ascorbic-acid and Neoplasm-Metastasis

The consumption of vitamins C and D for prevention and treatment of cancer is still an uncertain recommendation due to their controversial roles in cancer. The epidemiological studies document that vitamins C and D possess potential antineoplastic property. In addition, accumulating experimental studies strongly support their anticancer efficacy both in vitro and in vivo, although the mechanisms of action are not completely clear. Vitamin C at pharmacological concentration has cancer-selective cytotoxicity in several cancer cell lines. Moreover, the cognition of vitamin D has become "hormone D", which modulates a variety of molecular targets and signaling pathways, contributing to the inhibition of cancer. Furthermore, limited small-scale clinical trials favor their roles as the adjuncts of standard cancer therapies. On the other hand, opposite opinions also exist, and high-quality evidence are still lacking to ascertain the roles of vitamins C and D in cancer. In general, in light of the potential and promising anticancer values of vitamins C and D, it is essential to gain insight into their roles in cancer based on current epidemiological, experimental and clinical studies.

Topics: Animals; Antineoplastic Agents; Antioxidants; Ascorbic Acid; Cell Line, Tumor; Dietary Supplements; Epigenesis, Genetic; Humans; Incidence; Mice; Neoplasm Metastasis; Neoplasm Transplantation; Neoplasms; Signal Transduction; Vitamin D

Pharmacological ascorbate (P-AscH

Topics: Animals; Antineoplastic Agents; Ascorbic Acid; Carcinoma, Pancreatic Ductal; Cell Line, Tumor; Female; Humans; Hydrogen Peroxide; Liver Neoplasms; Mice; Mice, Nude; Neoplasm Metastasis; Neoplasm Transplantation; Neoplasms, Experimental; Neoplastic Cells, Circulating; Pancreatic Neoplasms; Peroxides

Preclinical studies suggest synergistic effectiveness of ascorbic acid (AA, vitamin C) and cytotoxic agents in gastrointestinal malignancies. This phase 1 study aimed to establish the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of AA combined with mFOLFOX6 or FOLFIRI regimens in patients with metastatic colorectal cancer (mCRC) or gastric cancer (mGC).. In the dose-escalation phase, patients received AA (0.2-1.5 g/kg, 3-h infusion, once daily, days 1-3) with mFOLFOX6 or FOLFIRI in a 14-day cycle until the MTD was reached. In the speed-expansion phase, AA was administered at the MTD or at 1.5 g/kg if the MTD was not reached at a fixed rate of 0.6, 0.8 or 1 g/min. Pharmacokinetics and preliminary efficacy were also assessed.. Thirty-six patients were enrolled. The MTD was not reached. The RP2D was established as AA at 1.5 g/kg/day, days 1-3, with mFOLFOX6 or FOLFIRI. No dose-limiting toxicity (DLT) was detected during dose escalation. The most common treatment-emergent adverse events (TRAEs) were sensory neuropathy (50%), nausea (38.9%), vomiting (36.1%) and neutropenia (27.8%). Grade 3-4 TRAEs were neutropenia (13.9%), sensory neuropathy (2.8%), vomiting (2.8%), diarrhea (2.8%) and leukopenia (2.8%). AA exposure was dose-proportional. The objective response rate was 58.3%, and the disease control rate was 95.8%. No difference in efficacy was found between mCRC patients with wild-type RAS/BRAF and mutant RAS or BRAF.. The favorable safety profile and preliminary efficacy of AA plus mFOLFOX6/FOLFIRI support further evaluation of this combination in mCRC or mGC.. ClinicalTrial.gov Identifier: NCT02969681 .

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Ascorbic Acid; Asian People; Colorectal Neoplasms; Female; Humans; Male; Maximum Tolerated Dose; Middle Aged; Neoplasm Metastasis; Stomach Neoplasms

Pancreatic cancer is among the most lethal cancers with poorly tolerated treatments. There is increasing interest in using high-dose intravenous ascorbate (IVC) in treating this disease partially because of its low toxicity. IVC bypasses bioavailability barriers of oral ingestion, provides pharmacological concentrations in tissues, and exhibits selective cytotoxic effects in cancer cells through peroxide formation. Here, we further revealed its anti-pancreatic cancer mechanisms and conducted a phase I/IIa study to investigate pharmacokinetic interaction between IVC and gemcitabine. Pharmacological ascorbate induced cell death in pancreatic cancer cells with diverse mutational backgrounds. Pharmacological ascorbate depleted cellular NAD+ preferentially in cancer cells versus normal cells, leading to depletion of ATP and robustly increased α-tubulin acetylation in cancer cells. While ATP depletion led to cell death, over-acetylated tubulin led to inhibition of motility and mitosis. Collagen was increased, and cancer cell epithelial-mesenchymal transition (EMT) was inhibited, accompanied with inhibition in metastasis. IVC was safe in patients and showed the possibility to prolong patient survival. There was no interference to gemcitabine pharmacokinetics by IVC administration. Taken together, these data revealed a multi-targeting mechanism of pharmacological ascorbate's anti-cancer action, with minimal toxicity, and provided guidance to design larger definitive trials testing efficacy of IVC in treating advanced pancreatic cancer.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Ascorbic Acid; Cell Proliferation; Deoxycytidine; Female; Follow-Up Studies; Gemcitabine; Humans; Infusions, Parenteral; Mice; Mice, Nude; Neoplasm Metastasis; Pancreatic Neoplasms; Prognosis; Prospective Studies; Tissue Distribution; Tumor Cells, Cultured; Xenograft Model Antitumor Assays

Treatment with high-dose intravenous (IV) ascorbic acid (AA) is used in complementary and alternative medicine for various conditions including cancer. Cytotoxicity to cancer cell lines has been observed with millimolar concentrations of AA. Little is known about the pharmacokinetics of high-dose IV AA. The purpose of this study was to assess the basic kinetic variables in human beings over a relevant AA dosing interval for proper design of future clinical trials. Ten patients with metastatic prostate cancer were treated for 4 weeks with fixed AA doses of 5, 30 and 60 g. AA was measured consecutively in plasma and indicated first-order elimination kinetics throughout the dosing range with supra-physiological concentrations. The target dose of 60 g AA IV produced a peak plasma AA concentration of 20.3 mM. Elimination half-life was 1.87 hr (mean, S.D. ± 0.40), volume of distribution 0.19 L/kg (S.D. ±0.05) and clearance rate 6.02 L/hr (100 mL/min). No differences in pharmacokinetic parameters were observed between weeks/doses. A relatively fast first-order elimination with half-life of about 2 hr makes it impossible to maintain AA concentrations in the potential cytotoxic range after infusion stop in prostate cancer patients with normal kidney function. We propose a regimen with a bolus loading followed by a maintenance infusion based on the calculated clearance.

