Biomedical subjects

Neil H Riordan

Publications and source records attributed to Neil H Riordan.

13 recordsLinked to original sources

PubMed2006

Induction of antitumor immunity through xenoplacental immunization.

Historically cancer vaccines have yielded suboptimal clinical results. We have developed a novel strategy for eliciting antitumor immunity based upon homology between neoplastic tissue and the developing placenta. Placenta formation shares several key processes with neoplasia, namely: angiogenesis, activation of matrix metalloproteases, and active suppression of immune function. Immune responses against xenoantigens are well known to break self-tolerance. Utilizing xenogeneic placental protein extracts as a vaccine, we have successfully induced anti-tumor immunity against B16 melanoma in C57/BL6 mice, whereas control xenogeneic extracts and B16 tumor extracts where ineffective, or actually promoted tumor growth, respectively. Furthermore, dendritic cells were able to prime tumor immunity when pulsed with the placental xenoantigens. While vaccination-induced tumor regression was abolished in mice depleted of CD4 T cells, both CD4 and CD8 cells were needed to adoptively transfer immunity to naïve mice. Supporting the role of CD8 cells in controlling tumor growth are findings that only freshly isolated CD8 cells from immunized mice were capable of inducing tumor cell caspases-3 activation ex vivo. These data suggest feasibility of using xenogeneic placental preparations as a multivalent vaccine potently targeting not just tumor antigens, but processes that are essential for tumor maintenance of malignant potential.

Journal Article↗

PubMed2006

A novel method of modifying immune responses by vaccination with lipiodol-siRNA mixtures.

The dendritic cell (DC) possesses the ability to stimulate both T helper 1 (Th1) and Th2 responses depending on activation stimuli. Although it is known that chemically or genetically modified DC can be used therapeutically to steer immune responses towards either Th1 or Th2, cellular therapy with ex vivo manipulated DC is clinically difficult. Here we demonstrate a novel method of switching immune responses from Th1 to Th2 through in vivo immune modulation by administration of siRNA. We demonstrate that siRNA targeting of the IL-12p35 gene leads to a Th2 bias in vitro through an IL-10 dependent mechanism. In vivo administration of siRNA admixed with the oil-based contrast agent lipiodol in the presence of antigen and adjuvant induced a deviation in recall response to reduced production of IFN-gamma and augmented IL-4 response using either KLH or ovalbumin. This simple method of in vivo modification of immune response possesses therapeutic potential in Th1-mediated diseases such as multiple sclerosis and autoimmune diabetes.

Journal Article↗

PubMed2006

Tumor growth parameters of in-vivo human breast carcinoma: a proposed mathematical model for tumor growth kinetics.

Many mathematical models have been proposed to study tumor growth parameters in vivo. Nevertheless most of the medical models have given variable results even when experimental conditions are exactly the same. There are multiple factors that are capable of affecting tumor growth that should be taken into account when proposing a mathematical model for tumor growth in vivo. We discuss here own proposed model for tumor growth kinetics utilizing a modified Gompertz function that better responds to the growth characteristic of in "vivo" tumors.

Breast Neoplasms↗

PubMed2005

Cancer is a functional repair tissue.

When a wound occurs, growth and repair genes (GR genes, such as oncogenes, proto-oncogenes, etc.) in surrounding cells are activated and secretion of growth and repair factors (GR factors, such as growth, stem cell, and stimulating factors, etc.) is induced to heal the wound. However, if the wound is persistent due to chronic physical (radiation, electromagnetic field, trauma, particles, etc.), chemical (carcinogens, toxic chemicals, heavy metals etc.) or biological (aging, free radicals, inflammation, nutrient deficiency, bacteria and virus infections, stress, etc.) damage, amplification of GR gene activation in surrounding cells may lead to a clinical cancer. Based on the commonalities between cancer and wound healing, a new hypothesis of cancer is presented: malignancies are not passive mutated useless masses; rather, they are functional tissues produced by GR gene activation to secrete GR factors in an effort to heal persistent wounds in the body. Based on the hypothesis, current cancer treatments aimed at killing cancer cells only may be misguided. The logical extension of the hypothesis is that cancer treatment focused on wound healing by limiting causes of persistent wounds, providing repair cells, GR factors, and substrates required by repair cells may yield more fruitful results than treatments focused on killing cancer cells alone. Spontaneous regressions of cancer, although rare, may be successful examples of serendipitous spontaneous wound healing. Standard therapies aimed at killing cancer cells, should be limited to adjuvant status for limiting symptoms or buying time for completion of the wound healing process. Attempts to destroy cancer cells without healing underlying persistent wounds will allow for eventual recurrence.

Animals↗

PubMed2005

Orthomolecular oncology review: ascorbic acid and cancer 25 years later.

