Sunday, February 17, 2013

Genetic and Epigenetic Mechanisms in metal carcinogenesis (6 of 6 in a series)

This is the last post in the series.  I started this post back in December prior to the trial in LA which have been the main content of the posts in the last month or so.

This is a difficult piece to understand. I am not a scientist but have done my best to suss out the messages.

Part One in the series can be found here: http://www.mydepuyhiprecall.com/2013/01/genetic-and-epigenetic-mechanisms-in.html

Part Two can be found here:http://www.mydepuyhiprecall.com/2013/01/genetic-and-epigenetic-mechanisms-in_7.html

Part Three: chromium 6 metabolism and DNA Damage:http://www.mydepuyhiprecall.com/2013/01/genetic-and-epigenetic-mechanisms-in_8.html

Part Four: Chromium (Cr)-DNA Adducts: http://www.mydepuyhiprecall.com/2013/01/genetic-and-epigenetic-mechanisms-in.html

Part Five: DNA Base Damage , Genomic Instability, Toxicity and Cr 6 carcinogenesis.  http://www.mydepuyhiprecall.com/2013/01/genetic-and-epigenetic-mechanisms-in_16.html

 

Part Six:  Chromium V1 as a Co carcinogen is below.  This is the last in the series

1.  While there are well documented situations of chromium 6 as a single agent , such as those encountered in chromate production, the majority of other occupational and probably all environmental exposures are actually co exposures with other carcinogens.
 
[ I am not sure that the hip chromium 6 - the initial exposed form of the chromium presented in the body- would be classified as environmental given it is internal to the body from the get go, this is an interesting observation.    Since the inception of my speaking to the cancer issue in these posts, it has been my observation that my cancer reoccurred because it was precipitated by the introduction of chromium.    This observation makes perfect sense to me....that is , the idea of a cocarcinogen and coexposure.]
 
2.  The possibility of co exposures (co carcinogenesis) has been discussed for  a long time BUT ONLY RECENTLY HAS CROMATE COCARCINOGENESS BEEN DEMONSTRATED IN ANIMAL STUDIES AND THE LIKELY UNDERLYING MECHANISTIC BASIS EMERGED.
TWO REPORTS PROVIDED STRONG EMPERIMENTAL DATA DEMONSTRATING THAT CR 6 IN DRINKING WATER CAUSED DOSE-DEPENDENT INCREASES IN THE FREQUENCY OF SKIN TUMORS IN UV-IRRADIATED HARLESS MICE.  CR 6 ALONE PRODUCED NO TRUMOR INDICATING THAT IT ACTED AS A STONG ENHANCER OF UV INITIATED TUMORIGENESIS.  SUPPLEMENTATION WITH VIT E OR SELNEOMETHIONINE HAD NO EFFECT ON CR 6 MEDICATED ENHANCEMENT OF SKIN CARCINOGENESIS SUGGESTING THAT COCARCINOCGENIC EFFECTS WERE NOT OXIDANT-MEDIATED.  THE SAME REGIMENT OF ANTIOXIDANTS WAS VERY EFFECTIVE IN SUPRESSING  AS 3-POTENTIATED SKIN CARCINOGENESIS IN UV-IRRATIATED HARELESS MICE DEMONSTRATING THAT CR 6 AND AS3 ENHANCED UV-INDUCED TUMORGENESIS VIA DIFFERENT MECHANISMS. 
 
3.  It should be noted that exposures to EVEN MIDLY OR NON TOXIC CR 6 CONCENTRATIONS PRODUCE VERY HIGH FREQUENCIES OF CR-DNA ADDUCTS.
 
4.  CR 6 APPEARS TO CAUSE A SELECTIVE INCREASE IN THE NUMBER OF BPDE ADDUCTS AT THE MUTATIONAL HOT SPOT OF P53........  SEE STUDY BELOW  ON THE P53 GENE AND RENAL CELL CARCINOMA (MY DIAGNOSIS)
 
 
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2010 Feb 15;116(4):780-90. doi: 10.1002/cncr.24841.

p53 and MDM2 in renal cell carcinoma: biomarkers for disease progression and future therapeutic targets?

Source

Division of Surgery and Oncology, School of Cancer Studies, University of Liverpool, Liverpool L69 3GA, United Kingdom.

Abstract

Renal cell carcinoma (RCC) is the most common type of kidney cancer and follows an unpredictable disease course. To improve prognostication, a better understanding of critical genes associated with disease progression is required. The objective of this review was to focus attention on 2 such genes, p53 and murine double minute 2 (MDM2), and to provide a comprehensive summary and critical analysis of the literature regarding these genes in RCC. Information was compiled by searching the PubMed database for articles that were published or e-published up to April 1, 2009. Search terms included renal cancer, renal cell carcinoma, p53, and MDM2. Full articles and any supplementary data were examined; and, when appropriate, references were checked for additional material. All studies that described assessment of p53 and/or MDM2 in renal cancer were included. The authors concluded that increased p53 expression, but not p53 mutation, is associated with reduced overall survival/more rapid disease progression in RCC. There also was evidence that MDM2 up-regulation is associated with decreased disease-specific survival. Two features of RCC stood out as unusual and will require further investigation. First, increased p53 expression is tightly linked with increased MDM2 expression; and, second, patients who have tumors that display increased p53 and MDM2 expression may have the poorest overall survival. Because there was no evidence to support the conclusion that p53 mutation is associated with poorer survival, it seemed clear that increased p53 expression in RCC occurs independent of mutation. Further investigation of the mechanisms leading to increased p53/MDM2 expression in RCC may lead to improved prognostication and to the identification of novel therapeutic interventions.

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If the TP53 gene is damaged, tumor suppression is severely reduced. . The TP53 gene can also be damaged in cells by mutagens (chemicals, radiation, or viruses), increasing the likelihood that the cell will begin decontrolled division. More than 50 percent of human tumors contain a mutation or deletion of the TP53 gene.[39] Increasing the amount of p53, which may initially seem a good way to treat tumors or prevent them from spreading, is in actuality not a usable method of treatment, since it can cause premature aging.[40] However, restoring endogenous p53 function holds a lot of promise.[41] Loss of p53 creates genomic instability that most often results in the aneuploidy phenotype.[42]

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