vitamin-k-semiquinone-radical and Lung-Neoplasms

Although vitamin deficiency is encountered infrequently in developed countries, inadequate intake of several vitamins is associated with chronic disease.. To review the clinically important vitamins with regard to their biological effects, food sources, deficiency syndromes, potential for toxicity, and relationship to chronic disease.. We searched MEDLINE for English-language articles about vitamins in relation to chronic diseases and their references published from 1966 through January 11, 2002.. We reviewed articles jointly for the most clinically important information, emphasizing randomized trials where available.. Our review of 9 vitamins showed that elderly people, vegans, alcohol-dependent individuals, and patients with malabsorption are at higher risk of inadequate intake or absorption of several vitamins. Excessive doses of vitamin A during early pregnancy and fat-soluble vitamins taken anytime may result in adverse outcomes. Inadequate folate status is associated with neural tube defect and some cancers. Folate and vitamins B(6) and B(12) are required for homocysteine metabolism and are associated with coronary heart disease risk. Vitamin E and lycopene may decrease the risk of prostate cancer. Vitamin D is associated with decreased occurrence of fractures when taken with calcium.. Some groups of patients are at higher risk for vitamin deficiency and suboptimal vitamin status. Many physicians may be unaware of common food sources of vitamins or unsure which vitamins they should recommend for their patients. Vitamin excess is possible with supplementation, particularly for fat-soluble vitamins. Inadequate intake of several vitamins has been linked to chronic diseases, including coronary heart disease, cancer, and osteoporosis

Topics: Ascorbic Acid; Avitaminosis; Blood Coagulation; Breast Neoplasms; Carotenoids; Chronic Disease; Colorectal Neoplasms; Coronary Disease; Dietary Supplements; Female; Folic Acid; Fractures, Bone; Humans; Lung Neoplasms; Male; Neoplasms; Neural Tube Defects; Prostatic Neoplasms; Risk Factors; Vitamin A; Vitamin B 12; Vitamin B 6; 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

A phase II trial of menadione [2.5 gm/m2 as a continuous intravenous (i.v.) infusion over 48 hours] followed by mitomycin C (10-20 mg/m2 i.v. bolus) administered every 4 to 6 weeks was performed in 23 patients with advanced lung cancer. Menadione, a vitamin K analog which lowers intracellular pools of reduced glutathione (GSH), was combined with mitomycin C in an attempt to overcome thiol-mediated resistance to alkylating agent chemotherapy. The median age of patients entered on this trial was 62 years; performance status ranged from 60-90%. Two of the 23 patients (9%; 95% confidence interval, 1% to 28%) had objective responses lasting 3.5 months and 13 months respectively, while 4 additional patients developed short unconfirmed responses (lacking follow-up response data to estimate response duration). Median survival for all patients was 5.5 months. Treatment with mitomycin C and menadione was well tolerated except for hematologic toxicity and cardiac events of unclear relationship to the study drugs. Thirty-one percent of treatment courses were complicated by grade 3 or 4 hematologic toxicity including one episode of hemolytic anemia. One patient developed interstitial pneumonitis. Two patients developed a decrease in left ventricular ejection fraction: one patient remained asymptomatic, but the other patient developed congestive heart failure. Although only 9% of patients had confirmed objective responses, 28% (5 of 18) of the patients with non-small cell lung cancer demonstrated biological activity (tumor regression fulfilling the criteria for objective response on a single occasion but 3 patients lacking a follow-up measurement to document response duration) to this combination of mitomycin C and menadione. We conclude that further studies of chemomodulation in non-small cell lung cancer are appropriate.

Topics: Adult; Aged; Antibiotics, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Carcinoma, Small Cell; Drug Interactions; Drugs, Investigational; Female; Humans; Infusions, Intravenous; Lung Neoplasms; Male; Middle Aged; Mitomycin; Vitamin K

