Dr. Johnson Chemotherapy Case Studies Page 1 of 6

Fun 2: 10:00 - 11:00Scribe: Rylee Burt

Thursday, December 10, 2009Proof:

Actinic Keratoses [S1]:
Skipped Intro about Mac computers and participation in the discussion
Who wants to read the first case? You don’t have the cases? He would love to email them out but they gave him the book, yesterday, at 4 o’clock.
The case reports are a little odd. You guys are optometry and dental students so I don’t really anticipate you prescribing chemotherapy drugs. Right? So let’s keep it in the context of an open discussion so you learn something and have a little fun but I fully realize you don’t want to know the dramatic ins and outs of prescribing chemotherapy medication.
So are you ready to hear the first case? A 66 year old man presents for evaluation of skin growths on his face. For several years he has had scaly rough growths on his face, forehead, and scalp. He has had individual lesions frozen off by previous physicians, but he keeps getting more and more. He has never been diagnosed with skin cancer. He has a long history of sun exposure and multiple sunburns, primarily as a result of working outdoors and playing golf. Lucky dude. He takes an aspirin a day and he takes a statin for cholesterol. He has no other significant medical history. On examination of his skin, which you guys will never do, you note multiple 4-7mm lesions on his face and scalp that are flat, pink, and scaly. They feel rough on palpitation, touching. They are all on areas that would have been sun exposed. He has several on the dorsal surfaces of his hands and forearms. You diagnose him as having actinic keratoses. Along with recommending skin protection to protect him from the sun you prescribe topical 5-fluorouracil (5-FU). Remember that was one of the drugs we talked about yesterday.
So the first question is what is the mechanism of action of 5-FU and what are the adverse effects of 5-FU when given systemically? So the physician is prescribing 5-FU as an ointment to rub. This is the condition-I had never seen it either. I looked up pictures late last night and because I had a Mac it was really easy to download. This is what his lesions look like. And of course you all studied the lecture carefully yesterday and have completely memorized 5-FU. Right? You remember that it is an anti-metabolite. So what are anti-metabolites again? They are analogs of purines and pyrimidines. Purines and pyrimidines are the base pairs that make up DNA and RNA. So they made all kinds of derivatives.
Antimetabolites [S2]
It is the pyrimidines that seem to work the best. So here is the anti-metabolite that was prescribed for that. It is the 5-FU. It is a derivative uracil so you see it has a fluoride group on the fifth position of the pyrimidine ring. The reason it is called an anti-metabolite is the body treats it just like uracil. So the body thinks it is uracil so it chucks it right into the uracil pathway. From your basic biochemistry and because you were so fascinated with uracil, I have no doubt that you completely remember how uracil is metabolized.
(Fluoro)pyrimidine Metabolic Pathway[S3]
I kind of blew past this yesterday because I thought it was a little more detail than you really wanted to know, but this is the case study and this is kind of where we are at in terms of what was prescribed for this patient for this skin condition. Here is the drug that is being administered. This drug here is called the prodrug because it is turned by the body into this drug. This is a new generation of drug that is kind of rationally designed and is called Capecitabine and it is marketed as Xeloda. The advantage of this drug is that you can give it orally, where as this drug (5-FU) is either topical for skin lesions or it is given systemically through i.v. or hepatically in the portal vein. You can send patients home with Capecitabine and they have to come into the clinic everyday for the 5-FU. When you take this orally, it actually gets converted by 2 enzymes into 5’deoxyfluorouridine. You don’t have to remember that. The reason it is a rationally designed drug is that a lot of solid tumors have overexpression of this enzyme called thymidine phosphorylase and because the tumors have an overexpression of this enzyme, this drug gets converted in the final and rate limiting step into 5-FU preferentially in the tumor. So it makes it a little more selective for solid tumor tissue as opposed to regular tissue. So that’s pretty clear. Certain tumors over express TP and Capecitabine preferentially gets converted to 5-FU in the tumor.
What was prescribed for the skin lesion was basically 5-FU. Why do think it is prescribed as a topical ointment instead of taking it orally or an i.v.? ANSWER: Localized. You would have a lot less toxicity. If you give someone this drug systemically, pump their system with it, you would see a lot more toxicity. If you apply it topically you would have it right where it needs to be. I am not sure I would actually agree with this physician in prescribing a chemotherapy agent because they apparently did a biopsy onthis guy and he has no evidence of skin cancer. So they are prescribing it as a preventative measure. Another preventative measure would be some serious sunblock, which I would kind of advocate.
They do talk about the other anti-metabolites, which are on the slide that I gave you yesterday. So if you want to see other drugs in this class, that’s it. They also talk about the mechanism of action of this guy. So this is why I have to go through this a little bit.
