Cancer Abstracts 5

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Ascorbic acid: chemistry, biology and the treatment of cancer.
            (Du et al., 2012) Download
Since the discovery of vitamin C, the number of its known biological functions is continually expanding. Both the names ascorbic acid and vitamin C reflect its antiscorbutic properties due to its role in the synthesis of collagen in connective tissues. Ascorbate acts as an electron-donor keeping iron in the ferrous state thereby maintaining the full activity of collagen hydroxylases; parallel reactions with a variety of dioxygenases affect the expression of a wide array of genes, for example via the HIF system, as well as via the epigenetic landscape of cells and tissues. In fact, all known physiological and biochemical functions of ascorbate are due to its action as an electron donor. The ability to donate one or two electrons makes AscH(-) an excellent reducing agent and antioxidant. Ascorbate readily undergoes pH-dependent autoxidation producing hydrogen peroxide (H(2)O(2)). In the presence of catalytic metals this oxidation is accelerated. In this review, we show that the chemical and biochemical nature of ascorbate contribute to its antioxidant as well as its prooxidant properties. Recent pharmacokinetic data indicate that intravenous (i.v.) administration of ascorbate bypasses the tight control of the gut producing highly elevated plasma levels; ascorbate at very high levels can act as prodrug to deliver a significant flux of H(2)O(2) to tumors. This new knowledge has rekindled interest and spurred new research into the clinical potential of pharmacological ascorbate. Knowledge and understanding of the mechanisms of action of pharmacological ascorbate bring a rationale to its use to treat disease especially the use of i.v. delivery of pharmacological ascorbate as an adjuvant in the treatment of cancer.

Multivitamins in the prevention of cancer in men: the Physicians' Health Study II randomized controlled trial.
            (Gaziano et al., 2012) Download
CONTEXT:  Multivitamin preparations are the most common dietary supplement, taken by at least one-third of all US adults. Observational studies have not provided evidence regarding associations of multivitamin use with total and site-specific cancer incidence or mortality. OBJECTIVE:  To determine whether long-term multivitamin supplementation decreases the risk of total and site-specific cancer events among men. DESIGN, SETTING, AND PARTICIPANTS:  A large-scale, randomized, double-blind, placebo controlled trial (Physicians" Health Study II) of 14 641 male US physicians initially aged 50 years or older (mean [SD] age, 64.3 [9.2] years), including 1312 men with a history of cancer at randomization, enrolled in a common multivitamin study that began in 1997 with treatment and follow-up through June 1, 2011. INTERVENTION:  Daily multivitamin or placebo. MAIN OUTCOME MEASURES:  Total cancer (excluding nonmelanoma skin cancer), with prostate, colorectal, and other site-specific cancers among the secondary end points. RESULTS:  During a median (interquartile range) follow-up of 11.2 (10.7-13.3) years, there were 2669 men with confirmed cancer, including 1373 cases of prostate cancer and 210 cases of colorectal cancer. Compared with placebo, men taking a daily multivitamin had a statistically significant reduction in the incidence of total cancer (multivitamin and placebo groups, 17.0 and 18.3 events, respectively, per 1000 person-years; hazard ratio [HR], 0.92; 95% CI, 0.86-0.998; P=.04). There was no significant effect of a daily multivitamin on prostate cancer (multivitamin and placebo groups, 9.1 and 9.2 events, respectively, per 1000 person-years; HR, 0.98; 95% CI, 0.88-1.09; P=.76), colorectal cancer (multivitamin and placebo groups, 1.2 and 1.4 events, respectively, per 1000 person-years; HR, 0.89; 95% CI, 0.68-1.17; P=.39), or other site-specific cancers. There was no significant difference in the risk of cancer mortality (multivitamin and placebo groups, 4.9 and 5.6 events, respectively, per 1000 person-years; HR, 0.88; 95% CI, 0.77-1.01; P=.07). Daily multivitamin use was associated with a reduction in total cancer among 1312 men with a baseline history of cancer (HR, 0.73; 95% CI, 0.56-0.96; P=.02), but this did not differ significantly from that among 13 329 men initially without cancer (HR, 0.94; 95% CI, 0.87-1.02; P=.15; P for interaction=.07). Conclusion In this large prevention trial of male physicians, daily multivitamin supplementation modestly but significantly reduced the risk of total cancer. TRIAL REGISTRATION:  clinicaltrials.gov Identifier: NCT00270647.

