Fundamentals II: 11:00-12:00 Scribe: Ashley Brewington

Fundamentals II: 11:00-12:00 Scribe: Ashley Brewington Wednesday, December 9, 2009 Proof: Susanna Pischek Dr. Johnson Cancer Chemotherapy Page 1 of 14 I. Objectives [S2] a. So, today we are going to talk a little about oral cancer. I’m happy to see all of the Apple notebooks up there. I just bought one too. I love it. No viruses, got to love those things. Apparently they made a huge profit this quarter. b. In terms of oral cancer, I want to discuss a little about risk factors associated with oral cancer, how it is diagnosed, what the treatment is, and why people fail treatment. That sounds pretty reasonable, other than this which is really what is going to happen. II. Brief History [S3] a. So, the first thing I want to talk about is kind of a history of chemotherapy. b. I work in cancer research. What do you think the most common question I get asked at cocktail parties? “Ya’ll about ready to cure that cancer thing yet?” We hear it all the time. c. Since the 50’s there has been the development of a trimodal type treatment regiment. d. What do you think is the major problem in curing cancer? e. Student: It’s the drug companies. That we had a cure years ago and that there is an economic interest in keeping people sick. That is truly a theory that some people believe. I don’t adhere to that because there are a lot of intensely rich people who have died of cancer who would have given virtually anything to live a little longer. Such as Kennedy, and the list goes on and on, and I intimately know that if a pharmaceutical company came up with a drug for cancer would be the richest pharmaceutical company and would be head and shoulders above all others. So, economically it doesn’t make a lot of sense. Insurance companies would have pay a lot also because they lose so much money in treating long term sick individuals. f. Biologically, the reason that it is so tough to cure cancer is the same reason it is so tough to cure any other disease. g. I want you to think of this for just a second. Would you all agree that we have many, many drugs that cure many, many diseases? Yes. Okay, everyone agrees to that roughly. Lets remove antibiotics from the mix because that is too easy. Now, name one drug that cures a disease. What’s a drug that cures a disease, just one, no antibiotics? Not quite so easy is it? You assume a lot. You assume too much. h. The diseases we cure are usually diseases of parasites in one way or another, whether it is bacteria, a virus, we don’t even have that much success with viruses. i. Antibiotics and inoculations are really the only two true successes we have. j. In using that type of physiology, we have tried to attack the disease of cancer. The real problem with cancer is that it is not an outside agent, or it is not an outside parasite. It is our own progenitor cells. The Fundamentals II: 11:00-12:00 Scribe: Ashley Brewington Wednesday, December 9, 2009 Proof: Susanna Pischek Dr. Johnson Cancer Chemotherapy Page 2 of 14 mechanism behind cellular replication within the cell is messed up for various reasons. It is a disease of self like many other diseases. k. For instance, I said give me a drug that cures a disease. Well, we have a lot of drugs to treat cholesterol, but all they do is keep cholesterol in check but they don’t really cure the disease. We have insulin for diabetes, but does it cure diabetes? No. Most of the medicines we are on treat the symptoms; they do not cure the disease. l. If there is actually a molecule basis for the disease and it is within our own progenitor cells, we really don’t have the ability to go in and fix it. I wanted to put that in your head when you think about cancer. m. So, since the 50’s we have developed this tripod therapy. What is the most effective treatment for cancer? Surgery. Cut it out. It remains the most effective treatment; it has always been the most effective treatment. Who invented the surgery thing for cancer? Egyptians about 3,000 years ago. Not that new. It still works though. n. What is the second most effective treatment? Radiation. I should have mixed up the order up here. True though, radiation. o. The third thing is chemotherapy. How old is chemotherapy? A hundred years old, fifty years old? About 3,000 years old, Egyptian actually treated people with alkaloids. p. So the only thing we have managed to come up with new in 3,000 years is radiation. q. In the 50’s through the 90’s, basically the way to develop new treatment, everyone new surgery was the best, radiation came on board as a major standard of care, and they tried to develop new chemotherapy drugs. The way they develop these drugs is you culture cancer cells in a dish and you add every kind of derivative of every kind of drug you can think of and if it wiped out the cancer cells then you’d put it in animals and if it killed