Limited reports from prospective human studies investigated the possible role of vitamin K in the development of lung cancer although vitamin K's anticarcinogenic activities were verified from several in vitro and in vivo studies. We investigated the associations between total vitamin K intake from food and the development of lung cancer based on this large prospective cohort study.. A validated food frequency questionnaire was used to examine vitamin K intake among 42,166 (16,341 men and 25,825 women) at the Japan Collaborative Cohort Study's baseline (1988-1990). Hazard ratios (HRs) and 95% confidence intervals (CIs) of incident lung cancer were calculated using the Cox proportional hazard regression method based on vitamin K consumption quartiles.. 430 cases (308 males and 122 women) of lung cancer were documented during a total of 564,127 person-years of follow-up (median follow-up, 14.6 years). Vitamin K consumption was shown to be inversely related to lung cancer risk; the multivariable hazard ratio [HR] for the highest versus lowest quartiles was 0.67 (95% confidence interval [CI], 0.46-0.96; P for trend = 0.010). This relationship appears to be stronger in males (HR 0.62; 95% CI, 0.40-0.96; P for trend = 0.016) than in females (HR 0.82; 95% CI, 0.42-1.61; P for trend = 0.39) (P for interaction = 0.012), and in ever smokers (HR 0.57; 95% CI, 0.36-0.91; P for trend = 0.006) than in never smokers (HR 0.79; 95% CI, 0.40-1.55; P for trend = 0.37) (P for interaction = 0.30). The individuals' age, body mass index, or alcohol consumption status had no effect on the observed connection.. Vitamin K consumption reduces the risk of lung cancer. More research is needed to clarify the molecular processes behind this connection.

Topics: Cohort Studies; Diet; Female; Humans; Japan; Lung Neoplasms; Male; Prospective Studies; Risk Factors; Smoking; Vitamin K

There is an ongoing need for additional interventions in idiopathic pulmonary fibrosis (IPF) as antifibrotic drugs currently available only inhibit and do not stall disease progression. Vitamin K is a co-factor for the activation of coagulation factors. However, it is also required to activate proteins with functions outside of the coagulation cascade, such as matrix Gla protein (MGP), a defender against soft tissue calcification. Vitamin K antagonists are anticoagulants that are, for unknown reasons, associated with increased mortality in IPF. Areas covered: We advance the hypothesis that modulation of vitamin K-dependent MGP activation in IPF patients by either vitamin K antagonism or administration may result in acceleration and deceleration of fibrosis progression, respectively. Furthermore, shortfall in vitamin K could be suspected in IPF based on the high prevalence of certain co-morbidities, such as vascular calcification and lung cancer. Expert commentary: We hypothesize that vitamin K status is reduced in IPF patients. This, in combination with studies suggesting that vitamin K may play a role in lung fibrosis pathogenesis, would provide a rationale for conducting a clinical trial assessing the potential mitigating effects of vitamin K administration on progression of lung fibrosis, prevention of co-morbidities and mortality in IPF.

Topics: Antifibrinolytic Agents; Calcium-Binding Proteins; Dietary Supplements; Disease Progression; Extracellular Matrix Proteins; Fibrosis; Humans; Idiopathic Pulmonary Fibrosis; Lung Neoplasms; Matrix Gla Protein; Vascular Calcification; Vitamin K

Extragonadal yolk sac tumors (YSTs) are rare. We herein report the case of a 66-year-old man with mediastinal, lung and liver tumors. The largest mass was located in the liver and contained a high concentration of protein induced by vitamin K absence or antagonist-II (PIVKA-II) and alpha-fetoprotein. Therefore, the lesion was difficult to distinguish from hepatocellular carcinoma. Finally, YST was diagnosed based on the results of a liver biopsy. Although chemotherapy was effective, the patient died of respiratory failure. The autopsy revealed primary mediastinal YST. In the current report, we describe this case of PIVKA-II-producing YST and review previous cases of PIVKA-II-producing tumors other than hepatoma.

Topics: Aged; alpha-Fetoproteins; Autopsy; Biomarkers; Biomarkers, Tumor; Carcinoma, Hepatocellular; Diagnosis, Differential; Endodermal Sinus Tumor; Fatal Outcome; Humans; Immunohistochemistry; Liver Neoplasms; Lung Neoplasms; Male; Mediastinal Neoplasms; Protein Precursors; Prothrombin; 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

Apurinic/apyrimidinic endonuclease is a key enzyme in the process of base excision repair, required for the repair of spontaneous base damage that arises as a result of oxidative damage to DNA. In mice, this endonuclease is coded by the Apex gene, disruption of which is incompatible with embryonic life. Here we confirm the embryonic lethality of Apex-null mice and report the phenotypic characterization of mice that are heterozygous mutants for the Apex gene (Apex+/-). We show that Apex heterozygous mutant cells and animals are abnormally sensitive to increased oxidative stress. Additionally, such animals manifest elevated levels of oxidative stress markers in serum, and we show that dietary supplementation with antioxidants restores these to normal levels. Apex+/- embryos and pups manifest reduced survival that can also be partially rescued by dietary supplementation with antioxidants. These results are consistent with a proposed role for this enzyme in protection against the deleterious effects of oxidative stress and raise the possibility that humans with heterozygous mutations in the homologous HAP1 gene may be at increased risk for the phenotypic consequences of oxidative stress in cells.