Once you have the drug in your system- anytime you take medication your body tries to get rid of it. It is not supposed to be there. And sure enough, 5-FU is not supposed to be there so there is this enzyme called dihydropyrimidine dehydrgenase and 85% of the drug breaks down. How long do you think it takes the body to break half of this down? What is the half-life? ANSWER: Hours? You would think hours but it takes 13 minutes. Chemotherapy drugs are so toxic that the half-life is pretty short. It is shorter than you might think.
One of the interesting things I can tell you is that about 5% of the population has a deficiency of this enzyme. So I actually did a case study with someone that had this skin condition and was prescribed this drug for topical use, and he almost died. He was very close. The guy was a Greek fisherman and he was like 95 years old. I hope to God I am in this guy’s shape when I am 95 years old! He was lively and had a great time and he had these skin lesions and his physician gave him topical 5-FU you and he was DPD deficient. This drug is so toxic to people that are DPD deficient it almost kills them. We went in and I took blood samples. I met the guy and sure enough he had no DPD activity. So that tells you a couple of things. If you are DPD deficient, you don’t have any symptoms. It really doesn’t hurt you in life. He is 95 years old and healthy as can be.
This is called the catabolic pathway and this is called the anabolic pathway. Basically, the only reason for DPD in this pathway here is to make beta alanine but we get plenty of beta alanine in our diets now so we don’t really need a synthetic route for beta alanine.
But the drug, when challenged with 5-FU, the way to get rid of the drug is through that the pathway and the gatekeeper for that pathway is the DPD enzyme. The mechanism of action of basically all anti-metabolites is to mess up DNA synthesis in some way.
So now I am going to tell how this drug actually messes up DNA synthesis. I am going to walk you through it. It inhibits this enzyme up here (thymidylate synthetase). If you looked at the diagram you would say it goes from TP to TS (that’s too easy). It looks good, but the kinetics don’t favor that route. What actually happens, depending on the tissue, it takes this convoluted way to get to fluorodeoxyuridine monophosphate. So this is normally dUMP, but it has that fluoride group on it. Remember in the 5th position of the ring it had that fluoride atom. TS doesn’t know, it can’t tell, that it is FdUMP. It thinks it is dUMP.So it binds it and what it is going to do is it is going to add a methyl group to that uracil group and end up with dTMP, a precursor to dTTP for DNA synthesis. Because of that fluoride group, once TS binds FdUMP it can’t let it go. It is called a suicide inhibitor. If knocks out the enzyme. It binds so tight it will not release it.
Once you shut TS down, you can’t produce dTMP. So pools of dUMP start building up. There is no new dTMP. This is methylene tetrahydrofolate. This is the methyl donor. So to get from uracil to thymine you have to have a methyl group and this is where the methyl group comes from. So if these pools (dTMP) dry up then you can’t synthesize dTTP. If you can’t synthesize dTTP, DNA synthesis shuts down. That would be toxic to rapidly dividing cells. So if I shut down rapidly dividing cells what do you think the side effects would be? ANSWER: Hair loss, diarrhea, nausea. Your GI tract starts sloughing off because they reproduce really quickly. Your white count plummets, leukopenia. All the classic signs of chemotherapy that we think of and all of the toxicity you think of with chemotherapy is actually what happens. Basically the drug is killing rapidly dividing cells.
Is this specific for a cancer cell? ANSWER: No, No it is not. Most chemotherapy drugs are not specific for cancer cells. They are specific for rapidly dividing cells. There are 2 other mechanisms for toxicity. Once you get to this area here, you can also get incorporation into DNA. So dUTP can actually be incorporated into DNA or RNA. It causes strand breakage, freezing of the fork that replicates the DNA, lack of translation and so forth. All kinds of mechanistic problems. It is an adduct so it doesn’t behave as normal DNA or RNA.
The main mechanism of action that you are going to get questioned on during a test or that people mostly recognized is the TS. This drug is almost always given (not in this case study) with radiation for solid tumors. It is considered a radiation sensitizer. Makes radiation work better.
They also want you to know about methotrexate (MTX). Have ya’ll heard of methotrexate. I won’t go into metholtrexate a whole lot. These drugs actually used to be given together for breast cancer, interestingly enough. Now remember in the previous metabolic step I said it converts dUMP to dTMP and basically all that it does is it takes a methyl group and adds it to uracil to make thymine and that’s a precursor for DNA. That methyl group has to come from somewhere. It basically comes from methylene tetrahydrofolate. That gets synthesized from folic acid. So folic acid-there is an enzyme called dihydrofolate reductase and you get tetrahydrofolate and then that gets metabolized into methylene tetrahydrofolate and that is basically the methyl donor group.