the tumor in animals, you’d say “Aha!” we’ve got a new cancer drug lets stick it in people. Before they even knew how it worked, it was in clinical trials. It is kind of a trial and error method. Bulldozer approach, which worked okay. r. Something happened in the late 80’s with the introduction of PCR, polymerase chain reaction. This opened up the ability to look at the molecular basis of cancer, we can now clone cDNAs, sequencing came on line, and we were looking for mutations in oncogenes and tumor suppressors. We were looking for differences between tumor cells and normal cells. So that specific targets could be identified. s. In the past, chemotherapy drugs basically killed rapidly dividing cells. Cells that are in S phase primarily, and this is where you get all of the side effects from cancer. Your hair falls out, your white count drops, these are all rapidly dividing cells. t. So, most chemotherapy drugs cannot discriminate between a cancer cell and a normal cell. They are just going to wipe out everything that is dividing rapidly. Fundamentals II: 11:00-12:00 Scribe: Ashley Brewington Wednesday, December 9, 2009 Proof: Susanna Pischek Dr. Johnson Cancer Chemotherapy Page 3 of 14 u. In a tumor, a solid tumor, there is a higher proportion of cells in S phase. So, that is why it is selective for the tumor. There is nothing magic about the drugs, and actually none of the drugs that I am going to talk about today there is nothing magic about them that is selective for a tumor cell. So, that is why these little buggers are so toxic. v. So anyway, in the 90’s what you saw is the human genome project that took off, this was a huge event. People started searching for the molecular basis of cancer. What screws up in a tumor cell that it just keeps dividing. You started to see the rational design of chemotherapy drugs and that is that they were looking at difference between normal and tumor cells. They would find a difference and a difference meant a potential target, and the money grubbing pharmaceutical companies, which I’ll agree with you, decided that that would be a nice target to go after since it was a difference and they targeted it a lot. So now you are seeing the introduction of a lot more specific therapy agents. III. Cancer Drug Development 1945-Present [S4] a. Here is kind of a trace of FDA approved drugs. You can see, I said that PCR was introduced right here before 1990, and look at the advent of new drugs. These are almost all targeted type therapies. b. The very first chemotherapy drug was a derivative of nitrogen mustard. You know what nitrogen mustard is right? Old mustard gas from WWI, the first chemotherapy drug. We have come quite a long way since nitrogen mustard. IV. Head and Neck Cancer [S5] a. You are here to talk about head and neck cancers. b. I guess the first question is what the heck is head and neck cancer? It is anything below the eyes and above the collarbones. c. You see a lot of structures here that you all could probably tell me more about. Obviously made up of a lot of different tissues and you can have a lot of different cancers in each one of these. d. I’m going to focus mainly on oral cancer in the tongue; I won’t get into the neck cancer too much. e. Most medical oncologists specialize in one or the other. You can specialize in head and neck cancers and then there are subdivisions with in that. V. Worldwide Epidemiology [S6] a. Is it an important type of cancer? Yes, it is the 8th most common. b. Especially in South East Asia. c. Primarily this is a behavioral issue. This is one of those times that our behavior and habits can affect our health dramatically. d. There is always that debate you can get into, is it genetic, is it my behavior. Usually, as with most things it is a combination of both. e. There are certainly some behaviors that I’ll talk about with South East Asia that preclude people to be more susceptible to this type of cancer. Fundamentals II: 11:00-12:00 Scribe: Ashley Brewington Wednesday, December 9, 2009 Proof: Susanna Pischek Dr. Johnson Cancer Chemotherapy Page 4 of 14 f. Anybody here chew tobacco? Come on, don’t be afraid. Nobody chews tobacco. Everybody see the Alabama game? Man there was a guy there chewing tobacco; it was the most disgusting habit I think I have ever seen in my life. That is pitiful. You know the little spit thing they’ve got. My apologies to anyone who actually chews that stuff, but man that is a disgusting habit. g. So, in the United States we have about 34,000 cases per year. h. Interestingly, do you think this is a treatable type cancer? Do you think people survive this type of cancer? Or is it very, very lethal? Lethal or more survivable? Lethal? Actually, it is more survivable. i. There is a reason for this. Your more lethal type cancers have a tendency to be found later, they are in inaccessible areas. They have symptoms