| Ch 9 | Page 6 / 34 | |
| Cancer chemotherapy |
Main drugs: antimetabolites (2) |
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These are fraudulent molecules, which, because of their chemical similarity to necessary intermediary metabolic components, are accepted as a substrate by cells and inhibit the biosynthesis of nucleic acids and proteins necessary for cell division.
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| Diagram of the action of antimetabolites which cannot be integrated in the DNA strand hence preventing cellular division. |
We can distinguish
These drugs resemble cytosine, thymine or uracile.
There are some standard examples:
And more recently synthesised products with different activities:
These drugs resemble guanine or adenine.
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There are some standard examples:
And more recently synthesised molecules with different activities:
5-FU has a more complex action mechanism than Methotrexate but also modifies the folate pathway (for this reason, it is often associated with folinic acid in FUFOL protocols for digestive tumours).
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| Diagram showing the action of 5-FU. It also inhibits thymidilate synthetase. The supply of folinic acid improves folate metabolism thus strengthening the action of 5-FU. |
Most of these molecules will be subjected to the intracellular enzymatic transformations of normal nucleotides and in particular for cytosine arabinoside the formation of complex mono-, then bi-, then tri-phosphorylated. Conversely they may also be deaminated thus rendering them inactive. It is therefore necessary to maintain a high level of dosage in order to saturate cellular metabolisms.
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| Importance of phosphorylation and deamination metabolism in antimetabolite activity. |
The deamination process is used by capecitabine to get 5-FU.
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