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Rich66 · 11-25-2009, 11:50 AM

Updated above with phase I IV ascorbic acid monotherapy in advanced Ca: no responses. May be of use with other therapies or in earlier cancer.

Anticancer Res. 2003 Jul-Aug;23(4):3279-87.
The in vitro antitumor activity of vitamins C and K3 against ovarian carcinoma.

von Gruenigen VE, Jamison JM, Gilloteaux J, Lorimer HE, Summers M, Pollard RR, Gwin CA, Summers JL.
Department of Obstetrics and Gynecology, SUMMA Health System, 525 E. Market Street, Akron, OH 44309, USA. vivian.vongruenigen@uhhs.com
BACKGROUND: The objective was to evaluate the cytotoxic effect and mechanism of action of vitamins C (VC) and K3 (VK3) on ovarian carcinoma. MATERIALS AND METHODS: Cytotoxicity assays were performed on ovarian cancer cell lines with VC, VK3 or a VC/VK3 combination. FIC index was employed to evaluate synergism. Flow cytometry was accomplished at 90% cytotoxic doses. Light, transmission electron microscopy and DNA isolation were performed. RESULTS: Antitumor activity was exhibited by both VC, VK3 and VC/VK3. VC/VK3 demonstrated synergistic activity. VC/VK3 may induce a G1 block in the cell cycle. Combined vitamin treatment resulted in cells that maintain apparently intact nuclei while extruding pieces of organelle-free cytoplasm. Degradation of chromosomal DNA was observed. CONCLUSION: Cell death (autoschizis) displayed characteristics of both apoptosis and necrosis. The cytotoxic effects observed may enable vitamins C and K3 to play an adjuvant role in the treatment of ovarian cancer.

PMID: 12926064 [PubMed - indexed for MEDLINE]

Eur J Med Chem. 2003 May;38(5):451-7.
The association of vitamins C and K3 kills cancer cells mainly by autoschizis, a novel form of cell death. Basis for their potential use as coadjuvants in anticancer therapy.

Verrax J, Cadrobbi J, Delvaux M, Jamison JM, Gilloteaux J, Summers JL, Taper HS, Buc Calderon P.
Unité de Pharmacocinétique, Métabolisme, Nutrition et Toxicologie, Département des sciences pharmaceutiques, Université Catholique de Louvain, Brussels, Belgium.

Deficiency of alkaline and acid DNase is a hallmark in all non-necrotic cancer cells in animals and humans. These enzymes are reactivated at early stages of cancer cell death by vitamin C (acid DNase) and vitamin K(3) (alkaline DNase). Moreover, the coadministration of these vitamins (in a ratio of 100:1, for C and K(3), respectively) produced selective cancer cell death. Detailed morphological studies indicated that cell death is produced mainly by autoschizis, a new type of cancer cell death. Several mechanisms are involved in such a cell death induced by CK(3), they included: formation of H(2)O(2) during vitamins redox cycling, oxidative stress, DNA fragmentation, no caspase-3 activation, and cell membrane injury with progressive loss of organelle-free cytoplasm. Changes in the phosphorylation level of some critical proteins leading to inactivation of NF-kappaB appear as main intracellular signal transduction pathways. The increase knowledge in the mechanisms underlying cancer cells death by CK(3) may ameliorate the techniques of their in vivo administration. The aim is to prepare the introduction of the association of vitamins C and K(3) into human clinics as a new, non-toxic adjuvant cancer therapy.

PMID: 12767595 [PubMed - indexed for MEDLINE]

Br J Cancer. 2010 Mar 23. [Epub ahead of print]
alpha-Tocopheryl succinate promotes selective cell death induced by vitamin K3 in combination with ascorbate.

