Post by Max on Oct 28, 2005 5:28:27 GMT -5
The future use of substances that significantly affect gene-expression at multiple levels
Substances used for cancer such as (Ro)accutane affect gene-expression at several levels. There are today good methods such as RT-PCR and Western blotting, for determining factors such as what genes are affected, which binding affinity to the substance they have and what role they play in the cell.
There is a lesser use of wide and well functioning determination rates of site directed mutagenesis/deletion of transcriptional promoter sites (through point mutagenesis) in association with the exposure of substances highly likely to result in mutagenesis, even though studies involving the induction of point mutagenesis exist.
Novel wide and accepted methods needed for determining and declaring the statistical rate of mutagenesis
A general problem is to determine and declare the prevalence of point mutagenesis. Some methods are discussed in Bajaj et al (2005) [1]. To declare the statistical rate of point mutagenesis is of highest importance, not only in the case of (Ro)accutane and other cancer treatments, but for all substances that significantly influence gene-expression. The rate of point mutagenesis will without doubt have an outcome on the patients long-term health. Factors such as a downregulation of the function of certain receptor types due to deletions of promoter binding sites may significantly affect further cancer reoccurrence, the development of diabetes, CVD and other diseases.
I am convinced that the future of medicine therefore holds:
1) A statistical method wide for determinination of overall probability of significant point mutagenesis of various critally important genes given any used substance and dose.
2) In the case of found significant point mutagenesis which could be expected in several areas for example with toxic exposure, significant receptor inhibition or growth factor inhibition, a statistical wide and accepted method for determination and declaration of the rate in percent and in intervals of mutagenesis given determined for the subjects critically important genes, dose of the substance used and time it is used. This declared data may in clinical practise serve as a very adequate additional information in the decision of the accuracy of the clinical use of any substance.
Simplified example of declaration of mutagenesis
An example of declaration may look as the following:
x Name of substance: Cancer substance X
x Clinically relevant rate of mutagenesis/deletion of transcriptional promoter sites: Yes
x Determination of critical areas for point mutagenesis
x Affected receptor subtypes: Receptor family Q
x Targeted transcription factors: Sp1, Sp3
x Estimated reduction of residue/protein function with deleted transcriptional promoter sites: 80%
x Active/inactive phenotype: Active at low and high initial expression
---
x Dose/plasma concentration 0,1A
Rate of average mutagenesis of sites for receptor/receptor family Q with time 1, 2 and 3
Deletion of functioning Q receptor transcriptional promoter sites with time 1: interval: 3% to 5% time 2: 8-12% time 3: 12-16%
x Dose/plasma concentration 0,5A
Rate of average mutagenesis of sites for receptor/receptor family Q with time 1, 2 and 3
Deletion of functioning Q receptor transcriptional promoter sites with time 1: interval: 15% to 25% time 2: 30-40% time 3: 40-55%
x Dose/plasma concentration 1,0A
Rate of average mutagenesis of sites for receptor/receptor family Q with time 1, 2 and 3
Deletion of functioning Q receptor transcriptional promoter sites with time 1: interval: 45% to 60% time 2: 70% to 85% time 3: >95%
---
x Conclusions, discussion of outcome and prevalence of cancer reoccurence given statistical rate of downregulation of receptor function due to mutagenesis.
Substances used for cancer such as (Ro)accutane affect gene-expression at several levels. There are today good methods such as RT-PCR and Western blotting, for determining factors such as what genes are affected, which binding affinity to the substance they have and what role they play in the cell.
There is a lesser use of wide and well functioning determination rates of site directed mutagenesis/deletion of transcriptional promoter sites (through point mutagenesis) in association with the exposure of substances highly likely to result in mutagenesis, even though studies involving the induction of point mutagenesis exist.
Novel wide and accepted methods needed for determining and declaring the statistical rate of mutagenesis
A general problem is to determine and declare the prevalence of point mutagenesis. Some methods are discussed in Bajaj et al (2005) [1]. To declare the statistical rate of point mutagenesis is of highest importance, not only in the case of (Ro)accutane and other cancer treatments, but for all substances that significantly influence gene-expression. The rate of point mutagenesis will without doubt have an outcome on the patients long-term health. Factors such as a downregulation of the function of certain receptor types due to deletions of promoter binding sites may significantly affect further cancer reoccurrence, the development of diabetes, CVD and other diseases.
I am convinced that the future of medicine therefore holds:
1) A statistical method wide for determinination of overall probability of significant point mutagenesis of various critally important genes given any used substance and dose.
2) In the case of found significant point mutagenesis which could be expected in several areas for example with toxic exposure, significant receptor inhibition or growth factor inhibition, a statistical wide and accepted method for determination and declaration of the rate in percent and in intervals of mutagenesis given determined for the subjects critically important genes, dose of the substance used and time it is used. This declared data may in clinical practise serve as a very adequate additional information in the decision of the accuracy of the clinical use of any substance.
Simplified example of declaration of mutagenesis
An example of declaration may look as the following:
x Name of substance: Cancer substance X
x Clinically relevant rate of mutagenesis/deletion of transcriptional promoter sites: Yes
x Determination of critical areas for point mutagenesis
x Affected receptor subtypes: Receptor family Q
x Targeted transcription factors: Sp1, Sp3
x Estimated reduction of residue/protein function with deleted transcriptional promoter sites: 80%
x Active/inactive phenotype: Active at low and high initial expression
---
x Dose/plasma concentration 0,1A
Rate of average mutagenesis of sites for receptor/receptor family Q with time 1, 2 and 3
Deletion of functioning Q receptor transcriptional promoter sites with time 1: interval: 3% to 5% time 2: 8-12% time 3: 12-16%
x Dose/plasma concentration 0,5A
Rate of average mutagenesis of sites for receptor/receptor family Q with time 1, 2 and 3
Deletion of functioning Q receptor transcriptional promoter sites with time 1: interval: 15% to 25% time 2: 30-40% time 3: 40-55%
x Dose/plasma concentration 1,0A
Rate of average mutagenesis of sites for receptor/receptor family Q with time 1, 2 and 3
Deletion of functioning Q receptor transcriptional promoter sites with time 1: interval: 45% to 60% time 2: 70% to 85% time 3: >95%
---
x Conclusions, discussion of outcome and prevalence of cancer reoccurence given statistical rate of downregulation of receptor function due to mutagenesis.