Topics: Adenocarcinoma, Papillary; Animals; Ascorbic Acid; Carbon-Oxygen Lyases; Cell Survival; Cells, Cultured; Dietary Supplements; Dinoprost; DNA-(Apurinic or Apyrimidinic Site) Lyase; Dose-Response Relationship, Drug; Embryo, Mammalian; Female; Fibroblasts; Genotype; Heterozygote; Lipid Peroxides; Lung Neoplasms; Lymphoma; Male; Mice; Mice, Inbred C57BL; Mice, Inbred Strains; Mice, Mutant Strains; Oxidative Stress; Paraquat; Phenotype; Vitamin E; Vitamin K

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

Molecular mechanisms of interplay between reactive oxygen (superoxide, hydroxyl radical, H2O2 etc.) and nitrogen (nitric oxide - NO, ONOO-, NO2-, NO3- etc.) forms are proposed to be of key importance for cell and tumor biology. Considering NO as a signal molecule we have studied the impact of NO release on processes of generation of H2O2 in different experimental systems including pleural effusions (PE) of lung cancer patients, human polymorphonuclear leukocytes (PMNs), and rat thymocytes. It was found that PE of lung cancer patients contain a high level of [NO2-+NO3-], i.e. 43.4 25.6 microM (n=15), and PE cells could effectively generate H2O2 in response to lectins from Viscum album (VAA), Phaseolus vulgaris (PHA), and Pisum sativum (PSA) as well as to menadione. A positive correlation between the [NO2-+NO3-] concentration and menadione-induced H2O2 generation (r=0.1964) was found, whereas the [NO2-+NO3-] concentration and lectin-induced H2O2 generation (PHA, r=-0.4099; PSA, r=-0.3949; VAA, r=-0.3225) were negatively correlated. Notably, an increase of H2O2 generation by PE cells was determined in the range of 20-35 microM [NO2-+NO3-]. When PMNs and rat thymocytes were treated with a donor of NO (sodium nitroprusside), the release of H2O2 in response to lectins or menadione was decreased in a dose-dependent manner. The end products of NO biochemistry, assayed as KNO2 and KNO3, were not able to affect significantly the H2O2 generation processes. In conclusion, the data indicate that the potential for triggered H2O2-generation of cells is modulated markedly by the presence of NO or derived reaction compounds. This relation may play an important role in the pathogenesis of PE malignancies with potential relevance for therapeutic strategies.

Topics: Adult; Aged; Animals; Female; Humans; Hydrogen Peroxide; Lectins; Leukocytes, Mononuclear; Lung Neoplasms; Male; Middle Aged; Nitrates; Nitric Oxide; Nitrites; Pleural Effusion, Malignant; Potassium Compounds; Rats; Thymus Gland; Vitamin K

We studied the regulation of GSH and the enzymes involved in GSH regulation, gamma-glutamylcysteine synthetase (gamma-GCS) and gamma-glutamyl transpeptidase (gamma-GT), in response to the oxidants menadione, xanthine/xanthine oxidase, hyperoxia, and cigarette smoke condensate in human alveolar epithelial cells (A549). Menadione (100 microM), xanthine/xanthine oxidase (50 microM/10 mU), and cigarette smoke condensate (10%) exposure produced increased GSH levels (240 +/- 6, 202 +/- 12, and 191 +/- 2 nmol/mg protein, respectively; P < 0.001) compared with the control level (132 +/- 8 nmol/mg protein), which were associated with a significant increase in gamma-GCS activity (0.18 +/- 0.006, 0.16 +/- 0.01, and 0.17 +/- 0. 008 U/mg protein, respectively; P < 0.01) compared with the control level (0.08 +/- 0.001 U/mg protein) at 24 h. Exposure to hyperoxia (95% O2) resulted in a time-dependent increase in GSH levels. gamma-GCS activity increased significantly at 4 h (P < 0.001), returning to control values after 12 h of exposure. Dexamethasone (3 microM) exposure produced a significant time-dependent decrease in the levels of GSH and gamma-GCS activity at 24-96 h. The activity of gamma-GT did not change after oxidant treatment; however, it was decreased significantly by dexamethasone at 24-96 h. Thus oxidants and dexamethasone modulate GSH levels and activities of gamma-GT and gamma-GCS by different mechanisms. We suggest that the increase in gamma-GCS activity but not in gamma-GT activity may be required for the increase in intracellular GSH under oxidative stress in alveolar epithelial cells.