Tomasetti M, Strafella E, Staffolani S, Santarelli L, Neuzil J, Guerrieri R.
Department of Molecular Pathology and Innovative Therapies, Polytechnic University of Marche, Ancona 60020, Italy.
Background: A strategy to reduce the secondary effects of anti-cancer agents is to potentiate the therapeutic effect by their combination. A combination of vitamin K3 (VK3) and ascorbic acid (AA) exhibited an anti-cancer synergistic effect, associated with extracellular production of H(2)O(2) that promoted cell death. Methods: The redox-silent vitamin E analogue alpha-tocopheryl succinate (alpha-TOS) was used in combination with VK3 and AA to evaluate their effect on prostate cancer cells.

Results: Prostate cancer cells were sensitive to alpha-TOS and VK3 treatment, but resistant to AA upto 3.2 mM. When combined, a synergistic effect was found for VK3-AA, whereas alpha-TOS-VK3 and alpha-TOS-AA combination showed an antagonist and additive effect, respectively. However, sub-lethal doses of AA-VK3 combination combined with a sub-toxic dose of alpha-TOS showed to induce efficient cell death that resembles autoschizis. Associated with this cell demise, lipid peroxidation, DNA damage, cytoskeleton alteration, lysosomal-mitochondrial perturbation, and release of cytochrome c without caspase activation were observed. Inhibition of lysosomal proteases did not attenuate cell death induced by the combined agents. Furthermore, cell deaths by apoptosis and autoschizis were detected.
Conclusion:These finding support the emerging idea that synergistic combinations of some agents can overcome toxicity and other side-effects associated with high doses of single drugs creating the opportunity for therapeutically relevant selectivity.
British Journal of Cancer advance online publication, 23 March 2010; doi:10.1038/sj.bjc.6605617 www.bjcancer.com.

PMID: 20332775 [PubMed - as supplied by publisher]

Dis Esophagus. 2009 Nov 23. [Epub ahead of print]
Pilot translational study of dietary vitamin C supplementation in Barrett's esophagus.

Babar M, Abdel-Latif MM, Ravi N, Murphy A, Byrne PJ, Kelleher D, Reynolds JV.
Departments of Clinical Surgery and Clinical Medicine, Trinity Centre for Health Sciences, St. James's Hospital, Dublin, Ireland.
Abstract

The transcription factor Nuclear factor kappa B (NF-kappaB) is central to the regulation of genes encoding for mediators of inflammation and carcinogenesis. In the esophagus, NF-kappaB is progressively activated from inflammation to Barrett's metaplasia and adenocarcinoma. Vitamin C, an antioxidant, can inhibit NF-kappaB in in vitro models, and the aim of this study was to prospectively assess the effect of supplemental vitamin C on NF-kappaB and associated cytokines in patients with Barrett's esophagus. Twenty-five patients with long-segment Barrett's and specialized intestinal metaplasia received dietary vitamin C (1000 mg/day) orally for four weeks, and had pre- and post-vitamin C endoscopic biopsies. NF-kappaB activity (activated p50 and p65 subunits) of nuclear extracts was assessed using the Active Motif NF-kappaB assay, and cytokines and growth factors were measured using the Evidence Investigator biochip array. NF-kappaB and related pro-inflammatory cytokines and growth factors (IL-8, VEGF, IL-10) were activated in all Barrett's tissue pre-treatment. Down-regulation in activated NF-kappaB and cytokines was observed in 8/25 (35%) patients. Dietary vitamin C supplementation may down-regulate pro-inflammatory markers in a subset of Barrett's patients. Further studies with larger numbers of endpoints will be needed to further evaluate this effect.

