Monday, September 19, 2005

High Rent Molecular Mechanisms Support Low Dose Chemical Carcinogenesis Risk

BrooklynDodger wades further into the uncharted swamp of fundamental mechanisms for carcinogenesis. All this stuff was invented after BrooklynDodger went to toxicology school; thus the Dodger warns this commentary to be metaphorical rather than grounded in deep knowledge of the field.

The Dodger reminds that importance of mechanism is whether a dose- [and implicitly exposure] response mechanism persists into the region where population effects can’t be directly observed. “Genotoxic” mechanisms are a type where a single deranged [initiated] cell progresses to a clone of malignant cells; thus, the relationship has no threshold [that is, no range where is the dose-response relationship is abolished.]

The Dodger previously blogged a Gaylor paper suggesting that carcinogens which enhance an underlying mechanism of carcinogenesis [this is a statistical paper, with none of this high rent molecular biology] will be linear to low doses.

BrooklynDodger further repeats that mutations – a putative mechanism of carcinogenesis – make for genes that don’t work [code for proteins that don’t work]. This frames mechanisms which turn off tumor prevention pathways.

p53 is a cell suicide [apoptotic] protein. BrooklynDodger will now have to learn what ATM, hTERT and TRF2h are.

BrooklynDodger notes that circulating lymphocytes are not the tumor. [Tumors sometimes have increased p53; the Dodger imagines this arises because the tumor cells are trying kill themselves and failing.] Biological plausibility for this observed association would be that whatever is reducing the protection in the lymphocytes also reduces the protection in the epithelial cells in the bladder.

As a token of common underlying mechanism, this paper supports low dose continuity of chemical carcinogenesis.

Carcinogenesis 2005 26(10):1741-1747; doi:10.1093/carcin/bgi126

Roles of tumor suppressor and telomere maintenance genes in cancer and aging—an epidemiological study
Jian Gu, Margaret R. Spitz, Hua Zhao, Jie Lin, H.Barton Grossman 1, Colin P. Dinney 1 and Xifeng Wu *
Department of Epidemiology and 1 Department of Urology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX, USA
Advanced age is strikingly linked to increased incidence of cancer. … we used a case-control design and measured the mRNA expression levels of p53, ATM, hTERT and TRF2, the four major protectors of genomic integrity, in isolated peripheral blood lymphocytes from 202 confirmed bladder cancer (BC) patients and 199 healthy controls. … expressions of p53, ATM and TRF2 significantly decreased with advancing age in cases … In controls, however, p53 expression significantly increased with advancing age (P for trend = 0.05). Among subjects (image placeholder)65 years of age, the expressions of p53, ATM and TRF2 were significantly lower in cases than in controls … suggesting that attenuated genomic maintenance mechanisms lead to increased cancer risk in older individuals. …low p53 expression was associated with a significantly increased BC risk in older people … older subjects without detectable hTERT expression had a significantly reduced BC risk ... Our study provides the first epidemiologic evidence that the increased genomic instability resulting from the combination of telomere dysfunction, impaired ATM- and p53-mediated DNA damage, and/or telomere dysfunction response pathway contributes to increased cancer incidence in the elderly population.

1 comment:

Rich Murray said...

largely unexamined co-factors:

Dark wines and liquors, as well as aspartame, provide similar levels of
methanol, above 100 mg daily, for long-term heavy users. Methanol is
inevitably largely turned into formaldehyde, and thence largely into formic acid.

Rich Murray, MA Room For All 505-501-2298
1943 Otowi Road Santa Fe, New Mexico 87505
group with 148 members, 1,216 posts in a public, searchable archive
hangover research relevant to toxicity of 11% methanol in aspartame (formaldehyde, formic
acid): Calder I (full text): Jones AW: Murray 2004.08.05 2005.09.21

Since no adaquate data has ever been published on the exact disposition of
toxic metabolites in specific tissues in humans of the 11% methanol component of aspartame,
the many studies on morning-after
hangover from the methanol impurity
in alcohol drinks are the main
available resource to date.
aspartame induces lymphomas and leukaemias in rats, full plain text,
M Soffritti, F Belpoggi, DD Esposti, L Lambertini: Ramazzini Foundation
study 2005.07.14: main results agree with their previous methanol and
formaldehyde studies: Murray 2005.09.21