that can be masked easy, lets say like pancreatic cancer has a death- incidence ratio of 1%. So in other words, you have a 99% chance of dying if you get pancreatic cancer because it is in an inaccessible area, you have to get a biopsy to diagnose it, it is in a hard to get area, you have to get an ultrasound endoscopic biopsy to get to it and it can be associated with stomach pain or gas. It is usually found in later stages. j. The advantage we have in oral cancer is something in your oral cancer is most often noticed early. You ask, “what is this thing?” It is irritating. k. Early diagnosis is usually the primary reason that we have such a low death rate in this country. VI. Risk Factors [S7] a. Risk factors of course, cigarette smoking up there with everything else. High alcohol consumption. b. Interestingly, these two seem to work together. If you drink and you smoke a lot, you really increase your risk. c. Chewing tobacco is a huge factor. d. South East Asia, a very common habit is the chewing of betal nuts. That is these ugly little buggers over here. They will take those and will chew them with lime, they will take a slice of lime, a betal nut and the leaves of the betal tree and chew it for a while. I guess that is their version of chewing tobacco. It has a mild narcotic stimulant in it. It gives you a little euphoria, a buzz. People that start chewing the betal nut at about 12-13 usually have no teeth by the time they are 20-25. e. And of course, we have HPVs as a risk factor. VII. Risk Factors [S8] a. So, you are relatively young and in this country we drink. How many people in this country drink alcohol? Okay, that’s pretty good, looks like all the drinkers went to this side of the room and a few migrating out. b. Well, alcohol consumption is a risk factor. Not something I wanted to tell all of the college students I was with Saturday during the game because boy they got hammered. c. Interestingly, a lot of people that drink start smoking when they are drinking. Fundamentals II: 11:00-12:00 Scribe: Ashley Brewington Wednesday, December 9, 2009 Proof: Susanna Pischek Dr. Johnson Cancer Chemotherapy Page 5 of 14 d. Have ya’ll seen that new commercial with the lady mixing a margarita at her desk. You know you don’t drink every time you smoke, but you smoke every time you drink. e. Anyway, smoking with excessive alcohol has a synergistic effect. Poor effect on the odds of you developing oral cancer. f. I don’t know a mechanism of action that has been proposed for that. VIII. Alcohol as a Risk Factor [S9] a. Basically, alcohol becomes a risk factor if you consume more than light amounts. b. A unit is approximately one beer, and I’m not talking about the high gravity beers. I’m talking about the normal beers that your college students drink, the bud lights, the American water stuff. I don’t drink that, I like the high gravity beers. c. The trick is avoid alcohol binging and at least two alcohol free days a week. IX. Head and Neck Cancer [S10] a. Who diagnoses cancers? Medical oncologist, your dentists? Dentists? No. b. Any cancer at all, who diagnoses it? Pathologists. c. Pathologists do all diagnosis of cancer. You actually have to have a piece of tissue and look at it under a microscope, examine it and that’s when a diagnosis can be made. You cannot tell by looking at it. d. The pathologist will stage the cancer. A diagnosis is always made by a pathologist, and whether it has metastasized and the stage of the tumor cells, their morphology there will be staging. e. The diagnosis and the staging dictate how the cancer will be treated. You treat later stage cancers different than you do early stage cancers. f. Even the age of the patient is factored in when you are deciding what type of treatment. g. You basically in cancer have three treatment options. All the treatment options that I told you are available. In some cancers you only do two, surgery and radiation. An example of that would be prostate cancer, you only do surgery and sometimes radiation. h. For localized tumors that you are not worried about metastatic disease you can do surgery and be done. i. For this type of cancer it is really dependent on how far it has gone. They may do surgery and stop, sometimes radiation, but if it has gone for a long time they will do all three. X. Head and Neck Cancer [S11] a. This as a dentist is what you will see. This is what your patient will come to you with. “I have a lesion in my mouth, it will not go away.” b. It can be a lot of different things, a lump or thickening in the cheek. You have a lot of lymphnodes up here. c. I had a lot of comments during the presidential race last year, John McCain had this large lymph node and a lot of people were asking, “does Fundamentals II: 11:00-12:00 Scribe: Ashley Brewington Wednesday, December 9, 2009 Proof: Susanna Pischek Dr. Johnson Cancer Chemotherapy