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How does the "leucovorin rescue" work exactly? Why doesn't it make cancerous tumours grow?
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Khadijah Khan
How does the "leucovorin rescue" work exactly? Why doesn't it make cancerous tumours grow?
I will interpret your question in the more generalised form of "why doesn't folic / folinic acid supplementation reduce the efficacy of methotrexate treatment?" The question may be better in this more generalised form so a moderator may want to edit it more towards that.
The review in [1] strongly suggests that folic acid supplementation does not reduce the efficacy of methotrexate treatment.
As for why that's the case, I don't think it's completely understood. But there are some pointers which I'll outline below.
In [2] the authors state that "Both folic acid (FA) and folinic acid (FLN) supplements have been shown to reduce the toxicity of MTX [...] and may prevent the formation of the less effective metabolite 7-hydroxy-MTX".
In [3] the authors state that "Methotrexate is a competitive antagonist of folic acid. It inhibits dihydrofolate reductase with resultant interference of DNA synthesis leading to apoptosis." They also state "inhibition of dihydrofolate reductase is not presumed to be the primary mediator [of efficacy] as supplementation with folic acid does not reduce the clinical efficacy"
In summary, methotrexate inhibits cancer growth by other unknown mechanisms than just preventing DNA synthesis by competing for folic acid uptake. Folic acid supplementation only reduces the effect of the latter. In addition, the speed at which cancer cells divide when compared to normal cells may skew the folic acid vs methotrexate uptake antagonism in a way that makes folic acid supplementation more beneficial for healthy cells than cancer cells.
As for your other question in the title "why doesn't folic acid supplementation make cancer tumours grow", I assume you mean why supplementation in it's own right doesn't make them grow. This is because the rate at which cancer grows is limited by a whole range of factors including many different nutrients like oxygen, water and many others. Increasing folic acid would be only one of the nutrients it needs.
I will interpret your question in the more generalised form of "why doesn't folic / folinic acid supplementation reduce the efficacy of methotrexate treatment?" The question may be better in this more generalised form so a moderator may want to edit it more towards that.
The review in [1] strongly suggests that folic acid supplementation does not reduce the efficacy of methotrexate treatment.
As for why that's the case, I don't think it's completely understood. But there are some pointers which I'll outline below.
In [2] the authors state that "Both folic acid (FA) and folinic acid (FLN) supplements have been shown to reduce the toxicity of MTX [...] and may prevent the formation of the less effective metabolite 7-hydroxy-MTX".
In [3] the authors state that "Methotrexate is a competitive antagonist of folic acid. It inhibits dihydrofolate reductase with resultant interference of DNA synthesis leading to apoptosis." They also state "inhibition of dihydrofolate reductase is not presumed to be the primary mediator [of efficacy] as supplementation with folic acid does not reduce the clinical efficacy"
In summary, methotrexate inhibits cancer growth by other unknown mechanisms than just preventing DNA synthesis by competing for folic acid uptake. Folic acid supplementation only reduces the effect of the latter. In addition, the speed at which cancer cells divide when compared to normal cells may skew the folic acid vs methotrexate uptake antagonism in a way that makes folic acid supplementation more beneficial for healthy cells than cancer cells.
As for your other question in the title "why doesn't folic acid supplementation make cancer tumours grow", I assume you mean why supplementation in it's own right doesn't make them grow. This is because the rate at which cancer grows is limited by a whole range of factors including many different nutrients like oxygen, water and many others. Increasing folic acid would be only one of the nutrients it needs.
I will interpret your question in the more generalised form of "why doesn't folic / folinic acid supplementation reduce the efficacy of methotrexate treatment?" The question may be better in this more generalised form so a moderator may want to edit it more towards that.
The review in [1] strongly suggests that folic acid supplementation does not reduce the efficacy of methotrexate treatment.
As for why that's the case, I don't think it's completely understood. But there are some pointers which I'll outline below.
In [2] the authors state that "Both folic acid (FA) and folinic acid (FLN) supplements have been shown to reduce the toxicity of MTX [...] and may prevent the formation of the less effective metabolite 7-hydroxy-MTX".
In [3] the authors state that "Methotrexate is a competitive antagonist of folic acid. It inhibits dihydrofolate reductase with resultant interference of DNA synthesis leading to apoptosis." They also state "inhibition of dihydrofolate reductase is not presumed to be the primary mediator [of efficacy] as supplementation with folic acid does not reduce the clinical efficacy"
In summary, methotrexate inhibits cancer growth by other unknown mechanisms than just preventing DNA synthesis by competing for folic acid uptake. Folic acid supplementation only reduces the effect of the latter. In addition, the speed at which cancer cells divide when compared to normal cells may skew the folic acid vs methotrexate uptake antagonism in a way that makes folic acid supplementation more beneficial for healthy cells than cancer cells.
As for your other question in the title "why doesn't folic acid supplementation make cancer tumours grow", I assume you mean why supplementation in it's own right doesn't make them grow. This is because the rate at which cancer grows is limited by a whole range of factors including many different nutrients like oxygen, water and many others. Increasing folic acid would be only one of the nutrients it needs.
[1] : https://www.ncbi.nlm.nih.gov/pubmed/8608361
[2] : https://www.ncbi.nlm.nih.gov/pubmed/21044441
[3] : T. Bayless, S. Hanauer: Advanced therapy in inflammatory bowel disease, vol II: IBD and Crohn's disease. Page 667.
I will interpret your question in the more generalised form of "why doesn't folic / folinic acid supplementation reduce the efficacy of methotrexate treatment?" The question may be better in this more generalised form so a moderator may want to edit it more towards that.
The review in [1] strongly suggests that folic acid supplementation does not reduce the efficacy of methotrexate treatment.
As for why that's the case, I don't think it's completely understood. But there are some pointers which I'll outline below.
In [2] the authors state that "Both folic acid (FA) and folinic acid (FLN) supplements have been shown to reduce the toxicity of MTX [...] and may prevent the formation of the less effective metabolite 7-hydroxy-MTX".
In [3] the authors state that "Methotrexate is a competitive antagonist of folic acid. It inhibits dihydrofolate reductase with resultant interference of DNA synthesis leading to apoptosis." They also state "inhibition of dihydrofolate reductase is not presumed to be the primary mediator [of efficacy] as supplementation with folic acid does not reduce the clinical efficacy"
In summary, methotrexate inhibits cancer growth by other unknown mechanisms than just preventing DNA synthesis by competing for folic acid uptake. Folic acid supplementation only reduces the effect of the latter. In addition, the speed at which cancer cells divide when compared to normal cells may skew the folic acid vs methotrexate uptake antagonism in a way that makes folic acid supplementation more beneficial for healthy cells than cancer cells.
As for your other question in the title "why doesn't folic acid supplementation make cancer tumours grow", I assume you mean why supplementation in it's own right doesn't make them grow. This is because the rate at which cancer grows is limited by a whole range of factors including many different nutrients like oxygen, water and many others. Increasing folic acid would be only one of the nutrients it needs.
[1] : https://www.ncbi.nlm.nih.gov/pubmed/8608361
[2] : https://www.ncbi.nlm.nih.gov/pubmed/21044441
[3] : T. Bayless, S. Hanauer: Advanced therapy in inflammatory bowel disease, vol II: IBD and Crohn's disease. Page 667.
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