Topics: Adenocarcinoma; Aged; Aged, 80 and over; Area Under Curve; Ascorbic Acid; Half-Life; Humans; Male; Middle Aged; Neoplasm Metastasis; Prostatic Neoplasms; Vitamins

Preclinical data support further investigation of ascorbic acid in pancreatic cancer. There are currently insufficient safety data in human subjects, particularly when ascorbic acid is combined with chemotherapy.. 14 subjects with metastatic stage IV pancreatic cancer were recruited to receive an eight week cycle of intravenous ascorbic acid (three infusions per week), using a dose escalation design, along with standard treatment of gemcitabine and erlotinib. Of 14 recruited subjects enrolled, nine completed the study (three in each dosage tier). There were fifteen non-serious adverse events and eight serious adverse events, all likely related to progression of disease or treatment with gemcitabine or erlotinib. Applying RECIST 1.0 criteria, seven of the nine subjects had stable disease while the other two had progressive disease.. These initial safety data do not reveal increased toxicity with the addition of ascorbic acid to gemcitabine and erlotinib in pancreatic cancer patients. This, combined with the observed response to treatment, suggests the need for a phase II study of longer duration.. Clinicaltrials.gov NCT00954525.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Ascorbic Acid; Deoxycytidine; Dose-Response Relationship, Drug; Drug Administration Schedule; Erlotinib Hydrochloride; Female; Gemcitabine; Humans; Infusions, Intravenous; Male; Middle Aged; Neoplasm Metastasis; Neoplasm Staging; Pancreatic Neoplasms; Pulmonary Embolism; Quinazolines; Treatment Outcome

Arsenic trioxide (As2O3) has demonstrated effectiveness in treating acute promyelocytic leukemia (APL). Therefore the FDA has approved it to treat APL. In patients with refractory metastatic colorectal carcinoma (CRC), we assessed the efficacy and toxicity of As2O3/AA (ascorbic acid) as the outcome of this trial. Five patients with refractory metastatic CRC who failed all previous standard chemotherapy were enrolled in this study. They were treated with 0.25 mg/kg body weight/day As2O3 and 1000 mg/day of ascorbic acid for 5 days a week for 5 weeks. Each treatment cycle extended for 7 weeks with 5 weeks of treatment and 2 weeks of rest. All the patients developed moderate to severe toxic side effects to arsenic trioxide/AA therapy and therefore the study was discontinued. No CR (complete remission) or PR (partial remission) was observed. CT scans demonstrated stable or progressive disease. Three of the five patients died within 2 to 5 months after cessation of the therapy. None of the deaths could be related to this clinical trial. Two years of follow-up study showed that two patients were alive with stable disease. Under the current treatment regimen all patients developed moderate to severe side effects with no clinically measurable activity. As an alternate, efforts may be made to reduce the dose and arsenic trioxide may be combined with other standard regimen in reversing the chemo resistance.

Topics: Adult; Aged; Arsenic Trioxide; Arsenicals; Ascorbic Acid; Colorectal Neoplasms; DNA Primers; Gene Expression Regulation; Humans; Middle Aged; Neoplasm Metastasis; Oxides; Thymidylate Synthase; Tomography, X-Ray Computed; Treatment Outcome

Thirty-two typical patients with breast cancer, aged 32-81 years and classified 'high risk' because of tumor spread to the lymph nodes in the axilla, were studied for 18 months following an Adjuvant Nutritional Intervention in Cancer protocol (ANICA protocol). The nutritional protocol was added to the surgical and therapeutic treatment of breast cancer, as required by regulations in Denmark. The added treatment was a combination of nutritional antioxidants (Vitamin C: 2850 mg, Vitamin E: 2500 iu, beta-carotene 32.5 iu, selenium 387 micrograms plus secondary vitamins and minerals), essential fatty acids (1.2 g gamma linolenic acid and 3.5 g n-3 fatty acids) and Coenzyme Q10 (90 mg per day). The ANICA protocol is based on the concept of testing the synergistic effect of those categories of nutritional supplements, including vitamin Q10, previously having shown deficiency and/or therapeutic value as single elements in diverse forms of cancer, as cancer may be synergistically related to diverse biochemical dysfunctions and vitamin deficiencies. Biochemical markers, clinical condition, tumor spread, quality of life parameters and survival were followed during the trial. Compliance was excellent. The main observations were: (1) none of the patients died during the study period. (the expected number was four.) (2) none of the patients showed signs of further distant metastases. (3) quality of life was improved (no weight loss, reduced use of pain killers). (4) six patients showed apparent partial remission.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Antioxidants; Ascorbic Acid; beta Carotene; Biomarkers; Breast Neoplasms; Carotenoids; Chemotherapy, Adjuvant; Coenzymes; Combined Modality Therapy; Fatty Acids, Essential; Female; Follow-Up Studies; Humans; Lymphatic Metastasis; Mastectomy; Middle Aged; Neoplasm Metastasis; Quality of Life; Remission Induction; Risk; Selenium; Treatment Outcome; Ubiquinone; Vitamin E

Nutritional antioxidants support prostacyclin synthesis by preventing lipid hydroperoxide-mediated inhibition of prostacyclin synthetase. Recent preliminary clinical studies indicate that supplementary antioxidants exert antithrombotic effects in vivo that are most likely attributable to enhanced prostacyclin production. Optimal antioxidant nutrition may thus have preventive and therapeutic value for disorders in which inappropriate platelet aggregation plays an etiologic role, including MI, stroke, atherogenesis, pre-eclampsia, and the vascular complications of diabetes. In light of evidence that platelet aggregation encourages the implantation of hematogenous tumor metastases, supplemental antioxidants should also impede tumor dissemination--an effect which will be complemented by the immunostimulant actions of these nutrients. By exerting anticarcinogenic, immunostimulant and anti-metastatic effects, nutritional antioxidants should act to inhibit neoplasia at each stage of its development.