Page 6 of 14 he have cancer?” I don’t know looks like it to me. So you can see a lump or thickening in the cheek. d. White or red patch on the lips or gums, I’ll show you a few pictures. e. A constant sore throat that doesn’t go away or difficulty chewing. f. Difficulty in swallowing or something. We have all swallowed that pill and it didn’t go down all the way. g. Moving your jaw, so the problem here you can tell is that these can be so many different things such as TMJ. h. This is the dangerous part, you have to be aware that this could be cancer. XI. Diagnosis [S12] a. So, some squamous cell cancers. b. I used to ask everybody do you think this is cancer or this is cancer, but since everyone now has a laptop up and you can see the answer so it doesn’t matter. c. They are both cancers, but they look very different. You can tell by looking. You have to take a biopsy here. d. This cold be as easily a cold sore, and they are both squamous cell carcinoma. XII. Diagnosis [S13] a. And of course this nasty looking thing here is an aspirin burn. I always wondered about that. I mean what did he do stick an aspirin under between his gums and hold it there for a long time? A little odd. XIII. Head and Neck Cancer [S14] a. So, who diagnoses cancer? Pathologist. b. How do they do it? Have to get a biopsy. c. Not you guys, the pathologist. d. So, even today what they normally do 99 times out of 100 is a little punch. A small punch of tissue, they get their punch and a little punch. e. There is a better way, it hasn’t been adopted widely and I’m not sure why. It is just a little brush and it basically causes no pain or bleeding and requires not anesthetic. As of last year, there were not a lot of use of these but there is no down side to using it. f. Essentially, you go in the pathologist will do a punch biopsy, H&E tissue stain, look under the microscope, make a diagnosis and staging and then you will be referred to a medical oncologist to decide the treatment. g. There are lots of flavors of oncologist. The medical onocologist is kind of the ring leader, there is a radiology oncologist that dictates if you are going to get radiation where they are going to localize the radiation, that is a different type of oncologist. The medical oncologist works with what types of medications you are going to receive and the surgical oncologist does the surgery. They work together as a team and everybody had their own specialty. They all base it on what the pathologist finds. There is actually a lot of confusion over this, but its actually a team effort. XIV. Principles of Cancer Treatment [S15] Fundamentals II: 11:00-12:00 Scribe: Ashley Brewington Wednesday, December 9, 2009 Proof: Susanna Pischek Dr. Johnson Cancer Chemotherapy Page 7 of 14 a. And I pretty much went through this. b. Have you heard T, N, M before? c. Tumor is basically the size of the tumor d. N is whether any of the lymph nodes are involved e. M is whether any distant metastases are present f. It is this indication that dictates the treatment g. I didn’t realize I had this on this slide, and early detection in this type of cancer there is usually an 80-90% cure rate and it usually involves surgery and radiation, and occasionally chemotherapy. h. When you get into the head and neck cancers, when it gets deeper you get later diagnosis and have to use chemotherapy i. If it is more to the surface it is usually detected early and treated with surgery and radiation XV. Principles of Chemotherapy [S16] a. The principles behind how chemotherapy work were actually developed in the 60’s b. Do you all know about Southern Research Institute? Right up the hill here? In the 60’s and 70’s they were actually one of the leaders in marketing and developing chemotherapy drugs. c. They came up with something called Skipper’s laws XVI. Skipper’s Laws—60’s Mouse Models [S17] a. Skipper was actually located at SRI in the 60s and they used a real new, radical technique that everyone uses now. b. They used a mouse acetograph model (??) and they used basically these L1220 cells leukemia line and inject them into mice and what they were trying to figure out is how does chemotherapy work, why do mice die when you inject them with tumor cells and how many tumor cells do you have to inject in the mouse, all of these basic questions. c. The most important thing, all this other stuff is common sense, if the tumor reaches a critical level the mouse dies, well yeah. d. The survival is a function of the number of tumor cells injected, so if I inject more tumor cells the mouse dies quicker, okay e. All of this is common sense. The surprising thing was that chemotherapy follows first-order kinetics. That was a surprising factor. f. Basically, the number of cells that are killed are constant depending on the dose of whatever you are giving and that holds true today. XVII. Log-Kill Hypothesis [S18] a. It