The effect of ascorbic acid on cancer has been a subject of great controversy. This is a follow-up review of the 1979 article by Cameron, Pauling, and Leibovitz published in Cancer Research. In this updated version, the authors address general aspects of ascorbic acid and cancer that have been presented before, while reviewing, analyzing, and updating new existing literature on the subject. In addition, they present and discuss their own mechanistic hypothesis on the effect of ascorbic acid on the cancer cell. The objective of this review is to provide an updated scientific basis for the use of ascorbic acid, especially intravenously as adjuvant treatment in pharmacological nutritional oncology.

Antioxidants↗

PubMed2005

A pilot clinical study of continuous intravenous ascorbate in terminal cancer patients.

Case studies suggest that vitamin C, given intravenously at doses of 10-100 grams/day can improve patient well being and in some cases, reduce tumor size. While ascorbate is generally considered safe, clinical data on high intravenous doses is limited. Twenty-four late stage terminal cancer patients were given continuous infusions of 150 to 710 mg/kg/day for up to eight weeks. Blood chemistry and blood count profiles were obtained at roughly one-week intervals while patient health, adverse events and tumor progression were monitored. The majority of patients were vitamin C deficient prior to treatment. Intravenous infusions increased plasma ascorbate concentrations to a mean of 1.1 mM. The most common adverse events reported were nausea, edema, and dry mouth or skin; and these were generally minor. Two Grade 3 adverse events 'possibly related' to the agent were reported: one patient with a history of renal calculi developed a kidney stone after thirteen days of treatment and another patient experienced hypokalemia after six weeks of treatment. White blood cell counts were stable while hemoglobin and hematocrit levels dropped slightly during treatment, consistent with trends observed prior to therapy. Blood creatinine, BUN, glucose, and uric acid concentrations decreased or remained stable during therapy, suggesting that ascorbate infusions did not adversely affect renal function. One patient had stable disease and continued the treatment for forty-eight weeks. These data suggest that intravenous vitamin C therapy for cancer is relatively safe, provided the patient does not have a history of kidney stone formation.

Ascorbic Acid↗

PubMed2004

L-ascorbic acid represses constitutive activation of NF-kappaB and COX-2 expression in human acute myeloid leukemia, HL-60.

There is increasing evidence that L-ascorbic acid (LAA) is selectively toxic to some types of cancer cells at pharmacological concentrations, functioning as a pro-oxidant rather than as an anti-oxidant. However, the molecular mechanisms by which LAA initiates cellular signaling leading to cell death are still unclear. In an effort to gain insight into these mechanisms, the effects of LAA on eukaryotic transcription nuclear factor NF-kappaB and cyclooxygenase-2 (COX-2) expression were investigated. In the present study, LAA suppressed DNA binding activity of NF-kappaB, composed of a p65/p50 heterodimer, through inhibition of degradation of inhibitory kappaB-alpha (IkappaB-alpha) and prevention of nuclear translocation of p65. The inhibitory effect of LAA on NF-kappaB activity was dependent upon glutathione levels in HL-60 cells, as well as generation of H2O2 but not superoxide anion. LAA also downregulated the expression of COX-2, which has a NF-kappaB binding site on its promoter, through repressing NF-kappaB DNA binding activity. Moreover, cotreatment of 1 microM arsenic trioxide (As2O3) with various concentrations of LAA enhanced an LAA-induced repression of NF-kappaB activity and COX-2 expression. In conclusion, our data suggest that LAA exerts its anti-tumor activity through downregulation of NF-kappaB activity and COX-2 expression, and these inhibitory effects can be enhanced by co-treatment with As2O3.

Apoptosis↗

PubMed2004

Cell membrane fatty acid composition differs between normal and malignant cell lines.

Twenty-eight fatty acids (C8:0 to C24:l n-9) were measured by gas chromatography in four normal cell lines (C3H / 10T1 / 2, CCD-18Co, CCD-25SK and CCD-37Lu) and seven cancer cell lines (C-41, Caov-3, LS-180, PC-3, SK-MEL-28, SK-MES-1 and U-87 MG). Results show differences in the content and proportions of fatty acids when comparing cancer cell lines with their normal counterparts. Cancer cell lines showed lower C20: 4 n-6, C24:1 n-9, polyunsaturated fatty acids (PUFA's) and ratios of C20:4 n-6 to C20:5 n-3 and C16:0 to C18:1 n-9 and stearic to oleic (SA/OA) than their normal counterparts. All cancer cell lines had SA/OA ratios lower than 7.0 while normal cell lines had ratios greater than 0.7 (p<0.05). In addition, the ratios of total saturated fatty acids (SFA) to PUFA'S and the concentration of C18:1 n-9, C18:2 n-6, C20:5 n-3 were higher in cancer cell lines as compared to normal cell lines. A positive correlation was detected between C16:0 and longer SFA'S (r = +0.511, p<0.05) in normal cell lines whereas a negative correlation (r=0.608, p<0.05) was obtained for malignant cell lines. Moreover, cancerous cell lines exhibited a particular desaturation defect and an abnormal incorporation of C18:2 n-6 and C20-4 n-6 fatty acids.