PMID: 19930402 [PubMed - as supplied by publisher]

http://www.nzherald.co.nz/nz/news/ar...ectid=10659956

Vitamin C blocks tumour growth: study

By Martin Johnston
4:00 AM Tuesday Jul 20, 2010 New Zealand researchers have established that vitamin C can help to block the growth of cancer cells - an important experimental finding they expect could be quickly adopted into cancer treatment.
The role of vitamin C in cancer treatment has been controversial for decades, with contradictory findings from various studies. In an international review of 20 human trials of vitamin C and other "anti-oxidant" supplements, the influential Cochrane Collaboration found no convincing evidence that they could prevent gastro-intestinal cancers - and said they "even seem to increase mortality".
But now a team from Otago University at Christchurch, in a paper published in leading international journal Cancer Research, have shown that vitamin C has a role in controlling tumour growth.
They say their study of tumorous and normal tissue samples from women with cancer of the uterine lining provides the first direct evidence of a link between vitamin C and a protein called HIF-1.
HIF (hypoxia inducible factor)-1 is considered a key protein in tumour survival. High activity of it promotes tumour growth and resistance to chemotherapy and radiotherapy and is linked with a poor prognosis for patients.
The Christchurch study, led by Associate Professor Margreet Vissers, of the university's Free Radical Research Group, found that high-grade tumours had around 40 per cent less vitamin C than matched, adjacent, normal tissue.
The researchers say their study suggests that restoring the vitamin C levels in tumours would limit factors that promote tumour growth, and recommend animal trials to test the hypothesis.
Professor Vissers said the study suggested it would be beneficial for people with cancer cells to have more vitamin C. It could help restrict the rate of tumour growth, increase responsiveness to chemotherapy and might prevent formation of solid tumours.
"There's enough information now for people to be seriously thinking about doing this, to apply this to the clinic or be setting up some clinical trials," she told the Herald yesterday.
"Anti-oxidant supplementation may not end up delivering any more vitamin C to the tumour.
"Just supplementing people may not actually have the effect that you want because you haven't done it in the right way," Professor Vissers said.
She said vitamin C levels in the body could be raised only to a certain level by oral supplementation.
Intravenous injections could achieve a higher level.
"That's the question: what's the best way to deliver vitamin C to the tumour."
By Martin Johnston

