General Pharmacology

Anti-neoplastics

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Note:
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You have to know that this lecture offers you a common knowledge about cancer. It contains only general concepts. So, we will not get into details and you will not be memorizing any name of drug.

*Principle of cancers chemotherapy: -Neoplasia (derived from a Greek word): It means a new growth, so that any cancer in our clinical terminology is called neoplasia. We know that the embryo or the fetus is a new growth inside the uterus of his mother. So, can we consider this condition as a neoplasm? Actually, No. We can't call this condition neoplasia or cancer because there are certain characteristics of cancer cells or cancerous growth that will be specific only for it and not available in any other types of growth like here in the case of fetus. Now, we will talk about those specific characteristics of cancer cells, but before doing that, you have to know that the cells in your body whether we are talking about epithelial, muscular or any other types of cells, are always adhered to something. For example, epithelial cells are attached to a basement membrane and endothelial cells are attached to something similar to the basement membrane which serves as a tolerate for those cells.

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Figure (1)

Let's assume that any cell in our body wants to become cancerous. So, how does that happen? Why does this cell in particular become cancerous and not another one? The answer can be fully understood after studying the characteristics of neoplastic cells:

1.Mutation.
Each cell in your body undergoes thousands of mutations per day. How can that lead to a level in which the cell becomes cancerous? That is because such cell has been mutated into a level that exceeded its own normal defense mechanisms. So even the repair mechanisms of the cell, like the DNA and protein synthesis repairs, can't defend the cell anymore, because they have been mutated into a level where they can't compensate anymore causing the cell to become cancerous.
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2.Uncontrolled proliferation.
It's unequivocally available in all cancer cells. Now, every cell in our body proliferates and divides in a regular way, giving it a specific shape and structure. Unlike those cancerous cells which have some sorts of barbaric proliferation . What is important here is that this uncontrollable proliferation may become in certain cases immortal, such that the cell cannot die at all, and we all know that the cells are programmed to die at a specific time.

3.Genomic instability.
It means that within the same population of cancer cells at one time, you will see different kinds of cells that dont even belong to this place, and thats because those proliferative cells started to transform and change their shape, structure and intracellular functions because of the large numbers of mutations they had. This is very important for you as a physician, because treating such condition is very hard. So, if you want to give a treatment that targets such kind of cells, you have to keep in your mind that this tumor may have other types of cells.

4.Ability to invade.
We said that the basement membrane provides an attachment for the cells. You have to know that if the cells want to proliferate, they shouldn't exceed this membrane and go beyond it. However, cancer cells have the ability to cross over this membrane and invade the local tissues. But at the same time not all cancers have this ability. So, all cancers have mutations and have the ability to proliferate uncontrollably but not all of them have the ability to invade.

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5.Metastatic potential.
It's a more sever condition at which the cancerous cells will have the ability to do angiogenesis. It means that the cell starts building up bridges and channels between the core of the tumor structure and the next supplying blood vessel, so it's going to take all the nutrients and oxygen and releases its wastage into the blood supply and then it goes into somewhere else and thats what we call metastasis. Not all cancer cells have the ability to metastasize.

Figure (2)

Normal cells.

Mutated cells.

Blood vessel.

Angiogenesis.

In the general clinical terminology, cancer is a progressive disease and again it has different stages and not all cancers may go through all these stages:
1 Normal cells Malignant tumor 4 2 Transformed cells Metastatic tumor.

Benign tumor

(14): Severity increases and treatment becomes harder.

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1 2 3 4

Mutation. So, shape, structure and function may change. Uncontrolled proliferation. Invading and going into the local tissues surrounding its tissues. Having potential to metastasize and going into a distant place.

We said that the uncontrolled proliferation is pathognomonic (seen in all types of cancers). It shows something called gompertzian growth curve.

Platue phase

Detectable region

Exponential phase

Undetectable region

Figure (3)

As you can notice from the figure above, the X- axis represents time and the Y- axis represents number of cancer cells. So, the growth of the cancer cells will follow this curve.
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This curve has two phases, the 1st one is the exponential phase and the 2nd one is the platue phase. In the exponential phase, the cells have been mutated and transformed, so they will undergo exponential growth that increases steadily with time, until it reaches a point where it stops. Why did that happen although we know that those cells like to proliferate? We talked about angiogenesis and we said that it's important for metastasis. So, the proliferating cells will get their oxygen and nutrients from the blood vessels, thus will increase in size until they reach a point where they stop growing. Now, the point is that their size increases too much against the physical boundaries of their locations, so they are going to have a much reduced blood supply, so that the oxygen and nutrients supplies will be less , so they will not be proliferating anymore because it's physically and chemically impossible, and thats actually the platue phase for any cancer. So, in cases of hypoxia and depletion of nutrients, cells will stop growing and dividing. In cancer chemotherapy, there is a threshold for the clinical detection of cancer, it occurs when the cancer cells number reaches 10^9. And we can never recognize the cancer cells if they are under 10^9. The mass of those cells is 1gram and the diameter is 1 cm. The clinical detection of cancers includes x-ray, CT-scan and blood tests. We have another threshold that represents death of the patient, it occurs when the number of cancer cells reaches 10^12. We said that the clinical detection begins at 10^9 and extends to 10^12. So, the detectable region for cancer ranges from (10^9-10^12) and any number that is below 10^9 will be in the undetectable region. So, it's hard to deal with cancer
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because most of the conditions are subclinical and most of the patients even die before reaching the detectable region of cancer. So, all what we do now is to look for the heritable or inherited cancers. For example, we have one sort of cancer that happens in the gut in the colon, we call it the familial polyposis. It has a very strong family history, and if it happens in one patient, then we have to start screening for the next case, because as we said earlier, it's here in the undetectable region and you are not aware of.