Folate malabsorption and its influence on DNA methylation during cancer development.
            (Hamid, 2012) Download
The folate transport across the epithelial of the intestine, colon, kidney, and liver is essential for folate homeostasis. The relative localization of transporters in membranes is an important determinant for the vectorial flow of substrates across the epithelia. Folate deficiency is a highly prevalent vitamin deficiency in the world, and alcohol ingestion has been the major contributor. It can develop because of folate malabsorption in tissues, increased renal excretion dietary inadequacy, and altered hepatobiliary metabolism. Additionally, folate-mediated one-carbon metabolism is important for various cellular processes, including DNA synthesis and methylation. In this regard, the contribution of alcohol-associated and dietary folate deficiency to methylation patterns is under intense investigation, especially in cancer. The epigenetic events have increasing relevance in the development of strategies for early diagnosis, prevention, and treatment of cancer.

The metabolic advantage of tumor cells.
            (Israël and Schwartz, 2011) Download
1- Oncogenes express proteins of "Tyrosine kinase receptor pathways", a receptor family including insulin or IGF-Growth Hormone receptors. Other oncogenes alter the PP2A phosphatase brake over these kinases. 2- Experiments on pancreatectomized animals; treated with pure insulin or total pancreatic extracts, showed that choline in the extract, preserved them from hepatomas. Since choline is a methyle donor, and since methylation regulates PP2A, the choline protection may result from PP2A methylation, which then attenuates kinases. 3- Moreover, kinases activated by the boosted signaling pathway inactivate pyruvate kinase and pyruvate dehydrogenase. In addition, demethylated PP2A would no longer dephosphorylate these enzymes. A "bottleneck" between glycolysis and the oxidative-citrate cycle interrupts the glycolytic pyruvate supply now provided via proteolysis and alanine transamination. This pyruvate forms lactate (Warburg effect) and NAD+ for glycolysis. Lipolysis and fatty acids provide acetyl CoA; the citrate condensation increases, unusual oxaloacetate sources are available. ATP citrate lyase follows, supporting aberrant transaminations with glutaminolysis and tumor lipogenesis. Truncated urea cycles, increased polyamine synthesis, consume the methyl donor SAM favoring carcinogenesis. 4- The decrease of butyrate, a histone deacetylase inhibitor, elicits epigenic changes (PETEN, P53, IGFBP decrease; hexokinase, fetal-genes-M2, increase). 5- IGFBP stops binding the IGF - IGFR complex, it is perhaps no longer inherited by a single mitotic daughter cell; leading to two daughter cells with a mitotic capability. 6- An excess of IGF induces a decrease of the major histocompatibility complex MHC1, Natural killer lymphocytes should eliminate such cells that start the tumor, unless the fever prostaglandin PGE2 or inflammation, inhibit them...

Consequences of Cancer Treatment
            Macmillan 2013 Download
There are more than two million people living with cancer in the UK today, but not all of them are living well. Cancer and its treatment often leaves a gruelling physical and mental legacy for many years afterwards. It begs the question – do we really understand the true cost of being cured?


 

Dietary supplements and cancer prevention: balancing potential benefits against proven harms
            (Martinez et al., 2012) Download
Nutritional supplementation is now a multibillion-dollar industry, and about half of all US adults take supplements. Supplement use is fueled in part by the belief that nutritional supplements can ward off chronic disease, including cancer, although several expert committees and organizations have concluded that there is little to no scientific evidence that supplements reduce cancer risk. To the contrary, there is now evidence that high doses of some supplements increase cancer risk. Despite this evidence, marketing claims by the supplement industry continue to imply anticancer benefits. Insufficient government regulation of the marketing of dietary supplement products may continue to result in unsound advice to consumers. Both the scientific community and government regulators need to provide clear guidance to the public about the use of dietary supplements to lower cancer risk.

