ascorbic-acid and Fibrosarcoma

At birth, a male child presented a 6 cm tumour in the right leg. The tumour was partially removed after just 12 days. Histology showed a congenital fibrosarcoma associated with reactive lymphadenitis. A first cycle of adjuvant chemotherapy did not prevent the rapid progression of the disease. Subsequent evaluation for surgical removal raised serious concerns due to the need for a major operation involving total amputation of the right leg and hemipelvectomy. Since surgery could not exclude the possibility of disease recurrence and since the traditional cycles of chemotherapy did not offer any possibility of a cure, the parents opted for the Di Bella Method. The combined use of Somatostatin, Melatonin, Retinoids solubilized in Vit. E, Vit. C, Vit. D3, Calcium, and Chondroitin sulfate associated with low doses of Cyclophosphamide resulted in a complete objective response, still present 14 years later, with no toxicity and without the need for hospitalization, allowing a normal quality of life and perfectly normal adolescent psycho-physical development.

Topics: Antineoplastic Combined Chemotherapy Protocols; Ascorbic Acid; Bromocriptine; Calcium; Cholecalciferol; Chondroitin Sulfates; Cyclophosphamide; Fibrosarcoma; Humans; Infant, Newborn; Leg; Maintenance Chemotherapy; Male; Melatonin; Remission Induction; Retinoids; Soft Tissue Neoplasms; Somatostatin; Vitamin E; Vitamins

As a part of our efforts to develop potential imaging agents for ascorbate bioactivity, 5-O-(4-[(125)I]iodobenzyl)-L-ascorbic acid ([(125)I]1) was prepared through a two-step sequence which involved radioiodo-destannylation of a protected tributylstannyl precursor 6, followed by hydrolysis in acidic methanol of the protecting groups in 61% overall radiochemical yield, with a radiochemical purity of over 98% and a specific activity of more than 15.4 GBq/μmol. Tissue distribution of [(125)I]1 in tumor-bearing mice showed signs of distribution profiles similar to the reported results for 6-deoxy-6-[(18)F]fluoro-L-ascorbic (6-(18)FAsA) acid and 6-deoxy-6-[(131)I]iodo-L-ascorbic acid (6-(131)IAsA) but with notable differences in the adrenal glands, in which considerably lower uptake of radioactivity and rapid clearance with time were observed. Pretreatment of mice with a known inhibitor of ascorbate transport, sulfinpyrazone, did not produce any significant change in the adrenal uptake of radioactivity after injection of [(125)I]1 compared to the control, suggesting that uptake in the adrenal glands is independent of the sodium-dependent vitamin C transporter 2 transport mechanism. Introduction of a bulky substituent at C-5 on AsA, such as an iodobenzyloxy group, may not be suitable for the design of analogs that may still be able to maintain characteristic distribution properties in vivo seen with AsA itself.

Topics: Animals; Ascorbic Acid; Chromatography, High Pressure Liquid; Fibrosarcoma; Iodine Radioisotopes; Mice; Molecular Structure; Radionuclide Imaging; Radiopharmaceuticals

Current treatment of fibrosarcoma, an aggressive cancer of the connective tissue, is generally associated with poor prognosis. Matrix metalloproteinases (MMPs), vascular endothelial growth factor (VEGF), and constituents of the extracellular matrix (ECM), such as fibronectin, play a critical role in angiogenesis and underlie neoplastic invasion and metastasis. This and anticancer properties of lysine, proline, arginine, ascorbic acid, and green tea extract (NM) prompted us to investigate the effect of these nutrients in vitro on human fibrosarcoma cells HT-1080 by measuring cell proliferation, modulation of MMP-2 and MMP-9, and invasive potential. In vivo, we studied the growth of human fibrosarcoma HT-1080 cells in athymic nude mice and the expression of MMPs and VEGF. Cell proliferation was evaluated by MTT assay, MMP expression by gelatinase zymography, and invasion through Matrigel and migration by scratch assay. Tumors were excised, weighed, and processed for histology in both the control and nutrient-supplemented groups. Results showed NM inhibited the growth and reduced the size of tumors in nude mice; decreased MMP-9 and VEGF secretion was found in the supplemented group tissues. NM inhibited invasion through Matrigel and migration with total inhibition at 1,000 microg/mL. These results offer promise in the therapeutic use of the nutrient mixture of lysine, proline, arginine, ascorbic acid, and green tea extract tested in the treatment of fibrosarcoma.