Topics: Cell Line; Dexamethasone; Epithelial Cells; gamma-Glutamyltransferase; Glutamate-Cysteine Ligase; Glutathione; Humans; Hyperoxia; Kinetics; Lung Neoplasms; Oxidants; Pulmonary Alveoli; Smoking; Tumor Cells, Cultured; Vitamin K; Xanthine

The cytotoxicities of mitomycin C (MMC) and doxorubicin (DOX) have been proposed to depend on intracellular reduction by reduced flavoproteins. We investigated whether MMC- and DOX-induced cytotoxicity could be inhibited by competing for electrons from reduced flavoproteins by the artificial electron acceptors phenazine methosulfate (PMS), menadione (MEN) and methylene blue (MB). In intact SW-1573 human lung tumor cells these compounds proved to be excellent electron acceptors, as judged from their capacity to induce high levels of cyanide-resistant respiration. In addition, PMS, MEN and MB were found to decrease the cytotoxicity of MMC, by 90, 63 and 29%, respectively, at concentrations that were themselves completely nontoxic. In contrast, DOX cytotoxicity was not detectably affected. These results suggest that in SW-1573 cells flavoprotein-mediated bioreduction is required for the cytotoxic effect of MMC, but not for that of DOX.

Topics: Carcinoma, Squamous Cell; Doxorubicin; Drug Interactions; Ellipticines; Humans; Lung Neoplasms; Methylene Blue; Methylphenazonium Methosulfate; Mitomycin; Mitomycins; Oxygen Consumption; Peroxides; Phenazines; tert-Butylhydroperoxide; Tumor Cells, Cultured; Vitamin K

A highly metastatic line of Lewis lung tumor cells established in fetal bovine serum (10%) was subcultured into normal rodent (mouse or rat) serum or rodent serum made deficient in functional vitamin K-dependent proteins (barium sulfate adsorption or warfarin treatment of animals). Following injection of cells cultured in normal rodent serum into C57BL/6 mice, Factor X activator activity in the primary tumors increased at a near linear rate per gram tumor and attained 5- to 8-fold higher levels than did cells grown in either of the deficient sera. Secondary lung foci were also visible in all mice of the normal-rodent serum groups within 10 days after injection, and by 21 days extensive tumor growth in the lungs had developed. No secondary lung foci were apparent in any mice of the deficient serum groups throughout 21 days of tumor burden. Cells cultured in nonrodent serum (fetal bovine serum) were less proficient than cells grown in normal mouse serum in developing primary tumor Factor X activator activity and producing secondary tumors. Exposure of cells cultured in barium sulfate-treated mouse serum to normal mouse serum for 3 h and 3 weeks prior to injection partially restored primary tumor Factor X activator and metastatic competence. These data strongly suggest that in Lewis lung tumor cells at least one species selective, plasma/serum vitamin K-dependent protein plays a major role in the regulation of metastatic events and demonstrate that there is a positive correlation between primary tumor Factor X activation activity and metastasis.

Topics: Animals; Blood Proteins; Coagulants; Cysteine Endopeptidases; Factor X; Lung Neoplasms; Male; Mice; Mice, Inbred C57BL; Neoplasm Metastasis; Neoplasm Proteins; Neoplasms, Experimental; Tumor Cells, Cultured; Vitamin K