led to this Log-Kill hypothesis b. So, if you were a cancer patient, and I said I have a magic drug that will kill 99% of the tumor in your body with one shot, you’d say, “line me up, I’m cured” c. Actually, when you start doing the math even if you kill 99%, you start doing the math you will realize that the tumor burden is never reduced to zero. d. This is also why chemotherapy is given in cycles. Fundamentals II: 11:00-12:00 Scribe: Ashley Brewington Wednesday, December 9, 2009 Proof: Susanna Pischek Dr. Johnson Cancer Chemotherapy Page 8 of 14 e. Remember that these compounds have a very narrow therapeutic window. What I mean by therapeutic window is when you give a drug you have a part where… it will be easier to just show you (draws graph on board) so if this is the concentration of the drug (y-axis) and this is time (x-axis), this is the effect that you are looking for and this is toxicity and this concentration of the drug. f. So you take a drug, even if you give a shot then you start off here and then you go up, if you give an oral medication you come up here and you give the therapeutic effect that you want and that happens for a certain amount of time and your body metabolizes it and you drop below the therapeutic level and then you’ll take another pill and go back up. g. This is why infusion with pumps is better because you can kind of keep them within this therapeutic window below the dose of toxicity and above the therapeutic effect. h. Over the counter drugs have a real wide window, so you can take a lot more than you need. So if you take six Tylenol, you only needed two and it won’t give you three times the effect but it won’t go above the toxic effect, you can’t take two bottles of it. Over the counter drugs have a wide window. i. Chemotherapy drugs have a very narrow window, you get into that beneficial effect and then this line is real close and if you take too much you are in to the toxicity zone real fast. That is the danger of chemotherapy drugs. j. So to keep people out of the toxic effect, you treat them in cycles. You give them a dose of the drug and it wipes out rapidly dividing cells. Then you let them clear that drug and you give them another dose of the drug and you have to monitor this very carefully, and that is what the medical oncologist does. k. The medical oncologist decides the dose, it is normally based on weight, the surface area of the patient, they monitor white count, and they do a balance. You can have two people that are the same weight and height same stage, one gets toxic to the drug and one doesn’t. You will have to scale back the drug on the one that gets toxic. They give people as much as they can handle at the time XVIII. Gompertzian Cell Growth [S19] a. Interestingly, there was a guy named Gompertzian, he was not a great mathematician, he was not a great M.D., I think he worked for an insurance company, and he was more of a second rate mathematician in a way. b. He came up with this curve that described population growths in cities (drew graph on board with sigmoid curve), does that look like a familiar curve? Well what happens is when you start out a city and you start getting population growth, the growth goes slow because you don’t have a lot of roads or food, then the infrastructure starts to build up and your population starts to increase. Then as your infrastructure increases, Fundamentals II: 11:00-12:00 Scribe: Ashley Brewington Wednesday, December 9, 2009 Proof: Susanna Pischek Dr. Johnson Cancer Chemotherapy Page 9 of 14 transportation increases, food increases, you build sewers, you get this explosion of population growth in the city until it exceeds the resources that the city has and then your population will start to peter out. c. It turns out a lot of biological processes follows the exact same curve, even a PCR reaction follows the exact same curve, it starts out slow, you hit exponential phase, you use up all of the reagents and it plateaus out. d. Tumors follow the same growth curve and are not linear. They actually start of slow and grow blood vessels for blood supply and nutrients, they build a certain mass up and hit a phase of exponential growth and then they outstrip the ability to grow any faster and they plateau out. e. Most tumors are detected about here, at 10^9 cells, at the top of the curve before you plateau. f. The reason this is important for treatment. The first primary treatment for a tumor, including oral cancers, is surgery. When you do surgery, you cut out the mass and bring it down on the curve. What happens when you bring it down? It starts to regrow, but it is regrowing in exponential phase and that makes it much more sensitive to chemotherapy drugs. XIX. Goldie-Coldman Hypothesis [S20] a. There is also this idea, in addition to there being a cure scam, that tumors cell are clonal. So, if you take one part of