Topics: Animals; Arginine; Ascorbic Acid; Cell Line, Tumor; Fibrosarcoma; Humans; Lysine; Male; Matrix Metalloproteinase Inhibitors; Mice; Neoplasm Transplantation; Phytotherapy; Plant Extracts; Proline; Tea; Transplantation, Heterologous

The reduction on peroxidation caused by benzopyrenes by some naturally occurring antineoplastic agents was studied in this experimental work. Inhibition/reduction of experimental carcinogenesis induced by benzo(a)pyrene by vitamin C alone and by vitamin C/vitamin E and selenium/ glutathione was attempted in 224 female Wistar rats divided in four groups. Injected with 10.08 mL benzo(a)pyrene, the animals were treated with some naturally occurring substances like vitamin C alone and a combination of anticarcinogens. By calculating the carcinogenic potency of benzo(a)pyrene and the anticarcinogenic potency of substances used as well as histological examination of developed tumors and survival time of treated animals, it was found that vitamin C exerts a significant anticarcinogenic effect of 8.3 units and that the combination of the two anticarcinogens used produced a significant prolongation of the animals survival time with anticarcinogenic potency of 22.1 and 22.2 units, respectively. This is considered a potent anticarcinogenic effect. The question of an additional supportive administration of such agents complementary to the conventional cancer chemotherapy in humans is raised. Of course, further studies are needed.

Topics: Animals; Antineoplastic Agents; Ascorbic Acid; Benzopyrenes; Drug Synergism; Female; Fibrosarcoma; Glutathione; Neoplasms, Experimental; Rats; Rats, Wistar; Selenium; Survival Analysis; Vitamin E

Genomic DNA was isolated from subcutaneous masses observed in CD-1 and p53+/- heterozygous mice during the course of carcinogenicity studies in the vehicle control groups. These masses resulted after daily subcutaneous injection of an antioxidant vehicle with a pH adjusted to 3-4. The vehicle was 1.0% ascorbic acid plus 0.05% sodium metabisulfite in 0.75% saline in a dosing volume of 10 ml/kg/day. These masses were first palpable after 13 and 37 weeks of dosing among p53+/- and CD-1 mice, respectively. By week 26, the incidence of these masses was 89% and 80% in male and female p53+/- mice, respectively (n = 15 mice/sex) and was 0% in both male and female CD-1 mice (n = 60 mice/sex). These masses originated from panniculus carnosus muscle. Histopathological examination of the p53+/- mouse masses indicated the tumors to be sarcomas of spindle-cell origin. The histopathological examination of the masses in the CD-1 mice revealed fibrosarcomas. Five mice/sex/strain were randomly selected from a pool of mice that developed these masses in the course of the two studies. Frozen tissues from these masses were used to examine the DNA for loss of the functional p53 allele in the p53+/- mice (i.e., loss of heterozygosity, or LOH) or for loss of one of the alleles in the wild type (p53+/+) CD-1 mice by the polymerase chain reaction (PCR) technique. Loss of the functional allele was observed only in the tumor from one p53+/- male mouse. These results support a nongenotoxic mechanism for these injection site masses.

Topics: Alleles; Animals; Antioxidants; Ascorbic Acid; Carcinogenicity Tests; Female; Fibrosarcoma; Heterozygote; Injections, Subcutaneous; Loss of Heterozygosity; Male; Mice; Mice, Inbred C57BL; Polymerase Chain Reaction; Rhabdomyosarcoma; Sensitivity and Specificity; Soft Tissue Neoplasms; Sulfites; Tumor Suppressor Protein p53