Copyright ©2010, APN Holdings NZ Limited

11-25-2009, 11:50 AM	#5
Rich66 Senior Member Join Date: Feb 2008 Location: South East Wisconsin Posts: 3,431	Re: Vitamin C Updated above with phase I IV ascorbic acid monotherapy in advanced Ca: no responses. May be of use with other therapies or in earlier cancer. Anticancer Res. 2003 Jul-Aug;23(4):3279-87. The in vitro antitumor activity of vitamins C and K3 against ovarian carcinoma. von Gruenigen VE, Jamison JM, Gilloteaux J, Lorimer HE, Summers M, Pollard RR, Gwin CA, Summers JL. Department of Obstetrics and Gynecology, SUMMA Health System, 525 E. Market Street, Akron, OH 44309, USA. vivian.vongruenigen@uhhs.com BACKGROUND: The objective was to evaluate the cytotoxic effect and mechanism of action of vitamins C (VC) and K3 (VK3) on ovarian carcinoma. MATERIALS AND METHODS: Cytotoxicity assays were performed on ovarian cancer cell lines with VC, VK3 or a VC/VK3 combination. FIC index was employed to evaluate synergism. Flow cytometry was accomplished at 90% cytotoxic doses. Light, transmission electron microscopy and DNA isolation were performed. RESULTS: Antitumor activity was exhibited by both VC, VK3 and VC/VK3. VC/VK3 demonstrated synergistic activity. VC/VK3 may induce a G1 block in the cell cycle. Combined vitamin treatment resulted in cells that maintain apparently intact nuclei while extruding pieces of organelle-free cytoplasm. Degradation of chromosomal DNA was observed. CONCLUSION: Cell death (autoschizis) displayed characteristics of both apoptosis and necrosis. The cytotoxic effects observed may enable vitamins C and K3 to play an adjuvant role in the treatment of ovarian cancer. PMID: 12926064 [PubMed - indexed for MEDLINE] Eur J Med Chem. 2003 May;38(5):451-7. The association of vitamins C and K3 kills cancer cells mainly by autoschizis, a novel form of cell death. Basis for their potential use as coadjuvants in anticancer therapy. Verrax J, Cadrobbi J, Delvaux M, Jamison JM, Gilloteaux J, Summers JL, Taper HS, Buc Calderon P. Unité de Pharmacocinétique, Métabolisme, Nutrition et Toxicologie, Département des sciences pharmaceutiques, Université Catholique de Louvain, Brussels, Belgium. Deficiency of alkaline and acid DNase is a hallmark in all non-necrotic cancer cells in animals and humans. These enzymes are reactivated at early stages of cancer cell death by vitamin C (acid DNase) and vitamin K(3) (alkaline DNase). Moreover, the coadministration of these vitamins (in a ratio of 100:1, for C and K(3), respectively) produced selective cancer cell death. Detailed morphological studies indicated that cell death is produced mainly by autoschizis, a new type of cancer cell death. Several mechanisms are involved in such a cell death induced by CK(3), they included: formation of H(2)O(2) during vitamins redox cycling, oxidative stress, DNA fragmentation, no caspase-3 activation, and cell membrane injury with progressive loss of organelle-free cytoplasm. Changes in the phosphorylation level of some critical proteins leading to inactivation of NF-kappaB appear as main intracellular signal transduction pathways. The increase knowledge in the mechanisms underlying cancer cells death by CK(3) may ameliorate the techniques of their in vivo administration. The aim is to prepare the introduction of the association of vitamins C and K(3) into human clinics as a new, non-toxic adjuvant cancer therapy. PMID: 12767595 [PubMed - indexed for MEDLINE] Br J Cancer. 2010 Mar 23. [Epub ahead of print] alpha-Tocopheryl succinate promotes selective cell death induced by vitamin K3 in combination with ascorbate. Tomasetti M, Strafella E, Staffolani S, Santarelli L, Neuzil J, Guerrieri R. Department of Molecular Pathology and Innovative Therapies, Polytechnic University of Marche, Ancona 60020, Italy. Background: A strategy to reduce the secondary effects of anti-cancer agents is to potentiate the therapeutic effect by their combination. A combination of vitamin K3 (VK3) and ascorbic acid (AA) exhibited an anti-cancer synergistic effect, associated with extracellular production of H(2)O(2) that promoted cell death. Methods: The redox-silent vitamin E analogue alpha-tocopheryl succinate (alpha-TOS) was used in combination with VK3 and AA to evaluate their effect on prostate cancer cells. Results: Prostate cancer cells were sensitive to alpha-TOS and VK3 treatment, but resistant to AA upto 3.2 mM. When combined, a synergistic effect was found for VK3-AA, whereas alpha-TOS-VK3 and alpha-TOS-AA combination showed an antagonist and additive effect, respectively. However, sub-lethal doses of AA-VK3 combination combined with a sub-toxic dose of alpha-TOS showed to induce efficient cell death that resembles autoschizis. Associated with this cell demise, lipid peroxidation, DNA damage, cytoskeleton alteration, lysosomal-mitochondrial perturbation, and release of cytochrome c without caspase activation were observed. Inhibition of lysosomal proteases did not attenuate cell death induced by the combined agents. Furthermore, cell deaths by apoptosis and autoschizis were detected. Conclusion:These finding support the emerging idea that synergistic combinations of some agents can overcome toxicity and other side-effects associated with high doses of single drugs creating the opportunity for therapeutically relevant selectivity. British Journal of Cancer advance online publication, 23 March 2010; doi:10.1038/sj.bjc.6605617 www.bjcancer.com. PMID: 20332775 [PubMed - as supplied by publisher] Dis Esophagus. 