a tumor, it is identical to the other part of the tumor. That was a real working hypothesis for many, many years. b. As our techniques improved and we were going in and sectioning tumors and looking at what mutations were occurring in oncogenes and tumor suppressor genes, what we actually found is that tumor cells are not clonal at all. c. The estimation for tumors, I said that most tumors are at about 10^ 9 cells, and you have about 10,000 different genetic representations in a tumor this size. 10,000 different flavors, so there is a lot of genetic diversity in a tumor. This is one of the reasons it makes it so hard to treat. d. You have something called intrinsic resistance, where it will have some mutation associated with it that makes it resistant to radiation or the treatment and it is inherent in the tumor and it is a small population in the tumor cells. So, you kill all of the sensitive cells that are sensitive to radiation, what grows back? The ones that are resistant to radiation. You treat it with radiation again, does it work? No. You have selected out the population of cells that were sensitive and not you have a selection of cells that are resistant population and the old treatments don’t work very well in second line therapy, same thing with drugs. e. You can give me the best chemotherapy in the world and I can make it resistant to that, but inherently in a large tumor due to the large genetic diversity, you will have some resistant lines in there, some resistant cells. The reason is Goldi-Coldman basically counted the mutation rate. XX. Categories of Chemotherapy Drugs [S21] Fundamentals II: 11:00-12:00 Scribe: Ashley Brewington Wednesday, December 9, 2009 Proof: Susanna Pischek Dr. Johnson Cancer Chemotherapy Page 10 of 14 a. So, back to treatment and chemotherapy drugs. b. If I tried to go through all of the chemotherapy drugs I would put either you or me asleep first, I’m not sure which. c. It is just a big table and this drug does that and this drug does that. d. I certainly don’t want to put you to sleep, all I want to do is give you the idea that this is a classification of chemotherapy drugs. There is a huge one missing down here called others or targeted, and that is the fastest growing group of targeted therapies, things like: Gleevec, Virseptin (sp?), things that target specific things in a tumor and each one of those you can talk about for an hour. e. The oldest group of chemotherapy drugs are these alkylating agents and that even includes the mustard gas. These things mutate the DNA. They put alkyl groups on guanine residues and DNA and block the replication of the DNA and is toxic to rapidly dividing cells. f. Nitrosoureas are actually the same thing as alkylating agents, the only thing unique about these is that they cross the blood-brain barrier, so they are used to treat brain tumors. They were the only treatment for brain tumors until the new alkylating agent came along called Temazolomide and it was held as a miracle cure, unfortunately it was released about four years ago and now they are finding that only 30% of people actually respond. g. Antimetabolites are kind of interesting. DNA and RNA is made of purines and pyrimidines and when it was realized that cancer cells use purines and pyrimidines, back in the 1950’s, they figured out that when they grew these cells in culture they were using up purines and pyrimidines— uracil and thymine—and using them up much faster than the normal growing cells. So they made every derivative of purine and pyrimidines you can think of and they came out with a whole class of chemotherapy drugs called antimetabolites. h. Antitumor antibiotics, I’m not going to talk too much about because they are not involved in oral cancers. Same thing with steroid hormones, these are going to be for breast cancer, estrogen positive breast cancer and things like that. i. The vinca alkaloids, I would call that the true oldest type of chemotherapy drug. There is evidence that the Egyptians actually used these to treat people and they interfere with mitotic spindle formation j. The drugs that are actually used in oral cancer are a type of alkylating agent called platinums, a type of antimetabolite called flurouracil, and a type of alkaloid, taxanes. XXI. Current (2009) NCCN Guidelines [S22] a. This is a great website, and I always like to give you guys a good website. b. If you ever want to know what the current treatment for a certain type of cancer, go here: nccn.org c. The thing that is nice about it is that you pick the type of cancer, and they flowchart everything. Fundamentals II: 11:00-12:00 Scribe: Ashley Brewington Wednesday, December 9, 2009 Proof: Susanna Pischek Dr. Johnson Cancer Chemotherapy Page 11 of 14 d. They will say, you did a biopsy and it is surgically resectable—yes or no? Then it will break it down further and constantly updating. e. This