Topics: Adjuvants, Immunologic; Animals; Antineoplastic Agents; Antioxidants; Ascorbic Acid; Clinical Trials as Topic; Diet; Epoprostenol; Humans; Lipid Peroxides; Neoplasm Metastasis; Neoplasms; Neoplastic Cells, Circulating; Platelet Aggregation; Selenium; Thrombosis; Vitamin E

A 58-year-old woman presented with a 1-week history of lower limb bruising. She had a medical history of recurrent metastatic colon cancer with a sigmoid colectomy and complete pelvic exenteration leading to colostomy and urostomy formation. She had malignant sacral mass encroaching on the spinal cord. This caused a left-sided foot drop for which she used an ankle-foot orthosis. She was on cetuximab and had received radiotherapy to the sacral mass 1 month ago. On examination, there were macular ecchymoses with petechiae on the lower limbs. There was sparing of areas that had been compressed by the ankle-foot orthosis. Bloods showed mild thrombocytopaenia and anaemia with markedly raised inflammatory markers. Coagulation studies consistent with inflammation rather than disseminated intravascular coagulation. She was found to have

Topics: Antineoplastic Agents, Immunological; Ascorbic Acid; Bacteremia; Colectomy; Colorectal Neoplasms; Diagnosis, Differential; Ecchymosis; Female; Humans; Klebsiella; Lower Extremity; Malnutrition; Middle Aged; Neoplasm Metastasis; Neoplasm Staging; Nutritional Support; Pelvic Exenteration; Scurvy; Skin; Treatment Outcome; Vitamins

Vitamin C supplementation has been shown to decrease triple-negative breast cancer (TNBC) metastasis. However, the molecular mechanism whereby vitamin C inhibits metastasis remains elusive. It has been postulated that vitamin C reduces the levels of HIF-1α, the master regulator of metastasis, by promoting its hydroxylation and degradation. Here, we show that vitamin C at 100 µM, a concentration achievable in the plasma in vivo by oral administration, blocks TNBC cell migration and invasion in vitro. The protein level of HIF-1α remains largely unchanged in cultured TNBC cells and xenografts, partially due to its upregulated transcription by vitamin C, suggesting that HIF-1α unlikely mediates the action of vitamin C on metastasis. Vitamin C treatment upregulates the expression of synaptopodin 2 and downregulates the expression of the transcription coactivator

Topics: Actins; Adaptor Proteins, Signal Transducing; Ascorbic Acid; Cell Line, Tumor; Cell Movement; Dietary Supplements; Down-Regulation; Female; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Microfilament Proteins; Neoplasm Metastasis; Transcription Factors; Triple Negative Breast Neoplasms; Up-Regulation; Vitamins; YAP-Signaling Proteins

HIF-1α is a transcriptional regulator that functions in the adaptation of cells to hypoxic conditions; it strongly impacts the prognosis of patients with cancer. High-dose, intravenous, pharmacological ascorbate (P-AscH

Topics: Adenocarcinoma; Animals; Ascorbic Acid; Cell Hypoxia; Cell Line, Tumor; Cell Proliferation; Cell Survival; Disease Progression; Dose-Response Relationship, Drug; Humans; Hydrogen Peroxide; Hypoxia-Inducible Factor 1, alpha Subunit; Mice; Mice, Nude; Neoplasm Metastasis; Pancreatic Neoplasms; Prolyl Hydroxylases; Protein Processing, Post-Translational; Vascular Endothelial Growth Factor A

Ovarian cancer is the deadliest gynecological malignancy in women, and fifth leading cause of death. Despite advances made in chemotherapy and surgery, the average time of clinical remission is approximately 2 years and the 5-year survival rate is 45%. Thus, there is an urgent need for the development of a novel therapeutic approach to ovarian cancer treatment. We investigated the effect of a specific nutrient mixture (EPQ) containing ascorbic acid, lysine, proline, green tea extract, and quercetin on human ovarian cancer cell A-2780 in vivo and in vitro. Athymic female nude mice (n = 12) were all inoculated intraperitoneally (IP) with 2 × 10⁶ cells in 0.1 mL of phosphate buffered saline (PBS) and randomly divided into two groups. Upon injection, the Control group (n = 6) was fed a regular diet and the EPQ group (n = 6) a regular diet supplemented with 0.5% EPQ. Four weeks later, the mice were sacrificed and tumors that developed in the ovary were excised, weighed, and processed for histology. Lungs were inspected for metastasis. In vitro, A-2780 cells were cultured in Dulbecco modified Eagle medium supplemented with 10% FBS and antibiotics. At near confluence, cells were treated with EPQ in triplicate at concentrations between 0 and 1000 μg/mL. Cell proliferation was measured via MTT assay, MMP-9 secretion via gelatinase zymography, invasion through Matrigel and morphology via hematoxylin and eosin (H & E) staining. All Control mice developed large ovarian tumors, whereas 5 out of 6 mice in the EPQ group developed no tumors, and one, a small tumor. Control mice also showed lung metastasis in 6 out of 6 mice, while no lung metastasis was evident in EPQ mice. Zymography demonstrated only MMP-9 expression, which EPQ inhibited in a dose-dependent fashion, with virtual total block at 250 μg/mL concentration. EPQ significantly inhibited invasion through Matrigel with total block at 250 μg/mL concentration. MTT showed dose-dependent inhibition of cell proliferation with EPQ, and H & E staining showed no morphological changes below 500 μg/mL EPQ. These results suggest that EPQ has therapeutic potential in the treatment of ovarian cancer by significantly suppressing ovarian tumor incidence and growth and lung metastasis, and by inhibiting MMP-9 secretion and invasion of A-2780 ovarian cancer cells.

Topics: Animals; Antioxidants; Ascorbic Acid; Cell Line, Tumor; Cell Proliferation; Dietary Supplements; Dose-Response Relationship, Drug; Female; Humans; Lung Neoplasms; Lysine; Matrix Metalloproteinase 9; Mice; Mice, Nude; Micronutrients; Neoplasm Metastasis; Ovarian Neoplasms; Plant Extracts; Proline; Quercetin; Tea; Xenograft Model Antitumor Assays

Hypoxia inducible factor-1 alpha (HIF-1α) is thought to play a role in melanoma carcinogenesis. Posttranslational regulation of HIF-1α is dependent on Prolyl hydroxylase (PHD 1-3) and Factor Inhibiting HIF (FIH) hydroxylase enzymes, which require ascorbic acid as a co-factor for optimal function. Depleted intra-tumoral ascorbic acid may thus play a role in the loss of HIF-1α regulation in melanoma. These studies assess the ability of ascorbic acid to reduce HIF-1α protein and transcriptional activity in metastatic melanoma and reduce its invasive potential.. HIF-1α protein was evaluated by western blot, while transcriptional activity was measured by HIF-1 HRE-luciferase reporter gene activity. Melanoma cells were treated with ascorbic acid (AA) and ascorbate 2-phosphate (A2P) to assess their ability to reduce HIF-1α accumulation and activity. siRNA was used to deplete cellular PHD2 in order to evaluate this effect on AA's ability to lower HIF-1α levels. A2P's effect on invasive activity was measured by the Matrigel invasion assay. Data was analyzed by One-way ANOVA with Tukey's multiple comparisons test, or Student-T test as appropriate, with p < .05 considered significant.. Supplementation with both AA and A2P antagonized normoxic as well as cobalt chloride- and PHD inhibitor ethyl 3, 4-dihydroxybenzoate induced HIF-1α protein stabilization and transcriptional activity. Knockdown of the PHD2 isoform with siRNA did not impede the ability of AA to reduce normoxic HIF-1α protein. Additionally, reducing HIF-1α levels with A2P resulted in a significant reduction in the ability of the melanoma cells to invade through Matrigel.. These studies suggest a positive role for AA in regulating HIF-1α in melanoma by demonstrating that supplementation with either AA, or its oxidation-resistant analog A2P, effectively reduces HIF-1α protein and transcriptional activity in metastatic melanoma cells. Our data, while supporting the function of AA as a necessary cofactor for PHD and likely FIH activity, also suggests a potential non-PHD/FIH role for AA in HIF-1α regulation by its continued ability to reduce HIF-1α in the presence of PHD inhibition. The use of the oxidation-resistant AA analog, A2P, to reduce the ability of HIF-1α to promote malignant progression in melanoma cells and enhance their response to therapy warrants further investigation.