2009 Nov 23. [Epub ahead of print] Pilot translational study of dietary vitamin C supplementation in Barrett's esophagus. Babar M, Abdel-Latif MM, Ravi N, Murphy A, Byrne PJ, Kelleher D, Reynolds JV. Departments of Clinical Surgery and Clinical Medicine, Trinity Centre for Health Sciences, St. James's Hospital, Dublin, Ireland. Abstract The transcription factor Nuclear factor kappa B (NF-kappaB) is central to the regulation of genes encoding for mediators of inflammation and carcinogenesis. In the esophagus, NF-kappaB is progressively activated from inflammation to Barrett's metaplasia and adenocarcinoma. Vitamin C, an antioxidant, can inhibit NF-kappaB in in vitro models, and the aim of this study was to prospectively assess the effect of supplemental vitamin C on NF-kappaB and associated cytokines in patients with Barrett's esophagus. Twenty-five patients with long-segment Barrett's and specialized intestinal metaplasia received dietary vitamin C (1000 mg/day) orally for four weeks, and had pre- and post-vitamin C endoscopic biopsies. NF-kappaB activity (activated p50 and p65 subunits) of nuclear extracts was assessed using the Active Motif NF-kappaB assay, and cytokines and growth factors were measured using the Evidence Investigator biochip array. NF-kappaB and related pro-inflammatory cytokines and growth factors (IL-8, VEGF, IL-10) were activated in all Barrett's tissue pre-treatment. Down-regulation in activated NF-kappaB and cytokines was observed in 8/25 (35%) patients. Dietary vitamin C supplementation may down-regulate pro-inflammatory markers in a subset of Barrett's patients. Further studies with larger numbers of endpoints will be needed to further evaluate this effect. PMID: 19930402 [PubMed - as supplied by publisher] http://www.nzherald.co.nz/nz/news/ar...ectid=10659956 Vitamin C blocks tumour growth: study By Martin Johnston 4:00 AM Tuesday Jul 20, 2010 New Zealand researchers have established that vitamin C can help to block the growth of cancer cells - an important experimental finding they expect could be quickly adopted into cancer treatment. The role of vitamin C in cancer treatment has been controversial for decades, with contradictory findings from various studies. In an international review of 20 human trials of vitamin C and other "anti-oxidant" supplements, the influential Cochrane Collaboration found no convincing evidence that they could prevent gastro-intestinal cancers - and said they "even seem to increase mortality". But now a team from Otago University at Christchurch, in a paper published in leading international journal Cancer Research, have shown that vitamin C has a role in controlling tumour growth. They say their study of tumorous and normal tissue samples from women with cancer of the uterine lining provides the first direct evidence of a link between vitamin C and a protein called HIF-1. HIF (hypoxia inducible factor)-1 is considered a key protein in tumour survival. High activity of it promotes tumour growth and resistance to chemotherapy and radiotherapy and is linked with a poor prognosis for patients. The Christchurch study, led by Associate Professor Margreet Vissers, of the university's Free Radical Research Group, found that high-grade tumours had around 40 per cent less vitamin C than matched, adjacent, normal tissue. The researchers say their study suggests that restoring the vitamin C levels in tumours would limit factors that promote tumour growth, and recommend animal trials to test the hypothesis. Professor Vissers said the study suggested it would be beneficial for people with cancer cells to have more vitamin C. It could help restrict the rate of tumour growth, increase responsiveness to chemotherapy and might prevent formation of solid tumours. "There's enough information now for people to be seriously thinking about doing this, to apply this to the clinic or be setting up some clinical trials," she told the Herald yesterday. "Anti-oxidant supplementation may not end up delivering any more vitamin C to the tumour. "Just supplementing people may not actually have the effect that you want because you haven't done it in the right way," Professor Vissers said. She said vitamin C levels in the body could be raised only to a certain level by oral supplementation. Intravenous injections could achieve a higher level. "That's the question: what's the best way to deliver vitamin C to the tumour." By Martin Johnston Copyright ©2010, APN Holdings NZ Limited __________________ Mom's treatment history (link)