MTX and 5-FU Inhibit DNA Synthesis [S4]
Methyltrexate inhibits dihydrofolate reductase. Your methylenetetrahydrofolate pools dry up. And you can kind of see (remember when we were talking about adding drugs together that would kind of help each other) if you really want to block this step (the TS) step? What if you really had a whole bunch of TS and you gave someone 5-FU but there was just so much TS it couldn’t inhibit it all? You gave MTX- it is like a double whammy on this portion of DNA synthesis. You are blocking production of this guy you are shutting down that enzyme. You are really shutting down dTMP. So you can see why it might be a good idea to give these guys together.
So what do you think would be a mechanism of resistance for MTX? What is the easiest way for a cell to overcome this? ANSWERS: Cell pump? Pump it out of the cell. Multidrug resistance is a role here. They don’t discuss it here, but yes it is. That is one mechanism. Another is cells just upregulate the dihydrofolate reductase.
Student Question: Where is MTX in the diagram? That’s actually the methyl group. That’s the MTX. That’s the end product of the dihydrofolate reductase. It makes this, which is the methyl donor that turns uracil monophosphate into thymidine monophosphate. So when you add MTX you shut down-your level of methylenehydrofolate drops. So mechanisms of resistance to 5-FU include high TS levels. You basically overwhelm the ability of the drug to suppress TS because you have too much TS and you have leak through. So you still end up making some dTMP. So to shut that down even more, what you do is cut back on tetrahydrofolate.
Which of the drugs inhibit thymidylate synthetase? Which drug inhibits TS? ANSWER: 5-FU does. It is this metabolite. It is FdUMP metabolite.
So what is true in general of combination cancer chemotherapy? I kind of gave you an example just now of MTX and 5-FU. It is administered during several cycles of treatment. It is less effective than monotherapy. It includes at least 2 drugs with similar dose limiting toxicities. It includes one drug that has no inherent therapeutic activity.
How do ya’ll answer these? Process of elimination? It is not that it is less effective than monotherapy. Which of the following is true, in general, of combination cancer chemotherapy? It includes one drug that has no inherent therapeutic activity? Is that true? NO. It’s less effective than monotherapy? Is that true? NO. A is it is administered during several cycles of treatment. Yes. And C is that it includes 2 drugs that have similar dose toxicities. When you combine 2 drugs do you want similar toxicities? They are going to add together right? So it makes sense that in combination chemotherapy-they are aiming for the same portion of pyrimidine biosynthesis pathway for DNA, but they have completely different toxicities and mechanisms of action. One is inhibiting formation of this tetrahydrofolate and one is actually inhibiting the enzyme that converts and they are combining both to decrease this but they have different mechanisms and different toxicities.
Now we have 3 pharmacological pearls. I think these are supposed to be pearls of wisdom. Smaller tumors are generally more responsive to chemotherapy than larger tumors. Is that true? Why? I actually covered that yesterday. Remember about Gomptertzian and it’s found in faster growing tumors. And even in this example you can see- if you have a tumor that is growing it is replicating their genome. So drugs that are going to affect DNA synthesis are going to be more toxic in tumors that are rapidly growing-small tumors. As you get bigger your growth phase starts to plateau out. Development of a mild leukopenia is evidence of the adequate absorption of locally administered alkylating agents.
What they are saying is-You give a patient this chemotherapy drug and you see their white count drops, leukopenia. Is that evidence that it is working? STUDENT ANSWER: No. Why Not? (Cannot hear the rest of student answer). Yes, but if you are seeing a drop in white cell count, the drug is doing what it is supposed to. This drug is not specific for tumors and it actually is evidence that it is working. You are going to have to play out the dose. You are going to have toxicity with these drugs and you will see a drop in white count. You can actually use that as an indicator as to how much to give a person. They adjust dose by body surface area, but that is not a perfect measurement. This DPD enzyme dictates how much enzyme goes into the cytotoxic pathway. This enzyme can vary 5 or 6 fold in a population of people. You can give the same group of people the same amount of 5-FU and they have different levels of toxicity. You have to balance that toxicity with the amount of drug you are giving. That is true of all chemotherapy drugs. That is why they monitor you so much when they start giving you cycles.
If you go to that NCCN website,it gives you that flow chart of this drug and that drug and will tell you how much to give. The medical oncologist will keep monitoring you and they try to up the dose as much as they can and they balance that with toxicity. So when they start to see some leukopenia, and in the case of this, that means that means your white count is dropping and the drug is working. If you had really high levels of DPD, systemically, and you cleared 5-FU really quick, you wouldn’t have leucopenia and the drug wouldn’t be working. If you had really low levels of DPD you would have massive leucopenia and would be in the toxic level like DPD deficient persons, like the old Greek guy. He got topical 5-FU and almost died from it.
STUDENT QUESTION: Would you go ahead and draw a DPD level on a patient before you prescribed this drug? ANSWER: That is a great question. How many people think you should do that? Consider that is 5% of the population. If I took the drug I’d want that test. I think that is an excellent point.