Topics: Ascorbic Acid; Cell Hypoxia; Cell Line, Tumor; Gene Expression; Gene Expression Regulation, Neoplastic; Genes, Reporter; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Melanoma; Neoplasm Metastasis; Protein Stability; Transcription, Genetic

Degradation of the extracellular matrix (ECM) plays a critical role in the formation of tumors and metastasis and has been found to correlate with the aggressiveness of tumor growth and invasiveness of cancer. Ascorbic acid, which is known to be essential for the structural integrity of the intercellular matrix, is not produced by humans and must be obtained from the diet. Cancer patients have been shown to have very low reserves of ascorbic acid. Our main objective was to determine the effect of ascorbate supplementation on metastasis, tumor growth and tumor immunohistochemistry in mice unable to synthesize ascorbic acid [gulonolactone oxidase (gulo) knockout (KO)] when challenged with B16FO melanoma or 4T1 breast cancer cells. Gulo KO female mice 36-38 weeks of age were deprived of or maintained on ascorbate in food and water for 4 weeks prior to and 2 weeks post intraperitoneal (IP) injection of 5x105 B16FO murine melanoma cells or to injection of 5x105 4T1 breast cancer cells into the mammary pad of mice. Ascorbate-supplemented gulo KO mice injected with B16FO melanoma cells demonstrated significant reduction (by 71%, p=0.005) in tumor metastasis compared to gulo KO mice on the control diet. The mean tumor weight in ascorbate supplemented mice injected with 4T1 cells was reduced by 28% compared to tumor weight in scorbutic mice. Scorbutic tumors demonstrated large dark cores, associated with increased necrotic areas and breaches to the tumor surface, apoptosis and matrix metalloproteinase-9 (MMP-9), and weak, disorganized or missing collagen I tumor capsule. In contrast, the ascorbate-supplemented group tumors had smaller fainter colored cores and confined areas of necrosis/apoptosis with no breaches from the core to the outside of the tumor and a robust collagen I tumor capsule. In both studies, ascorbate supplementation of gulo KO mice resulted in profoundly decreased serum inflammatory cytokine interleukin (IL)-6 (99% decrease, p=0.01 in the B16F0 study and 85% decrease, p=0.08 in the 4T1 study) compared to the levels in gulo KO mice deprived of ascorbate. In the B16FO study, ascorbate supplementation of gulo KO mice resulted in profoundly de

Topics: Animals; Antioxidants; Apoptosis; Ascorbic Acid; Ascorbic Acid Deficiency; Breast Neoplasms; Cell Proliferation; Dietary Supplements; Female; Humans; Immunoenzyme Techniques; L-Gulonolactone Oxidase; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Melanoma, Experimental; Mice; Mice, Inbred BALB C; Mice, Knockout; Neoplasm Metastasis; Tumor Cells, Cultured; Vascular Endothelial Growth Factor A

Chemoprevention is regarded as one of the most promising and realistic approaches in the prevention of cancer. All-trans retinoic acid (ATRA) is an active metabolite of vitamin A under the family retinoids, derived by irreversible oxidation of retinol (vitamin A), the parent compound for all natural retinoids. The aim of the present study is to divulge the chemopreventive and chemoprotective nature of ATRA during benzo(a)pyrene (B(a)P) induced lung cancer development in BALB/c mice. Administration of B(a)P (50 mg/kg body weight) to mice resulted in increased lipid peroxides (LPO), lipid hydroperoxides (LOOH) and nitric oxide (NO) with concomitant decrease in the levels of tissue anti-oxidants like superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), reduced glutathione (GSH) and vitamin C. ATRA supplementation (0.585 mg/kg body weight) attenuated all these alterations, which indicates the anti-cancer effect that was further confirmed by histopathological analysis. Overall, the above data show that the anti-cancer effect of ATRA is more pronounced when used as an chemopreventive agent against B(a)P-induced lung carcinogenesis.

Topics: Animals; Ascorbic Acid; Behavior, Animal; Benzo(a)pyrene; Catalase; Chemoprevention; Glutathione; Glutathione Peroxidase; Lipid Peroxidation; Lipid Peroxides; Liver; Lung; Lung Neoplasms; Mice; Mice, Inbred BALB C; Neoplasm Metastasis; Nitric Oxide; Oxidative Stress; Superoxide Dismutase; Treatment Outcome; Tretinoin

Our main objective was to determine the effect of ascorbate supplementation in mice unable to synthesize ascorbic acid (gulo KO) when challenged with murine B16FO cancer cells.. Gulo KO female mice 36-40 weeks of age were deprived of or maintained on ascorbate in food and water for 4 weeks prior to subcutaneous injection of 2.5×10(6) B16FO murine melanoma cells in the right flank of mice. A control group of wild type mice were also injected with the melanoma cells and maintained on a regular murine diet. Mice were continued on their respective diets for another 2 weeks after injection. The mice were then sacrificed, blood was drawn and their tumors were measured, excised and processed for histology.. Mean weight of animals decreased significantly (30%, p < 0.0001) in the ascorbate-restricted group but increased slightly, but insignificantly, in the ascorbate-supplemented group. The mean tumor weight in ascorbate supplemented mice was significantly reduced (by 64%, p = 0.004) compared to tumor weight in ascorbate-deprived gulo mice. The mean tumor weight of wild type mice did not differ significantly from the ascorbate-supplemented mice. Gulo KO mice supplemented with ascorbate developed smaller tumors with more collagen encapsulation and fibrous capsule interdigitation, while gulo KO mice deprived of ascorbate hosted large tumors with poorly defined borders, showing more necrosis and mitosis. Ascorbate supplementation of gulo KO mice resulted in profoundly decreased serum inflammatory cytokine IL-6 (90% decrease, p = 0.04) and IL-1β (62% decrease) compared to the levels in gulo KO mice deprived of ascorbate.. Ascorbate supplementation modulated tumor growth and inflammatory cytokine secretion as well as enhanced encapsulation of tumors in scorbutic mice.