Combined application of cyclophosphamide, methotrexate, 5-fluorouracil (CMF) has been followed in the treatment of breast cancer. The combined effect of CMF and vitamin C on plasma lipid and lipoprotein is important, since vitamin C encumbers the lipid abnormalities instigated by CMF. Hence, the study was launched to appraise the salubrious role of vitamin C in CMF administered fibrosarcoma-bearing rats. Fibrosarcoma cell line-induced rats were treated with CMF (cyclophosphamide 10 mg/kg b.w., methotrexate 1 mg/kg b.w., 5-fluorouracil 10 mg/kg b.w. and vitamin C 200 mg/kg b.w.) individually and in combination for 120 days. The concentration of plasma lipids and lipoprotein was determined in control and experimental rats. The untreated as well as CMF administered fibrosarcoma-bearing rats divulged significantly in increased levels of plasma total cholesterol, triglycerides, phospholipids, very low density lipoprotein (VLDL) and low density lipoprotein (LDL) cholesterol, as compared with their respective control animals. Whereas ester and high density lipoprotein (HDL) cholesterol levels exhibited a marked decrease in these animals. However, these lipid abnormalities were found to be moderated by co-administration of vitamin C. These results suggested that some clinical entanglement of CMF was refrained by co-administration of vitamin C in tumor stress condition.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Ascorbic Acid; Breast Neoplasms; Cholesterol; Cyclophosphamide; Female; Fibrosarcoma; Fluorouracil; Lipid Metabolism; Lipids; Methotrexate; Neoplasm Transplantation; Neoplasms, Experimental; Rats; Rats, Wistar

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

The combined effect of cyclophosphamide and ascorbic acid on plasma lipids and lipoprotein profiles are important since, ascorbic acid encumbered the lipid abnormalities initiated by cyclophosphamide during cancer chemotherapy. Hence, the study was launched to appraise the salutary role of ascorbic acid in cyclophosphamide administered fibrosarcoma bearing rats. Fibrosarcoma cell line induced rats were treated with cyclophosphamide (10 mg/kg body weight) and ascorbic acid (200 mg/kg body weight) individually and in combination for 28 days. The concentration of plasma lipids and lipoprotein profiles were determined in control and experimental animals. The untreated, as well as cyclophosphamide administered fibrosarcoma bearing rats, divulged significantly increased levels of plasma total cholesterol, triglycerides, phospholipids, VLDL- and LDL-cholesterol, as compared with their respective control animals. In contrast, ester and HDL-cholesterol levels exhibited a marked decrease in these animals. Similar observations were also noticed in liver lipid values, as well. However, these lipid abnormalities were corrected by the co-administration of ascorbic acid. These results suggested, that some clinical entanglement of cyclophosphamide was refrained by co-administration of ascorbic acid in tumor stress condition.

Topics: Animals; Ascorbic Acid; Cholesterol, LDL; Cholesterol, VLDL; Cyclophosphamide; Fatty Acids, Nonesterified; Fibrosarcoma; Hyperlipidemias; Lipid Metabolism; Male; Methylcholanthrene; Neoplasm Transplantation; Phospholipids; Rats; Rats, Wistar; Sarcoma, Experimental; Triglycerides

Sodium 5,6-benzylideneascorbate (SBA), which is known to be an antitumor substance, was found to induce apoptotic cell death of L929 tumor cells directly in a concentration- and time-dependent manner. The dying cells exhibited cell shrinkage, disappearance of cell surface microvilli, chromatin condensation and DNA fragmentation into nucleosomal oligomers characteristic of apoptosis. These results indicate a possible mechanism by which SBA induces tumor regression in vivo.

Topics: Animals; Antineoplastic Agents; Apoptosis; Ascorbic Acid; Benzylidene Compounds; DNA Damage; DNA, Neoplasm; Electrophoresis, Agar Gel; Fibrosarcoma; Kinetics; Mice; Microscopy, Electron; Molecular Structure; Tumor Cells, Cultured

In studies of isotransplants of a murine fibrosarcoma, FSaII, ascorbic acid administered 50 min before whole-body radiation significantly increased the dose of radiation required to cause a fatal radiation syndrome and the dose of radiation required to obtain skin desquamation. A single intraperitoneal dose of 4.5 g/kg body wt was not cytotoxic and did not affect the radiation dose required to control 50% of tumors or to achieve remissions. The mechanism of this differential radiomodification of normal tissue sensitivity and tumor tissue response is unclear. The data suggest that after high-dose ascorbic acid the radiation dose given to cancer patients could be increased without increasing acute complications but with an expected increase in tumor-control probability. However, only acute radiation reaction endpoints have been studied. Application of these findings to humans must therefore await further studies confirming that late reacting tissues are similarly protected by ascorbic acid.