The cell clone ecology hypothesis and the cell fusion model of cancer progression and metastasis: history and experimental support.
            (Parris, 2006b) Download
The two-stage initiation-progression model of cancer is widely accepted. Although mutations explain initiation of neoplasia, the assumption that mutations are responsible for progression of neoplasia to cancer appears to have little experimental support. The "cell clone ecology hypothesis" explains why neoplasia evolve and the "cell fusion model of cancer progression and metastasis" describes how they evolve into clinically significant tumors. A brief history of important concepts and experiments is provided. Clinically significant cancers are effectively new parasite species that live, expand and evolve within the host. It is hypothesized that survival and fate of the parasite clones called "cancer" are governed by the principles of ecology. It is argued that while mutations or aneuploidy (asexual reproduction) can result in transient/self-limiting neoplasia, neither of these asexual modes of forming new karyotypes can maintain the ecologically fit parasites that develop into clinically significant cancer. Mutations and/or unstable genomes (aneuploidy) progressively degrade cell lines and if only these mechanisms were at work, neoplasia would spontaneously become extinct or benign (enfeebled) before reaching clinical significance (an example of "Muller's ratchet"). In the cell fusion model of (clinically significant) cancer progression and metastasis, cell-cell fusion is the essential element allowing normal cells or (transient) neoplasia to evolve into clinically significant cancers. Cell-cell fusion is required for producing and sustaining clinically significant cancer because it provides a sex-like mode of reproduction essential for an ecologically fit parasite organism. Cell-cell fusion provides the opportunity needed for tumors to rejuvenate cell lines containing abnormal genomes and rapidly evolve to acquire dramatically aggressive traits such as metastasis. Indeed, metastasis appears to require cell-cell fusion. Cell-cell fusion also partially overcomes erosion of teleomeres during clone expansion and allows the essential elements of a tumorigenic genome to hide from chemotherapy as recessive traits in cells with normal phenotypes and re-emerge (by cell-cell fusion) as a new cancer after the phenotypically cancerous cells have been eradicated by classical chemotherapy. Eradication of the cancer parasite cannot be routinely achieved by classical toxic chemotherapy alone or even by chemotherapy augmented with techniques needed to overcome anti-apoptotic traits of cancer cells. Direct chemical intervention against cell-cell fusion concurrent with classical toxic chemotherapy holds a promise of preventing re-lapse of the disease. Intervention against cell-cell fusion may also directly suppress metastasis based on the model presented here. The paper also summarizes work on the cell surface glycoprotein CD44 that implicates it as a key element in cell-cell fusion and hence cancer.

The cell clone ecology hypothesis and the cell fusion model of cancer progression and metastasis (II): three pathways for spontaneous cell-cell fusion and escape from the intercellular matrix.
            (Parris, 2006a) Download
The two-stage initiation-progression model of cancer is widely accepted. Initiation appears to result most often from accumulation of damage to the DNA expressed as multiple mutations in the phenotype. Unsymmetrical chromosome segregation during mitosis of normal or mutated cells produces aneuploid cells and also contributes to the evolution of neoplasia. However, it has been pointed out (Parris GE. Med Hypotheses 2005;65:993-4 and 2006;66:76-83) that DNA damage and loss of chromosomes are much more likely to lead the mutant clones of cells to extinction than to successful expansion (e.g., an example of Muller's Ratchet). It was argued that aneuploid neoplasia represent new parasite species that successfully evolve to devour their hosts by incorporating sex-like redistribution of chromosomes through spontaneous or virus-catalyzed cell-cell fusion into their life-cycle. Spontaneous cell-cell fusion is generally blocked by the intercellular matrix to which the cells are bound via surface adhesion molecules (frequently glycoproteins, e.g., CD44). In order for progression of matrix-contained neoplasia toward clinically significant cancer to occur, the parasite cells must escape from the matrix and fuse. Release from the matrix also allows the parasite cells to invade adjacent tissues and metastasize to remote locations. Both invasion and metastasis likely involve fusion of the migrating parasite cells with fusion-prone blast cells. There are at least three pathways through which parasite cells can be liberated from the confining matrix: (i) Their adhesion molecules may be modified (e.g., by hyper-glycosylation) so that they can no longer grip the matrix. (ii) Their adhesion molecules or matrix may be saturated with other ligands (e.g., polyamines). (iii) Their adhesion molecules may be cleaved from the cell surface or the matrix itself may be cleaved (e.g., by MMPs or ADAMs). It is hypothesized that mobilization of parasite cells and cell-cell fusion go hand-in-hand in the progression of neoplasia to clinically significant cancer through invasion and metastasis. The latency between tumor recognition and exposure to mutagens and the increased incidence of cancer with age can probably be related to slow breakdown of the intercellular matrix that provides a barrier to cell-cell fusion.