Topics: Animals; Antineoplastic Agents; Ascorbic Acid; Ascorbic Acid Deficiency; Body Weight; Cell Proliferation; Diet, Carbohydrate-Restricted; Female; Inflammation Mediators; Melanoma, Experimental; Mice; Mice, Inbred BALB C; Mice, Knockout; Neoplasm Metastasis; Tumor Burden

During breast cancer metastasis to bone, tumor cells home to bone marrow, likely targeting the stem cell niche, and stimulate osteoclasts, which mediate osteolysis required for tumor expansion. Although osteoblasts contribute to the regulation of the hematopoietic stem cell niche and control osteoclastogenesis through production of proresorptive cytokine RANKL (receptor activator of NF-κB ligand), their role in cancer metastases to bone is not fully understood. C57BL/6J mouse bone marrow cells were treated for 3-12 days with ascorbic acid (50 μg/ml) in the presence or absence of 10% medium conditioned by breast carcinoma cells MDA-MB-231, 4T1, or MCF7. Treatment with cancer-derived factors resulted in a sustained 40-60% decrease in osteoblast differentiation markers, compared with treatment with ascorbic acid alone, and induced an osteoclastogenic change in the RANKL/osteoprotegerin ratio. Importantly, exposure of bone cells to breast cancer-derived factors stimulated the subsequent attachment of cancer cells to immature osteoblasts. Inhibition of γ-secretase using pharmacological inhibitors DAPT and Compound E completely reversed cancer-induced osteoclastogenesis as well as cancer-induced enhancement of cancer cell attachment, identifying γ-secretase activity as a key mediator of these effects. Thus, we have uncovered osteoblasts as critical intermediary of premetastatic signaling by breast cancer cells and pinpointed γ-secretase as a robust target for developing therapeutics potentially capable of reducing both homing and progression of cancer metastases to bone.

Topics: Amyloid Precursor Protein Secretases; Animals; Antigens, Differentiation; Antioxidants; Ascorbic Acid; Benzodiazepinones; Bone Marrow Cells; Bone Neoplasms; Breast Neoplasms; Cell Differentiation; Cell Line, Tumor; Culture Media, Conditioned; Female; Humans; Mammary Neoplasms, Animal; Mice; Neoplasm Metastasis; Osteoblasts; Osteoclasts; Osteoprotegerin; RANK Ligand; Signal Transduction

Currently there is no satisfactory treatment for metastatic melanoma. Radioimmunotherapy (RIT) uses the antigen-antibody interaction to deliver lethal radiation to target cells. Recently we established the feasibility of targeting melanin in tumors with 188-Rhenium ((188)Re)-labeled 6D2 mAb to melanin. Here we carried out pre-clinical development of (188)Re-6D2 to accrue information necessary for a Phase I trial in patients with metastatic melanoma.. TCEP proved to be effective in generating a sufficient number of -SH groups on 6D2 to ensure high radiolabeling yields with (188)Re and preserved its structural integrity. (188)Re-6D2 was quickly cleared from the blood with the half-life of approximately 5 hrs and from the body--with the half-life of 10 hr. The doses of 0.5, 1.0 and 1.5 mCi significantly (p < 0.05) slowed down A2058 tumor growth in nude mice, also causing release of melanin into the extracellular space which could provide additional target for repeated treatments. Transient effects of RIT on WBC and platelet counts resolved by Day 14 post-treatment.. Tris(2-Carboxyethyl) Phosphine Hydrochloride (TCEP) was evaluated as potential agent for generation of -SH groups on 6D2 mAb. TCEP-treated 6D2 mAb was radiolabeled with (188)Re and its radiochemical purity and stability was measured by ITLC and HPLC and its immunoreactivity--by melanin-binding ELISA. The pharmacokinetics, therapeutic efficacy and acute hematologic toxicity studies were performed in nude mice bearing lightly pigmented A2058 human metastatic melanoma tumors.. We have developed radiolabeling and quality control procedures for melanin-binding (188)Re-6D2 mAb which made possible currently an on-going Phase I clinical trial in patients with metastatic melanoma.

Topics: Animals; Ascorbic Acid; Drug Screening Assays, Antitumor; Enzyme-Linked Immunosorbent Assay; Female; Humans; Immunoglobulin M; Melanins; Mice; Mice, Nude; Neoplasm Metastasis; Neoplasm Transplantation; Radioimmunotherapy; Radioisotopes; Rhenium

A systematic study of the reduction of (ImH)[trans-RuCl(4)(dmso)(Im)] (NAMI-A; dmso is dimethyl sulfoxide, Im is imidazole), a promising antimetastasing agent entering phase II clinical trial, by L-ascorbic acid is reported. The rapid reduction of trans-[Ru(III)Cl(4)(dmso)(Im)](-) results in formation of trans-[Ru(II)Cl(4)(dmso)(Im)](2-) in acidic medium (pH = 5.0) and is followed by successive dissociation of the chloride ligands, which cannot be suppressed even in the presence of a large excess of chloride ions. The reduction of NAMI-A strongly depends on pH and is accelerated on increasing the pH. Over the small pH range 4.9-5.1, the reaction is quite pH-independent and the influence of temperature and pressure on the reaction could be studied. On the basis of the reported activation parameters and other experimental data, it is suggested that the redox process follows an outer-sphere electron transfer mechanism. A small contribution from a parallel reaction ascribed to inner-sphere reduction of aqua derivatives of NAMI-A, was found to be favored by lower concentrations of the NAMI-A complex and higher temperature. In the absence of an excess of chloride ions, the reduction process is catalyzed by the Ru(II) products being formed. The reduction of NAMI-A is also catalyzed by Cu(II) ions and the apparent catalytic rate constant was found to be 1.5 x 10(6) M(-2) s(-1) at 25 degrees C.

Topics: Ascorbic Acid; Electrons; Humans; Hydrogen-Ion Concentration; Imidazoles; Kinetics; Neoplasm Metastasis; Organometallic Compounds; Oxidation-Reduction; Pressure; Solutions; Temperature

Curative potential of riboflavin, niacin and ascorbic acid against tamoxifen mediated endometrial carcinoma was established by studies on carbohydrate metabolizing enzymes. The enzymes investigated were glycolytic enzymes namely, hexokinase; aldolase; phosphoglucoisomerase and the gluconeogenic enzymes namely, glucose-6-phosphatase and fructose-1, 6-biphosphatase in endometrial carcinoma bearing rats. A significant increase in glycolytic enzymes and a subsequent decrease in gluconeogenic enzymes were observed in plasma, liver and kidney of endometrial carcinoma animals. The administration of riboflavin (45 mg/kg bw/day), niacin (100 mg/kg bw/day) and ascorbic acid (200 mg/kg bw/day) along with tamoxifen (45 mg/kg bw/day) caused a significant decrease in the activity of glycolytic enzymes and a significant increase in the activities of gluconeogenic enzymes to near normal levels in experimental animals. Our results suggest that riboflavin, niacin and ascorbic acid have potential combination therapy against tamoxifen mediated secondary endometrial carcinoma in experimental rats. However, there were no deleterious side effects observed in combinants alone treated animals.