Topics: Animals; Ascorbic Acid; Bone Marrow; Dose-Response Relationship, Radiation; Female; Fibrosarcoma; Male; Mice; Mice, Inbred C3H; Neoplasm Transplantation; Radiation-Protective Agents; Skin

Depletion of glutathione by pretreatment with buthionine sulphoximine greatly enhances the radiosensitizing efficiency of misonidazole in mammalian cells in vitro, but a similar effect has not yet been observed in vivo. In thiol-depleted V79 Chinese hamster cells and human HT1080 fibrosarcoma cells, physiological concentrations of ascorbate greatly reduce misonidazole radiosensitization, although there is little effect of ascorbate on misonidazole sensitization in untreated cells. The effect of ascorbate on misonidazole radiosensitization is not markedly dependent on the extracellular concentration of ascorbate; this may be explained by the non-equilibrium uptake of ascorbate at different extracellular concentrations. Failure to obtain a large enhancement of misonidazole radiosensitization as a result of buthionine sulphoximine treatment in vivo may be due, in part at least, to the presence of ascorbate.

Topics: Animals; Ascorbic Acid; Cell Line; Cell Survival; Cricetinae; Fibrosarcoma; Glutathione; Humans; Misonidazole; Radiation Tolerance; Tumor Cells, Cultured

Ascorbic acid (ASC) has been shown to radioprotect nonmalignant tissue and to enhance the effects of misonidazole (MISO) on hypoxic cells in vitro. Since ASC is minimally toxic, it is an interesting candidate for improving the radiotherapeutic gain factor in vivo. The in vivo radiomodifying effects of ASC on a C3H/fSed murine fibrosarcoma (FSaII), on normal skin, and on bone marrow were determined with the use of the tumor growth delay and TCD50 (i.e., radiation dose required to control 50% of treated tumors for a minimum of 120 days) assays and the RD50 (i.e., dose required to cause a peak skin reaction of 2 in 50% of treated hind limbs) and LD50 (i.e., whole-body radiation lethal dose) assays, respectively. ASC was buffered to pH 7.35 and delivered ip at a dose of 4.5 mg g-1 body weight. ASC did not modify tumor growth delay induced by radiation or the TCD50 [87.1 Gy (control) vs. 85.6 Gy (ASC)]. Normal tissues, however, were radioprotected by ASC. RD50 values for 2+ acute skin reactions were 46.4 and 55.7 Gy for control and ASC-treated subjects, respectively; LD50 (30 days) values were 7.2 and 8.5 Gy. The enhancement ratios for skin and bone marrow were 1.20 and 1.18, and 95% confidence limits were (1.07 ... 1.34) and (1.14 ... 1.23), respectively. The therapeutic gain factor was 1.22 calculated as the ratio of the TCD50 and the reference normal tissue (RD50 or LD50). When ASC and MISO were combined, ASC reduced the in vivo radiosensitizing effects of MISO.

Topics: Animals; Ascorbic Acid; Bone Marrow; Cell Division; Drug Interactions; Female; Fibrosarcoma; Male; Mice; Mice, Inbred C3H; Misonidazole; Radiation Tolerance; Radiation-Protective Agents; Skin

Topics: Animals; Ascorbic Acid; Benzo(a)pyrene; Benzopyrenes; Carcinogens; Female; Fibrosarcoma; Neoplasms, Experimental; Rats; Rats, Inbred Strains; Rhabdomyosarcoma; Sarcoma, Experimental

We have studied and discussed the significance of the use of ascorbic acid in 51Cr labelling of cells. The following two advantages seem credible if cells (mouse fibrosarcoma) in culture are incubated for about 2 h in a medium containing Na2 51CrO4 and then ascorbic acid is added to the medium and incubation continued for ten more minutes: (a) the natural intracellular conversion of Cr6+ to Cr3+ appears to be aided, (b) the incorporation of chromium by cells is higher.