is very nice when you want to know the current standard of care for cancer. f. If you see here, and look at the drugs I tried to get it as specific as I could, but you can see this is for the oral cavity and as you get into the head and neck, things start to change a little bit. g. Basically, what we are dealing with here are platinums, flurouracil, and paclitaxil or docetaxel in terms of chemotherapy drugs. XXII. Alkylating Drugs [S23] a. So, going back into the alkylating agents. b. Here is our first little group and our first chemotherapy agent up here derived from mustard gas from WWI. c. They actually found that soldiers that were exposed to mustard gas had a higher rate of cancer, so they found it backwards. d. If you think about it, things that mutate DNA would cause cancer and radiation causes cancer. Isn’t kind of ironic that we treat cancer with carcinogens? e. Well, carcinogens are most toxic to things that are rapidly dividing, that’s why they work. f. There is a whole issue about secondary cancers that are caused by treatment with things like radiation and alkylating agents. g. If you read over here, you’ll see that platinums are basically a certain type of alkylating agent, one of the most effective type of alkylating agents. XXIII. Alkylating Drugs [S24] a. Their structure is very, very simple. b. Their metabolism is easy. c. Alkylating agents in general remain one of the most widely used chemotherapy drugs today. d. When you talk about resistance, what you are talking about is DNA repair enzymes. So you have enzymes and there is a whole lot of them that go in there and repair DNA damage. Upregulation of those genes in the tumor cells will make it resistant to alkylating agents and radiation. e. An example is GST another example is MGMT, metylguaninemethyltransferase, there is a whole host of them all of your XRCC’s and ERCC’s make you resistant to radiation. f. The cells have compensatory mechanisms, when you challenge them with something toxic like this or with radiation, they try to survive. They upregulate these DNA repair genes. XXIV. Platinums [S25] a. Here is a picture of Cisplatin and its daughter compounds. b. A lot of work now with Oxaliplatin because of lower toxicity c. The biggest toxicity here is in the kidneys with the Cisplatins. d. The parent compound Cisplatin is mostly used with oral cancer Fundamentals II: 11:00-12:00 Scribe: Ashley Brewington Wednesday, December 9, 2009 Proof: Susanna Pischek Dr. Johnson Cancer Chemotherapy Page 12 of 14 XXV. Antimetabolites [S26] a. Antimetabolites are the second oldest group. b. These are the ones that I told you are basically analogs of purines and pyrimidines. c. The purine analogs are just about of use now, the pyrimidine analogs are widely used to this day. XXVI. Antimetabolites [S27] a. Fluorouracil is probably the 3rd most used chemotherapy drug to this day even though it was developed in the 1950s. b. Capecitibine was introduced about 10 years ago, approved for oral cancer, approved for breast cancer, and recently a study was done that showed it was effective in brain tumors. c. Gemcitabine is a hideous drug, that was actually approved for the treatment of pancreatic cancer based on the fact that it would extend life by 2 or 3 weeks, but the treatment now is so bad for pancreatic cancer and the death rate is so high that they when ahead and approved Gemcitabine anyway. There is a lot of toxicity with that one. XXVII. MTX and 5-FU Inhibit DNA Synthesis [S28] a. Here a little picture of 5-FU for treatment with oral cancer. b. As usual, toxicity is about the same, mild suppression and rapidly dividing cells kick off. c. The mechanism of action is inhibition of TS. TS is an enzyme that synthesizes a precursor for DNA synthesis, dTMP. d. The diagram of that. e. So, what happens is you have a methyl donor, methylene tetrahydrofolate is the methyl donor, and it takes uridine and the methyl group and turns it into thymidine. So deoxyuridine monophosphate gets converted to deoxythymidine monophosphate, this gets phosphorylated two more times and you get deoxythimidine triphosphate which is a precursor for DNA synthesis f. 5-FU shuts down TS, so you block synthesis of DT and (????) and when those dry up you cannot replicate the genome. g. This is a different drug (MTX) methyltraxate and it actually blocks formation of tetrahydrofolate, so these were given together for many years and would hit the same pathway in two different areas blocking formation of the methyl donor and formation of the dTMP and DNA replication shut down and this is where it effects rapidly dividing cells XXVIII. (Fluoro)pyrimidine Metabolic Pathway [S29] a. And I will not go into this intensely detailed diagram b. Just lets say, that the metabolism, here it the parent compound 5-FU, here is Capecitabine, you can see there are lots and lots of steps c. I’ll tell