Topics: Animals; Antineoplastic Agents; Ascorbic Acid; Carbohydrate Metabolism; Carcinoma; Drug Evaluation, Preclinical; Endometrial Neoplasms; Female; Neoplasm Metastasis; Niacin; Rats; Rats, Sprague-Dawley; Riboflavin; Tamoxifen

Antioxidative vitamins are known to inhibit metastasis. Therefore we evaluated the impact of vitamins A (retinol), C (ascorbic acid) and E (alpha-tocopherol) on liver metastasis in a model of ductal pancreatic adenocarcinoma in hamster.. One hundred and twenty male Syrian hamsters were randomized into 8 groups (Gr.) (n = 15). Gr. 1-4 were given 0.5 ml normal saline subcutaneously (s.c.) weekly, whereas Gr. 5-8 received 10 mg N-nitrosobis(2-oxopropyl)amine (BOP)/kg body weight s.c. for 3 months for tumor induction. In the 13th week Gr. 2 and 6 were administered retinol, Gr. 3 and 7 received ascorbic acid and Gr. 4 and 8 were given alpha-tocopherol orally. No treatment was performed in Gr. 1 and 5. After 24 weeks animals were sacrificed, pancreas and liver were histologically determined. Activities of glutathione-peroxidase (GSH-Px), superoxide dismutase (SOD) and concentration of thiobarbituric-acid-reactive substances (TBARS) were analyzed in hepatic tissue.. Retinol and alpha-tocopherol decreased the incidence of liver metastases (44.4 vs. 86.7%, p < 0.05). The number and size of liver metastases were significantly reduced by retinol. Activities of GSH-Px and SOD were increased and concentration of TBARS was decreased in NML and LiMe by all vitamins.. Obviously, antioxidative vitamins prevent oxidative stress in hepatocytes. This may be one mechanism decreasing liver metastasis in pancreatic cancer in the present trial.

Topics: Administration, Oral; Animals; Antineoplastic Agents; Antioxidants; Ascorbic Acid; Carcinoma, Pancreatic Ductal; Cricetinae; Disease Models, Animal; Glutathione Peroxidase; Lipid Peroxidation; Liver Neoplasms; Male; Mesocricetus; Neoplasm Metastasis; Nitrosamines; Pancreatic Neoplasms; Superoxide Dismutase; Thiobarbituric Acid Reactive Substances; Vitamin A; Vitamin E

Degradation of extracellular matrix (ECM) is a hallmark of tumor invasion, metastasis and angiogenesis. Based on the Rath multitargeted approach to cancer using natural substances to control ECM stability and enhancing its strength, we developed a novel formulation (NM) of lysine, proline, ascorbic acid and green tea extract that has shown significant anti-cancer activity against a number of cancer cell lines. The aim of the present study was to determine whether NM exhibits anti-angiogenic and anti-metastatic effects using in vitro and in vivo experimental models. Angiogenesis was measured using a chorioallantoic membrane (CAM) assay in chick embryos and bFGF-induced vessel growth in C57BL/6J female mice. To determine the in vivo effect of NM on the tumor xenograft growth, male nude mice were inoculated with 3 x 10(6) MNNG-HOS cells. Control mice were fed a mouse chow diet, while the test group was fed a mouse chow diet supplemented with 0.5% NM for 4 weeks. In vitro studies on cell proliferation (MTT assay), MMP expression (zymography) and Matrigel invasion were conducted on human osteosarcoma U2OS, maintained in McCoy medium, supplemented with 10% FBS, penicillin and streptomycin in 24-well tissue culture plates and tested with NM at 0, 10, 50, 100, 500, and 1000 microg/ml in triplicate at each dose. NM at 250 microg/ml caused a significant (p<0.05) reduction in bFGF-induced angiogenesis in CAM. NM inhibited tumor growth of osteosarcoma MNNG-HOS cell xenografts in nude mice by 53%; furthermore, tumors in NM-treated mice were less vascular and expressed lower levels of VEGF and MMP-9 immunohistochemically than tumors in the control group. In addition, NM exhibited a dose-dependent inhibition of osteosarcoma U2OS cell proliferation (up to 60% at 1000 microg/ml), MMP-2 and -9 expression (with virtual total inhibition at 500 microg/ml NM), and invasion through Matrigel (with total inhibition at 100 microg/ml NM). Moreover, NM decreased U2OS cell expression of VEGF, angiopoietin-2, bFGF, PDGF and TGFbeta-1. These results together with our earlier findings suggest that NM is a relatively non-toxic formulation, which inhibits growth, invasion, metastasis, and angiogenesis of tumor cells.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Ascorbic Acid; Cell Line, Tumor; Cell Proliferation; Chick Embryo; Chorioallantoic Membrane; Collagen; Dose-Response Relationship, Drug; Drug Combinations; Extracellular Matrix; Fibroblast Growth Factor 2; Formaldehyde; Humans; Immunohistochemistry; In Vitro Techniques; Laminin; Lysine; Matrix Metalloproteinases; Mice; Mice, Inbred C57BL; Mice, Nude; Neoplasm Invasiveness; Neoplasm Metastasis; Neoplasm Transplantation; Neovascularization, Pathologic; Osteosarcoma; Plant Extracts; Platelet-Derived Growth Factor; Proline; Proteoglycans; Tea; Tetrazolium Salts; Thiazoles; Time Factors; Transforming Growth Factor beta; Transforming Growth Factor beta1; Vascular Endothelial Growth Factor A

The tumor growth-inhibiting and chemo-potentiating effects of vitamin C and K(3)combinations have been demonstrated both in vitro and in vivo. The purpose of this study was to investigate the influence of orally administered vitamin C and K(3) on the metastasis of mouse liver tumor (T.L.T.) cells implanted in C3H mice. Adult male C3H mice were given water containing vitamin C and K3 (15 g/0.15 g dissolved in 1000 ml) beginning 2 weeks before tumor transplantation until the end of the experiment. T.L.T. cells (106) were implanted intramuscularly in the right thigh of mice. All mice were sacrificed 42 days after tumor transplantation. Primary tumor, lungs, lymph nodes and other organs or tissues suspected of harboring metastases were macroscopically examined. Samples of primary tumors, their local lymph nodes, lungs and main organs such as liver, kidneys, spleen were taken for histological examination. Forty-two percent of control mice exhibited lung metastases and 27% possessed metastases in local lymph nodes whereas 24% of vitamin-treated mice exhibited lung metastases and 10% possessed local lymph nodes metastases. The total number of lung metastases was 19 in control group and 10 in vitamin C and K(3)-treated mice. Histopathological examination of the metastatic tumors from the vitamin-treated mice revealed the presence of many tumor cells undergoing autoschizic cell death. These results demonstrate that oral vitamin C and K(3) significantly inhibited the metastases of T.L.T. tumors in C3H mice. At least a portion of this inhibition was due to tumor cell death by autoschizis.