Mouse Lewis lung (LL) carcinoma cells possess a factor X activator (procoagulant) that is inhibited in vivo by warfarin treatment or diet-induced vitamin K deficiency. This inhibition suggests that vitamin-K-dependent proteins are involved in LL cell activation of factor X. A LL primary tumor clone (LL13) was isolated which contained a warfarin-sensitive vitamin-K cycle of metabolism and expressed factor X procoagulant activity. LL13 cells exposed to media containing warfarin or deficient in vitamin K grew as well as cells in normal media, and activated factor X to similar extents. In contrast, administration of warfarin to mice bearing LL13 cells inhibited factor X procoagulant activity as well as the vitamin K cycle of metabolism in the primary tumors. In relation to LL13 cells grown in media containing fetal bovine serum, those incubated for 20 hr in media containing mouse serum or the sera from LL13-bearing mice exhibited 9- to 10-times higher levels of factor X procoagulant activity. However, LL13 cells exposed to media containing the sera of warfarin-treated LL-13-bearing mice or to barium-sulfate-adsorbed normal mouse serum activated factor X much less efficiently. Collectively, these data suggest that inhibition of vitamin K function in LL cells does not affect the extent of factor X activation and thus the intrinsic factor X procoagulant is not a vitamin-K-dependent protein. They further suggest that both a warfarin-sensitive (vitamin-K-dependent) protein present in normal mouse serum and a LL13 cell component participate in factor X procoagulant activity.

Topics: Animals; Biotransformation; Blood Coagulation Factors; Cell Line; Culture Media; Factor X; Lung Neoplasms; Male; Mice; Mice, Inbred C57BL; Neoplasm Metastasis; Vitamin K; Vitamin K Deficiency; Warfarin

Microsomes isolated from Lewis lung (LL) primary tumors raised in C57BL/6 mice have been shown to (i) contain a 4-hydroxycoumarin (warfarin)-sensitive cycle of vitamin K metabolism which is at least qualitatively similar to that of liver, and (ii) catalyze the incorporation of NaH14 CO3 into endogenous protein in a vitamin-K hydroquinone-dependent reaction to produce gamma-carboxyglutamate. As in liver microsomes, LL microsomal reduction of vitamin K 2,3-epoxide to vitamin K was greatly enhanced by exogenous dithiols such as dithiothreitol, but under identical conditions the former was 10-fold faster. The R(+) and S(-) warfarin enantiomers were highly and equally effective inhibitors of both the liver and tumor vitamin K 2,3-epoxide reductases-the average I50 against the tumor enzyme was 0.25 microM. Partially purified reductases isolated by centrifugation of sodium-cholate-treated liver and LL tumor microsomes over a discontinuous sucrose gradient were also inhibited by the sulfhydryl reagent N-ethylmaleimide following their reduction by dithiothreitol. Like the activity of the epoxide reductase, that of the gamma-carboxylase was much lower in tumor than in liver microsomes and was only detectable in microsomes isolated from tumor-bearing mice previously administered S(-) warfarin. In view of the reported inhibition of LL tumor metastasis by warfarin and diet-induced vitamin-K deficiency, vitamin-K-dependent proteins may play a role in the spread and/or subsequent growth of LL cells.

Topics: Animals; Dithiothreitol; Liver; Lung Neoplasms; Male; Mice; Mice, Inbred C57BL; Microsomes; Mixed Function Oxygenases; Neoplasm Metastasis; Neoplasm Proteins; Vitamin K; Vitamin K Epoxide Reductases; Warfarin

Topics: Animals; Blood Coagulation Factors; Factor X; Lung Neoplasms; Mice; Mice, Inbred C57BL; Neoplasm Metastasis; Neoplasms, Experimental; Vitamin K; Vitamin K Deficiency; Warfarin

Topics: Administration, Oral; Animals; Blood Coagulation; Female; Idoxuridine; Injections, Intravenous; Iodine Isotopes; Leukemia, Experimental; Lung Neoplasms; Mice; Mice, Inbred C3H; Mice, Inbred Strains; Neoplasm Metastasis; Neoplasm Transplantation; Neoplastic Cells, Circulating; Sarcoma, Experimental; Transplantation, Homologous; Vitamin K; Warfarin

Topics: Adult; Antineoplastic Agents; Arsenicals; Breast Neoplasms; Carcinoma, Bronchogenic; Carcinoma, Squamous Cell; Choriocarcinoma; Colonic Neoplasms; Drug Synergism; Female; Fluorides; Heparin; Humans; Lung Neoplasms; Male; Malonates; Melanoma; Neoplasms; Ovarian Neoplasms; Pharyngeal Neoplasms; Pregnancy; Rectal Neoplasms; Sarcoma; Stomach Neoplasms; Testicular Neoplasms; Thyroid Neoplasms; Time Factors; 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