you something interesting though, everybody studied this side of the pathway (left side) because this side is what kills the cancer cells. Here is FdUMP, it binds to this TS and shuts it down and you will block Fundamentals II: 11:00-12:00 Scribe: Ashley Brewington Wednesday, December 9, 2009 Proof: Susanna Pischek Dr. Johnson Cancer Chemotherapy Page 13 of 14 synthesis here and you dry up your dTMP pools and block DNA synthesis, 40 years went into that. d. Then there was this little group of people and they’d give them this drug and they’d drop dead. That is called a severe side effect in medical terms. It turns out that about 5% of the population is deficient in the DPD enzyme (dehydropyrimidine dehydrogenase) and if you are deficient in this enzyme, you cannot break the drug down and eliminate it. So it is like giving you a massive overdose. It turns out that if you crack a tumor open and look at the levels of DPD, high DPD level predict the tumor would be resistant to that drug because the tumor can clear the drug rapidly. Low TS levels predict it would be sensitive to this drug. There was actually a study two or three years ago by Schmorberg (sp?) and Schmorberg stratified colorectal patients based on TS and DPD enzyme expression in the tumor. He increased response from 21 to 35% by only giving the drug to people that had low DPD and low TS. This is kind of the future of where medicine is going where you can actually take a tissue biopsy, and not just stage the tumor and look at the tumor and diagnose it, but you can actually do a molecular profile and predict whether or not it would respond or not to a certain type of drug. e. We are seeing more and more of these biomarker type studies, stratification of the treatment based on the profile of the tumor XXIX. Plant (Vinca) Alkaloids [S30] a. Here we have our last group the Taxanes, part of the Vinca Alkaloids XXX. Taxanes [S31] a. Basically the mechanism of action and mechanisms of resistance b. Primary mechanism of resistance is P-glycoprotein, this is a pump and it pumps the drug out of the cell. It is a nonspecific pump. c. One of the problems with chemotherapy that was poorly understood about a decade ago was you could give people are certain chemotherapy drug and it would work extremely well. Then three or four years later, the tumor comes back and they given them the same chemotherapy drug and it doesn’t work at all. We have grown back resistant cells, so lets give them something completely different and it still didn’t work. No one knew why. It was P-glycoprotein. d. P-glycoprotein is a nonspecific pump and pretty much flushes out xenobiotics out of the cell, so they couldn’t build up concentrations of the drug high enough to be efficacious. XXXI. Combined Modality Approaches [S32] a. Combines chemotherapy with surgery, radiation (trimodal) in order to achieve best response. XXXII. Combination of Chemothrepay [S33] a. What you’ll see, and the reason we had to talk about three drugs is that you never actually give one drug alone. Fundamentals II: 11:00-12:00 Scribe: Ashley Brewington Wednesday, December 9, 2009 Proof: Susanna Pischek Dr. Johnson Cancer Chemotherapy Page 14 of 14 b. What you do is combine different drugs, so that you have different mechanisms of action, different types of toxicity and different mechanisms of resistance. c. This is pretty much common sense, you want to his from as many angles as possible. d. Two words you’ll hear a lot are additive and synergistic. i. Additive is exactly what it says, 1+1=2 ii. Synergistic is 1+1=4, when you put two drugs together they actually work better than additive, anything better than additive is synergistic XXXIII. Why Does Chemo Fail? [S34] a. Why does chemotherapy fail? b. Intrinsic vs. acquired resistance i. There can be a molecular make up in the tumor prior to being given the drug that makes it resistant, making it intrinsic resistance ii. Acquired is where compensatory mechanisms in the tumor change c. Decreased intracellular drug levels, such as MDR pumping the drug out of the cell d. Increased inactivation or decreased conversion to active forms, this is actually altering the metabolism of the drug e. Tumors are very good at adaptation and they will actually increase degradation or inactivation of cancer drugs f. Increasing repair of the drugs effect, this would be upregulation of DNA repair enzymes g. All of these have been clinically observed XXXIV. Good Luck [S35] a. STUDENT QUESTION: Should we focus mainly on the mechanism and not really the names of the drugs or…? b. ANSWER: I would focus on the drugs used to treat oral cancer. There is nothing that I will ask that is not on these slides. If you look here (slide 22), the number of drugs that are actually used to treat oral cancer—we are only talking three drugs. I would certainly know about these three.

[End of Second Hour]