Topics: Adjuvants, Immunologic; Animals; Ascorbic Acid; Liver Neoplasms, Experimental; Male; Mice; Mice, Inbred C3H; Neoplasm Metastasis; Neoplasm Transplantation; Vitamin K 3

Tumor metastasis and invasion were shown to be inhibited by the 2-O-phosphorylated form (Asc2P) of L-ascorbic acid (Asc); intact Asc did not inhibit tumor invasion when added once, but appreciably inhibited it upon repeated addition. The anti-metastatic effect is attributable to a marked enrichment of intracellular Asc by Asc2P, subsequently dephosphorylated. Asc2P scavenged most of the intracellular reactive oxygen species (ROSin), and notably inhibited production of matrix metalloproteases and cell motility. ROSin was decreased by Asc2P more markedly than by Asc added once. Thus, involvement of ROSin in tumor invasion and a potent anti-metastatic therapy by ROSin-decreasing agents are suggested.

Topics: Animals; Antineoplastic Agents; Ascorbic Acid; Cell Movement; Extracellular Matrix; Female; Fibrosarcoma; Free Radical Scavengers; Humans; Melanoma, Experimental; Mice; Mice, Inbred C57BL; Neoplasm Invasiveness; Neoplasm Metastasis; Oxidative Stress; Reactive Oxygen Species

Analysis of cultured rat "Nb2 lymphoma" cell lines, showing different degrees of malignant progression, can lead to identification of phenotypic changes associated with this phenomenon in T-cell cancers. In the present study we have compared the metastatic sublines, Nb2-11 and Nb2-SFJCD1, with regard to ascorbate and glutathione recycling, important processes in cellular protection from oxidative stresses. Whereas the Nb2-11 subline is prolactin (PRL)-dependent, the genetically related Nb2-SFJCD1 subline is growth factor-independent and shows more chromosomal alterations, indicative of more advanced progression. The Nb2-SFJCD1 cells, compared to the Nb2-11 cells, were less sensitive to toxic effects of dehydroascorbate, a potentially toxic oxidation product of ascorbate. Results were consistent with a significantly higher production of reducing equivalents (e.g., NADPH, GSH) and an accelerated reduction of dehydroascorbate by homogenates of Nb2-SFJCD1 cells. However, the increased resistance was apparently not directly related to the cellular uptake and reduction of dehydroascorbate by whole cells, which was similar in both cell lines. Observations indicate that Nb2 lymphoma cells, in their progression to malignancy, can acquire an enhanced capability to protect themselves from oxidative damage assisting them in withstanding the oxidative stress that anti-neoplastic drugs can cause. The adaptation may also be a mechanism that is utilized by tumor cells in suppressing apoptosis and other protective cellular functions facilitating, or potentiating, a tumor cell's ability to become more metastatic. However, the mechanism leading to this augmented capacity of Nb2 lymphoma cells to resist oxidative stress in not known and is the subject for further study.

Topics: Animals; Apoptosis; Ascorbic Acid; Biological Transport, Active; Dehydroascorbic Acid; DNA Fragmentation; Glutathione; Lymphoma, T-Cell; NADP; Neoplasm Metastasis; Oxidative Stress; Phenotype; Rats; Tumor Cells, Cultured

A lipophilic and auto-oxidation-resistant derivative of ascorbic acid (Asc), Asc-2-O-phosphate-6-O-palmitate (Asc2P6Plm), was shown to exert an invasion-inhibitory action as promptly as 30-40 min for 50% inhibition and 60-90 min for 80% inhibition after entering fibrosarcoma HT-1080 cells. Invasive inhibition of 95-97% was accomplished by Asc2P6Plm of doses exhibiting no cytotoxicity under the same conditions. Asc2P6Plm was dephosphorylated and esterolyzed to Asc, which enriched the intracellular Asc dose dependently in invasion-suppressed cells, contrasting with no detectable Asc in invasive cells fed without Asc2P6Plm. Intracellular dehydroAsc (DehAsc), unexpectedly, amounted to 1.02-1.65-fold as much as intracellular Asc, suggesting that invasive cells underwent oxidative stress, the repression of which resulted in both inhibition of tumor invasion and oxidative conversion of Asc to DehAsc. Correspondingly, intracellular oxidants fluorometrically detected with a redox indicator CDCFH were more abundant in invasive cells than in invasion-suppressed cells fed with Asc2P6Plm. Invasion inhibitory effects of Asc2P6Plm necessitated the extensive inhibition of the major gelatinases MMP-9 and MMP-2, as shown by zymography and Western blots, but did not necessitate direct expression of the metastasis suppressor gene nm23, taking as long as 6-18 h in contrast to a prompt action of Asc2P6Plm. Antimetastatic effects on melanoma B16BL6 cells were given dose dependently by intravenous administration or pretreatment with Asc2P6Plm. Thus, Asc2P6Plm is anticipated as an antimetastatic agent via the potent antioxidant activity.

Topics: Animals; Antineoplastic Agents; Antioxidants; Ascorbic Acid; Cell Survival; Dose-Response Relationship, Drug; Female; Humans; Immunohistochemistry; Lung Neoplasms; Matrix Metalloproteinases; Mice; Mice, Inbred C57BL; Microscopy, Confocal; Neoplasm Invasiveness; Neoplasm Metastasis; Neoplasm Transplantation; Oxidative Stress; Reactive Oxygen Species; Time Factors; Tumor Cells, Cultured

The enhancing effect on liver metastasis produced by the excessive surgical stress of thoraco-laparotomy (TL), and its regulation with a radical scavenger, were studied in 10-week-old Donryu rats. The rats were divided into three groups: those given thoraco-laparotomy for 1 h (the TL group); those given laparotomy alone for 1 h (the L group); those given a short laparotomy (the C group). The effects of treatment with 5 mg/kg of EPC-K1 was assessed in the TL group. A rat hepatocellular carcinoma cell line AH 60C (5 x 10(5) cells) was administered into the portal vein under general anesthesia. The number of metastatic liver nodules was counted 3 weeks later, and the lipid peroxide (LPO) levels of the liver and serum were measured by the TBA method on postoperative days (PODs) 1, 2, and 3. The number of metastatic liver nodules was 40.6 +/- 29.7, 15.0 +/- 15.8, and 13.7 +/- 9.4 in the TL, L, and C groups, respectively. When EPC-K1 was administered to the TL group, the LPO level on POD 1 decreased from 49.8 +/- 25.8 to 18.9 +/- 7.9 nM/g, and the number of metastatic liver nodules decreased from 27.2 +/- 30.0 to 8.9 +/- 12.7 in parallel. The findings of this study suggested that the excessive surgical stress produced by thoraco-laparotomy enhanced liver metastasis in parallel with an increase in LPO levels; however, the radical scavenger EPC-K1 could aid in reversing this effect.

