-mentioned effects.

Topics: Adenocarcinoma; Ascorbic Acid; Breast Neoplasms; Carcinoma, Squamous Cell; Catalase; Cell Division; Drug Synergism; Female; Humans; Mouth Neoplasms; Tumor Cells, Cultured; Uterine Neoplasms; Vitamin K

6-[211At]astato-MNDP is currently being investigated as a potential high LET endoradiotherapeutic drug. Biodistribution and whole-body radiation retention studies have been carried out with 6-[211At]astato-MNDP and 211At- in a murine rectal tumour model; results indicate that the 211At-C bond in the compound is metabolically stable for at least 6 h. The Mean Biological Concentration of 6-[211At]astato-MNDP in tumour tissue ranged from 170-253% over an initial 12 h period; this was higher than that observed for the [211At]astatide anion. Conversely, the uptake of compound into radiobiologically critical organs was significantly lower.

Topics: Adenocarcinoma; Animals; Antineoplastic Agents; Astatine; Female; Male; Mice; Mice, Inbred C57BL; Neoplasm Transplantation; Rectal Neoplasms; Tissue Distribution; Vitamin K; Vitamin K 3

A potential endoradiotherapeutic drug, 6-211At-astato-2-methyl-1,4-naphthoquinol bis (diphosphate salt), incorporating the alpha-emitting radio-halogen astatine-211 of half-life 7.2 h, is shown to be valuable for localization studies by means of alpha-particle track autoradiography in malignant and normal cells and tissues in the mouse with transplanted adenocarcinoma of the rectum.

Topics: Adenocarcinoma; Alpha Particles; Animals; Antineoplastic Agents; Astatine; Autoradiography; Colon; Lung; Male; Mice; Mice, Inbred C57BL; Neoplasm Transplantation; Neoplasms, Experimental; Rectal Neoplasms; Spleen; Subcellular Fractions; Vitamin K; Vitamin K 3

Previous studies have identified gamma-carboxyglutamic acid as a constituent of one or more protein(s) synthesized by rat and chicken kidney microsomes in vitro in a vitamin K-dependent post-translational reaction [1]. Incubation of microsomes from a mouse kidney cell line (RAG) with [14C]NaHCO3 results in formation of protein-bound [14C]gamma-carboxylglutamic acid. Incorporation is stimulated threefold by addition of the active vitamin K compound 2-methyl, 3-farnesyl, 1,4-naphthoquinone. At least 90% of incorporated, nondialyzable [14C] is situated in the gamma-carboxyl group of gamma-carboxyglutamic acid residues.

Topics: 1-Carboxyglutamic Acid; Adenocarcinoma; Animals; Calcium; Carbon-Carbon Ligases; Glutamates; Kidney; Kidney Neoplasms; Ligases; Mice; Neoplasms, Experimental; Protein Biosynthesis; Vitamin K

Topics: Adenocarcinoma; Aged; Atrial Fibrillation; Blood Transfusion; Cephalothin; Digoxin; Disseminated Intravascular Coagulation; Gangrene; Gastrointestinal Hemorrhage; Gentamicins; Heparin; Humans; Hydronephrosis; Hypothermia; Lymphatic Metastasis; Male; Prostatic Neoplasms; Pyelonephritis; Stomach Neoplasms; Vitamin K

Topics: Adenocarcinoma; Adenoma, Bile Duct; Adult; Aged; Bile; Bile Duct Neoplasms; Bile Ducts; Biliary Tract Diseases; Bilirubin; Carbon Isotopes; Enzymes; Fats; Female; Humans; Intestinal Absorption; Lymph; Male; Middle Aged; Pancreatic Neoplasms; Solubility; Thoracic Duct; Thymol; Time Factors; Tritium; Vitamin A; Vitamin D; Vitamin E; Vitamin K

Topics: Adenocarcinoma; Adult; Aged; Animals; Breast Neoplasms; Carcinoma; Colonic Neoplasms; Cystadenoma; Female; Humans; Iodine Radioisotopes; Kidney Neoplasms; Lymphoma, Large B-Cell, Diffuse; Male; Mice; Middle Aged; Mouth Neoplasms; Neoplasm Metastasis; Neoplasms; Neoplasms, Experimental; Peritoneal Neoplasms; Radiation-Sensitizing Agents; Radionuclide Imaging; Rats; Rectal Neoplasms; Sigmoid Neoplasms; Stomach Neoplasms; Vitamin K

Topics: Adenocarcinoma; Adult; Animals; Arsenicals; Carcinoma, Ehrlich Tumor; Carcinoma, Squamous Cell; Choriocarcinoma; DNA, Neoplasm; Female; Fluorides; Heparin; Humans; Lung Neoplasms; Lymphoma; Male; Malonates; Mandibular Neoplasms; Mice; Middle Aged; Neoplasms; Pregnancy; RNA, Neoplasm; Sarcoma; Testicular Neoplasms; Vitamin K

Topics: Adenocarcinoma; Autoradiography; Colonic Neoplasms; Dysgerminoma; Female; Gallbladder Neoplasms; Hodgkin Disease; Humans; Injections, Intra-Arterial; Injections, Intravenous; Melanoma; Neoplasm Metastasis; Neoplasms; Ovarian Neoplasms; Radiotherapy Dosage; Skin Neoplasms; Tritium; Vitamin K

Topics: Adenocarcinoma; Adrenal Cortex Hormones; Electrodiagnosis; Iatrogenic Disease; Lumbosacral Region; Osteitis Deformans; Pathology; Radiography; Toxicology; Vitamin A; Vitamin K; Vitamins