Phase I clinical trial to evaluate the safety, tolerability, and pharmacokinetics of high-dose intravenous ascorbic acid in patients with advanced cancer.
            (Stephenson et al., 2013) Download
PURPOSE:  This phase I clinical trial evaluated the safety, tolerability, and pharmacokinetics of high-dose intravenous (i.v.) ascorbic acid as a monotherapy in patients with advanced solid tumors refractory to standard therapy. METHODS:  Five cohorts of three patients received i.v. ascorbic acid administered at 1 g/min for 4 consecutive days/week for 4 weeks, starting at 30 g/m² in the first cohort. For subsequent cohorts, dose was increased by 20 g/m² until a maximum tolerated dose was found. RESULTS:  Ascorbic acid was eliminated by simple first-order kinetics. Half-life and clearance values were similar for all patients of all cohorts (2.0 ± 0.6 h, 21 ± 5 dL/h m², respectively). C(max) and AUC values increased proportionately with dose between 0 and 70 g/m², but appeared to reach maximal values at 70 g/m² (49 mM and 220 h mM, respectively). Doses of 70, 90, and 110 g/m² maintained levels at or above 10-20 mM for 5-6 h. All doses were well tolerated. No patient demonstrated an objective antitumor response. CONCLUSIONS:  Ascorbic acid administered i.v. at 1 g/min for 4 consecutive days/week for 4 weeks produced up to 49 mM ascorbic acid in patient's blood and was well tolerated. The recommended dose for future studies is 70-80 g/m².


 

References

Du, J, JJ Cullen, and GR Buettner (2012), ‘Ascorbic acid: chemistry, biology and the treatment of cancer.’, Biochim Biophys Acta, 1826 (2), 443-57. PubMed: 22728050
Gaziano, JM, et al. (2012), ‘Multivitamins in the prevention of cancer in men: the Physicians’ Health Study II randomized controlled trial.’, JAMA, 308 (18), 1871-80. PubMed: 23162860
Hamid, A (2012), ‘Folate malabsorption and its influence on DNA methylation during cancer development.’, DNA Cell Biol, PubMed: 22468673
Israël, M and L Schwartz (2011), ‘The metabolic advantage of tumor cells.’, Mol Cancer, 10 70. PubMed: 21649891
Martinez, M. E., et al. (2012), ‘Dietary supplements and cancer prevention: balancing potential benefits against proven harms’, J Natl Cancer Inst, 104 (10), 732-39. PubMed: 22534785
Parris, G (2006a), ‘The cell clone ecology hypothesis and the cell fusion model of cancer progression and metastasis (II): three pathways for spontaneous cell-cell fusion and escape from the intercellular matrix.’, Med Hypotheses, 67 (1), 172-76. PubMed: 16516400
Parris, GE (2006b), ‘The cell clone ecology hypothesis and the cell fusion model of cancer progression and metastasis: history and experimental support.’, Med Hypotheses, 66 (1), 76-83. PubMed: 16169667
Stephenson, CM, et al. (2013), ‘Phase I clinical trial to evaluate the safety, tolerability, and pharmacokinetics of high-dose intravenous ascorbic acid in patients with advanced cancer.’, Cancer Chemother Pharmacol, 72 (1), 139-46. PubMed: 23670640