Topics: Animals; Antioxidants; Ascorbic Acid; Carcinoma, Hepatocellular; Free Radical Scavengers; Laparotomy; Lipid Peroxides; Liver Neoplasms; Male; Mice; Neoplasm Metastasis; Oxidative Stress; Rats; Rats, Inbred Strains; Tumor Cells, Cultured; Vitamin E

Topics: Animals; Ascorbic Acid; Carcinogens; Dimethylhydrazines; Estradiol; Female; Mice; Mice, Inbred CBA; Neoplasm Metastasis; Sarcoma, Experimental; Uterine Neoplasms

CuPu(Py)2 and CuPu(Im)2, two novel dischiffbase coordinated low Mr active centre analogues of Cu2Zn2 superoxide dismutase, were shown to effectively catalyze the production of hydroxyl radicals in the presence and absence of TPA-activated polymorphonuclear leukocytes. These stable copper chelates exhibited a pronounced anticarcinogenic reactivity in male Sprague Dawley rats implanted with Walker 256 carcinosarcoma cells. When four doses of 5 mumol/kg CuPu(Py)2 and CuPu(Im)2, respectively, were administered intratumorally, reduction in tumor size, delay of metastasis and a significant increase in survival of the hosts were observed, resulting in 75% of total remissions. 60% of the animals recovered totally from the carcinosarcoma, when CuPu(Py)2 was applicated intravenously.

Topics: Animals; Antineoplastic Agents; Antioxidants; Ascorbic Acid; Carcinoma 256, Walker; Copper; Free Radicals; Hydrogen Peroxide; Male; Neoplasm Metastasis; Neoplasm Transplantation; Neutrophils; Organometallic Compounds; Oxygen; Rats; Rats, Inbred Strains; Remission Induction; Schiff Bases; Structure-Activity Relationship; Superoxide Dismutase

Topics: Adenocarcinoma; Adult; Aged; Ascorbic Acid; Carcinoma; Combined Modality Therapy; Female; Fluorouracil; Gastrectomy; Humans; Male; Middle Aged; Neoplasm Metastasis; Postoperative Care; Stomach Neoplasms

The possible inhibitory effect of vitamin C (sodium ascorbate) on metastases from two transplantable murine tumors was studied. The first murine tumor, colon carcinoma CA-51, was subcutaneously transplanted into male Balb/c mice. Immediately after tumor implantation, the mice were given either 1.0% sodium ascorbate or tap water. Subcutaneous tumors were surgically removed from one half of the animals in each group when the tumors reached a size of 1.5 cm. Results indicated no differences in survival, in the number of mice with metastases, or in the size of metastases between treated and untreated groups. The second murine tumor, lymphosarcoma 6C3HED, was subcutaneously implanted into C3H male and female mice. Sodium ascorbate (1.0% or 3.0%) was administered as above, but surgery was not performed. Again, no significant differences in the number of mice with metastases were observed between treated and untreated groups, with the exception of brain and regional lymph node metastases (enhanced, in males, by ascorbate).

Topics: Animals; Ascorbic Acid; Carcinoma; Colonic Neoplasms; Female; Lymphoma, Non-Hodgkin; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C3H; Neoplasm Metastasis; Neoplasms, Experimental

The aims of follow up of patients with bronchial carcinoma are: 1. Complete use of all therapeutical possibilities. 2. Avoidance of preventable complications of therapeutical prescriptions. 3. Prevention of sicknesses beside the basic complaint. 4. The rehabilitation of the patient. The medical structure for realizing these aims, we suppose in the cooperation of the doctor of the family or the factory, who will see the patient in intervals of four weeks, and the ambulant working pulmologist, who will see the patient in intervals of 3 months, and the thorax-centre, what the patient will consult once or twice the year, and the centre for rehabilitation, where patients with limited cardiorespiratoric function will get an appropriated training of condition. Two cure-places with this special direction will satisfy the require in the GDR. The oncologist of the district where the patient lives will be the coordinator of all parts of this system and the controller to keep its function. The effectivity of follow up will be realised by clear and proofed recommendations by the therapeutical centres and the continued consultations on actual problem cases with the shared doctors. The data processing can do an useful help in this cooperation.

Topics: Aftercare; Ascorbic Acid; Bronchial Neoplasms; Germany, East; Humans; Hypertension; Legislation, Medical; Neoplasm Metastasis; Physical Therapy Modalities; Work Capacity Evaluation

Present evidence suggests that a high fat intake may be one of the factors in the aetiology of breast cancer. Patients with breast cancer may show an increased requirement for thiamin particularly when treated with 5-fluorouracil, and a number of metabolic disturbances in which ascorbic acid may play a central role.

Topics: Animals; Ascorbic Acid; Bone Neoplasms; Breast Neoplasms; Calcium; Dietary Fats; Feeding Behavior; Female; Fluorouracil; Humans; Hydroxyproline; Lipase; Lipids; Mammary Neoplasms, Experimental; Mice; Neoplasm Metastasis; Rats; Thiamine Deficiency; Thiamine Pyrophosphate

Topics: Ascorbic Acid; Ascorbic Acid Deficiency; Breast Neoplasms; Female; Humans; Hydroxyproline; Lipid Metabolism; Neoplasm Metastasis; Neoplasms; Thiamine Deficiency; Vitamin A; Vitamin A Deficiency

Topics: Age Determination by Skeleton; Ascorbic Acid; Breast Neoplasms; Collagen; Female; Humans; Hydroxyproline; Leukocytes; Male; Neoplasm Metastasis

Topics: Ascorbic Acid; Bone Neoplasms; Breast Neoplasms; Female; Humans; Hydroxyproline; Leukocytes; Male; Neoplasm Metastasis; Time Factors

Topics: Adenocarcinoma; Ascorbic Acid; Bone Neoplasms; Breast Neoplasms; Humans; Neoplasm Metastasis

Topics: Abdomen; Aged; Antiemetics; Ascorbic Acid; Bismuth; Carcinoma, Basal Cell; Diverticulum; Duodenal Diseases; Epididymitis; Gastrectomy; Humans; Liver Neoplasms; Male; Neoplasm Metastasis; Pain; Stomach Neoplasms; Tracheotomy

Topics: Adrenal Glands; Animals; Ascorbic Acid; Carcinoma, Brown-Pearce; Cholesterol; Glucocorticoids; Histocytochemistry; Lipids; Male; Neoplasm Metastasis; Pituitary Gland; Rabbits

Topics: Adult; Ascorbic Acid; Brain Neoplasms; Child; Female; Humans; Iodine Radioisotopes; Iron; Male; Medulloblastoma; Middle Aged; Neoplasm Metastasis; Radiometry; Radionuclide Imaging; Sarcoma, Synovial; Technetium