Animals↗

PubMed2004

Intravenous vitamin C as a chemotherapy agent: a report on clinical cases.

A series of seven cases are presented in which intravenous vitamin C has been used as antineoplastic agent in the treatment of different types of cancers. The cancers cases reviewed are the following: Renal cell carcinoma (2), Colorectal cancer (1), Pancreatic cancer (1), Non-Hodgkin's lymphoma (2) and breast cancer (1). Toxic reactions were not observed at these high doses of intravenous Vitamin C. All patients were prescreened for Glucose 6--phosphate dehydrogenase deficiency before administering intravenous Vitamin C in order to prevent hemolysis.

Aged↗

PubMed2003

Intravenous ascorbic acid: protocol for its application and use.

High dose intravenous(i.v.) ascorbic acid (AA) has been used as therapy for infectious disease from bacterial and viral origin and adjuvant therapy for cancer. In this publication we describe a clinical protocol that has been developed over the past twenty years utilizing high dose i.v. AA as therapy for cancer. This includes principles of treatment, rationale, baseline workup, infusion protocol, precautions and side effects.

Anti-Infective Agents↗

PubMed2002

Inhibition of human breast carcinoma cell proliferation by ascorbate and copper.

We tested the effect of different concentrations of ascorbic acid (AA), 50, 100, 250 mg/500 mg/dL) with copper sulfate (CS), 10 mg/dL) on human breast carcinoma (MDA-MB231) cell proliferation in vitro. Cell proliferation was measured using a colori-metric assay (Cell proliferation kit II (XTT), Boehringer, NJ). The results of the mean absorbance of the tissue culture at different AA concentrations and a constant CS concentration were as follow: 0.82 +/- 0.03 (control, mean +/- SE), 0.64 +/- 0.02 (CS above); 0.48 +/- 0.03 (50 mg/dL) AA), 0.21 +/- 0.02 (100 mg/dL), 0.08 +/- 0.01 (250 mg/dL) AA, 0.60 +/- 0.05 (500 mg/dL). These results show that a combination of AA and CS inhibits human breast carcinoma cell proliferation in vitro. This cell proliferation inhibitory effect is directly proportional to the AA concentration with the exception of the 500 mg/dL AA dose. This chemotherapeutic effect was optimally enhanced when AA was added at a concentration of 250 mg/dL. The AA concentrations of 500 mg/dL had a biphasic effect on tumor cell proliferation probably due to back and forth redox reactions between AA and dehydroascorbic acid in a closed system. This study provides preliminary evidence that AA and SC can be used as biological response modifiers (BRM) for tumor growth inhibition.

Ascorbic Acid↗

PubMed2002

Orthomolecular oncology: a mechanistic view of intravenous ascorbate's chemotherapeutic activity.

The effect of vitamin C in cancer has been a subject of great controversy; mainly because of the inconsistent results obtained by oral intakes of ascorbate when used as an anticancer agent. We believe the intravenous application of ascorbate will provide more consistent results in cancer patients since Vitamin C blood levels attained are substantially higher in a range proven cytotoxic to malignant cells. In this article we will present and discuss our proposed mechanism on the chemotherapeutic activity exhibited by ascorbate.

Antioxidants↗

PubMed2002

Effects of a high molecular mass Convolvulus arvensis extract on tumor growth and angiogenesis.

BACKGROUND: Plant materials represent promising sources of anti-cancer agents. We developed and tested a novel extract from the ubiquitous plant Convolvulus arvensis. MATERIALS AND METHODS: Convolvulus arvensis components were extracted in boiling water, and small molecules were removed by high-pressure filtration. The extract's biological activity was assessed by measuring its effects on S-180 fibrosarcoma growth in Kun Ming mice and on heparin-induced angiogenesis in chick embryos. We also examined the extract's effects on lymphocytes ex vivo and tumor cell growth in vitro. RESULTS: The extract (primarily proteins and polysaccharides) inhibited tumor growth in a dose-dependent fashion when administered orally. At the highest dose tested, 200 mg/kg/day, tumor growth was inhibited by roughly seventy percent. Subcutaneous or intraperitoneal administration at 50 mg/kg/day also inhibited tumor growth by over seventy percent. The extract's acute LD50 in Kun Ming mice was 500 mg/kg/day when injected, indicating that tumor growth inhibition occurred at non-toxic doses. It inhibited angiogenesis in chick embryos, improved lymphocyte survival ex vivo, and enhanced yeast phagocytosis, but did not kill tumor cells in culture. CONCLUSION: High molecular mass extract deserves further study as an anti-cancer agent.

Animals↗