Topics: Animals; Ascorbic Acid; Cell Line; Cells, Cultured; Chromium Radioisotopes; Fibrosarcoma; Isotope Labeling; Mice

Extracellular matrices produced by cultured rat smooth muscle cells in the presence or absence of ascorbic acid wee used as substrates for the human fibrosarcoma cell line HT1080. The matrix elaborated by smooth muscle cells in the presence of ascorbic acid contained glycoproteins, elastin, and collagen, and all of these components were digested by the tumor cells. In contrast, the matrix elaborated in the absence of ascorbic acid which contained glycoproteins and underhydroxylated elastin but no collagen was more resistant to tumor-induced hydrolysis. The underhydroxylated elastin was particularly refractory to the tumor proteases, suggesting that the elastolytic activity produced by HT1080 cells showed a marked preference for the natural substrate containing hydroxyproline. The digestion by HT1080 cells of elastin from living cultures of smooth muscle cells was also retarded if the extracellular proteins were produced under ascorbic acid-deficient conditions. These experiments therefore do not support the notion that connective tissues made under scorbutic conditions are inherently more susceptible to tumor hydrolysis.

Topics: Ascorbic Acid; Cell Line; Collagen; Connective Tissue; Elastin; Extracellular Space; Fibrosarcoma; Glycoproteins; Humans; Hydrolysis; Kinetics; Muscle Proteins; Muscle, Smooth; Peptide Hydrolases

The s.c. infection of 10 mg benzo(a)pyrene dissolved in 1 ml tricaprylin induced in Wistar rats local malignant tumors, such as fibrosarcoma, rhabdomyosarcoma, and polymorph cell sarcoma. The growth of the tumors was relatively rapid, reaching weights of 140-155 g before rats died 142-168 days after the administration of the carcinogen. On the contrary, under the same experimental conditions, high doses of Vitamin C about 525 mg/day/rat administered orally in drinking water (total amount of Vitamin C 55 g/rat corresponding to 40% of their body weight ) inhibited to a great extent the benzo(a)pyrene carcinogenesis. Only one slowly growing rhabdomyosarcoma (13 g of weight) was developed showing characteristic damage of malignant cells and partial replacement of the neoplastic area with granuloma tissue. The significance ov Vitamin C for cancer prevention and treatment is discussed.

Topics: Animals; Ascorbic Acid; Benzopyrenes; Dose-Response Relationship, Drug; Fibrosarcoma; Neoplasms, Experimental; Rats; Rhabdomyosarcoma; Sarcoma, Experimental

The growth of tumours in guinea-pigs was observed for 20 weeks after placing them on various doses of vitamin C. Complete tumour regression occurred in 55% of those animals receiving 0-3 mg/kg/day ascorbic acid, whereas animals given 10 mg/kg/day showed tumour inhibition but no regression. In contrast, tumours in animals maintained on 1 g/kg/day ascorbic acid grew without sign of retardation. When increased amounts of ascorbic acid were restored to the diet of scorbutic tumour-bearing animals, tumours which had not regressed responded with enhanced growth. Likewise, animals previously maintained on 10 mg/kg ascorbic acid responded in turn to the additional vitamin with enhanced tumour growth. In contrast, all tumour-bearing animals maintained on 1 g/kh ascorbic acid died within 3 weeks when this dose was replaced with 0-3 mg/kg.

Topics: Animals; Ascorbic Acid; Ascorbic Acid Deficiency; Fibrosarcoma; Guinea Pigs; Liposarcoma; Male; Neoplasms, Experimental; Sarcoma, Experimental

Topics: Administration, Oral; Ascorbic Acid; Breast Neoplasms; Carcinoma; Colonic Neoplasms; Dose-Response Relationship, Drug; Drug Evaluation; Drug Stability; Female; Fibrosarcoma; Humans; Injections, Intravenous; Neoplasms; Papilloma; Rectal Neoplasms; Stomach Neoplasms; Time Factors; Urinary Bladder Neoplasms

Topics: Ascorbic Acid; Ascorbic Acid Deficiency; Fibrosarcoma; Humans; Neoplasms; Sarcoma