day 114 – FAC stands for fluorouracil, adriamycin & cyclophosphamide

As promised on day 110, today I am writing about the drugs in the second phase of chemo that I am doing. FAC is a combination chemotherapy, made up of three different drugs, that can be thought of as variations on a single theme: inhibiting the copying of the DNA that makes up our genetic material. 

The F is for fluorouracil (http://en.wikipedia.org/wiki/Fluorouracil), a chemical modification (fluoro) of a basic building block of genetic material (uracil), which gums up the machinery that makes new DNA. Cancer cells, which are rapidly dividing, have a constant need to make new DNA so that when a cell divides, each of the new daughter cells gets a copy. One of the metabolites used for DNA synthesis is uracil, and when you add a fluorine group to it you change a regular metabolite into a smartbomb that inhibits the enzyme that ordinarily processes it to make it available for DNA synthesis. So not only can you not make a building block out of fluorouracil, it also stops the conversion of the body’s uracil from being made into a building block. The result is that you starve the cell of a necessary raw material needed to make DNA and so to divide. This is analogous to a car assembly line stopping because you run out of transmissions. 

In many cases starving a cancer cell of a key building block leads to the cell’s death. This response is related to the fact that the cell is no longer well controlled. It has lost the mechanisms normal cells use to check that everything is in place for them to divide. When the cancer cells find themselves mid cell-cycle, but unable to complete the cell division, they end up entering a programmed death pathway. Good riddance. You can imagine this process like the checks before a space flight where the flight controller checks in with each station before launch. Remember the Apollo 13 movie where it was Ed Harris (https://www.youtube.com/watch?v=kgHYGw9OL7c)? In the same way the cell has so called checkpoints in the cell cycle (http://en.wikipedia.org/wiki/Cell_cycle_checkpoint) where it ensures it has enough energy, building blocks and the right positive signals telling it to divide, and no negative signals telling it not to. In a normal cell, if there is a “no go” signal, the cell will remain quiet until whatever caused the halt is remedied. That is why chemo suppresses hair growth and intestinal function, and suppresses bone marrow production of blood cells. In each case, the relevant stem cells are put into a hold until the chemo is gone again. But these cells all come back eventually, because they are only forced into a kind of dormancy. In cancer, there is no flight controller, and the rocket launches as often as it can regardless of its state. Well, if half way up it runs out of fuel, it crashes – the chemo kills the cancer cell. 

The A is for adriamycin (http://en.wikipedia.org/wiki/Adriamycin), which is a variation on the same theme. It is a red chemical, that works by gumming up a different part of the machinery, the toposiomerases that unwind DNA before it can be copied during cell division. I wrote about adriamycin, also known as doxorubicin on day 42 (“a doctor with heart or why a cancer center has cardiologists”), and won’t repeat myself here. In brief, if the DNA can’t be unwound after the cell has committed to cell division (because it failed to check properly), the rocket crashes.

The C is for cyclophosphamide (http://en.wikipedia.org/wiki/Cyclophosphamide) an alkylating agent that alters another DNA building block, in this case guanine and the backbone of DNA, and causes cross-links. These cross links prevent the two strands of DNA from coming apart, which is again essential for replication, and so just like the toposiomerase inhibitors they prevent the elegant molecular dance that needs to be orchestrated in order to allow the DNA to be copied and divided between the two daughter cells of a cell division event. Again, cells committed to reckless cell division often perish when confronted with this obstacle. As an aside, the alkylating agents are derivatives of the mustard gases (http://en.wikipedia.org/wiki/Mustard_gas) used in chemical warfare. It was noticed that these weapons caused suppression of blood formation in its victims, and so they were tried for blood tumors, and later for solid tumors too. Of course, myelosuppression is one major side effect of cyclophosphamide.

Given this biology, it is pretty easy to see that FAC hammers the same component process of cell division namely DNA replication, from three different angles with the hope that any one cancer cell is unlikely to be resistant to all three mechanisms and so that they will be effective together. They are distinct from the taxol, which also targets cell division, but not DNA replication, rather inhibits the pulling apart of the replicated chromosomes.

So here’s hoping that the triple hit of FAC is going to make my tumor cells crash and burn. 

 

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