Growth fraction.
In any kind of cell populations, whether it's cancerous or not, the cells are divided into two types: 1- Proliferating or actively dividing populations. 2- Quiescent cells.

Figure (4) [8]

In the cell cycle, and as you can see above; the cell starts at the G1 phase. It will prepare itself for the DNA synthesis and replication. Then it goes to the S phase, where the synthesis of DNA occurs. Then to the G2 phase, where it will prepare for mitosis at which the cell will divide. Some of these cells will not go through the G1 phase, but rather, they will go to the G0 phase where they don't proliferate (stay at rest), and this is actually the part of cell populations that we call quiescent cells. So, the growth fraction is simply the fraction of cells that are proliferating from the whole population of cells. This is actually different between a tissue and another. For example, in the bone marrow, the growth fraction is very high, because the progenitor and stem cells are always there, so the percentage of proliferating cells will be high. However, in the brain, the growth factor will be extremely different; because the quiescent cells will be much more. The growth fraction is always related to the growth rate and they work together hand by hand. That means if the growth fraction increases, then the growth rate is also going to increase. For example, if I take leukemia which is a type of progenitors cell cancer the growth fraction would be high, the growth rate would be also high and the disease would be much disseminated and sever. However, if you compare it to a tumor that arises in cells that are not that proliferating, then the growth factor, growth rate and the dissemination of the disease would be much less.

Management of cancer.
In the general concept, its achieved by the cooperation between 3 things: 1. Surgery. 2. Radiotherapy. 3. Chemotherapy. In most cases, we will use all the 3 classes together to treat one cancer type.
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 Aims of Chemotherapy:
1. Cure. This should be your main target as a physician. Get the cancer level from 10^9 to zero. But in most of the cases, we can't achieve 100% cure. 2. Regression strategy. It's more realistic than the cure. It's just reducing the number of cancerous cells. 3. Adjuvant therapy. We said that the cancer cells do angiogenesis and dissemination. And thus they will have the ability to metastasize. They could reach certain organs and become metastatic tumors there. Now, in most cases, we can't recognize those areas of metastatic tumors because they are very small. They have to reach a certain size, diameter and weight to be able to recognize them. Those subclinical tumors that we can't recognize them are called micro-metastasis. An example is seen in breast cancer. You might do surgery and take out the breast, but the problem is that those patients still have micrometastasis that you can't see even if you do a bone CT-scan. You are 100% sure that there is metastasis, but you can't see them. Now, if you give chemotherapy for such patients, you will be treating the metastasis before it happens or before becoming clinically detectable. And this is what we call adjuvant therapy. So, chemotherapy can be given as a prophylactic method to prevent the dissemination of cancerous cells.

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4.Neoadjuvant therapy.
It means that you give chemotherapy prior to the surgery by 2 or 3 days or even one month to make it easier for the surgeon to come and excise the tumor. So, it's just like decreasing the size of the tumor, making it easier to be removed. This can be seen in the case of brain tumors. Traditionally, they used to open the skull and then dealing with many complications to take out the tumor. But now, you can go through the nose or any kind of sinuses and get into the tumor and remove it with a gamma knife without the need to open the skull. And as we said earlier, this should be preceded by chemotherapy, to shrink the size of the tumor, and this is what we call neoadjuvant therapy. A summary: - Hypothetically, we aim to cure and decrease the number of tumors to zero. Realistically, we regress the tumor and decrease its size. - We give chemotherapy prophylactically to prevent the occurrence of micro-metastasis Adjuvant therapy. - We give it prior to surgery to shrink the size of tumor making it easier to be removed Neoadjuvant therapy.

How do chemotherapeutic agents work?

In general terms, they work by two mechanisms: 1- They produce toxicity in the neighbourhood to kill the cell (they have cytotoxic effects). 2- They induce apoptosis and then the cell will die (induction of apoptosis).
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Now, in both cases, we are killing the cancerous cells. But unfortunately, killing the cancerous cell is not a simple thing; because they belong to something called the log kill hypothesis. Let's imagine that we have a population of cancer cells and we got the chemotherapeutic agent, so it came and killed some of these cells. In this case, what would be the efficacy of this anti-neoplastic agent? Can I define it by saying that this agent has killed 1000 cancerous cells or do I need to provide a percentage like 10%? In cancer killing we can never deal with the absolute numbers of cells kills. The efficacy for any anti-neoplastic drug should be defined by a percentage and not by the absolute numbers of cells. So, we will use a fraction to know the remaining cells. If you want to give chemotherapy, it has to be given in cycles and repeatedly, because as we said earlier, anti-neoplastic agents kill 99 % of the cells not 100%, so there are always remaining cells and that's why you need to use another cycle. You should also look to the remaining cells and you will find that there will be huge numbers of remaining cells! I told you at the beginning that if you want to check for the cure or regression of tumor, you should use the curve showed in figure (3).Actually, this is wrong. We use another curve showed here in figure (5).

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This is the 1st cycle. This is 1st regrowth period. This is the 2nd cycle.

Figure (5)

So, you give the 1st cycle, followed by the 2nd one, etc until you get to the maximum number of cells being killed. In each cycle, you are killing by something called the log kill. So, if I reduce the number of cells from the 10^9 to the 10^7, then this is called a two log kill.

Why do we give the drug in cycles? Why don't we use it continuously and every day for the rest of the patient's life? Its because of the toxic effects of those chemotherapeutic agents. And at certain points they may never recognize if this is a cancer or a normal cell. So, you can never use chemotherapeutic agents continuously and forever, they have to be given in cycles to reduce their toxicity. But there is a problem, when you reduce the size of those cells, the oxygen and nutrients will become much more, so that between cycles, you can have periods of re-growth.
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 For example, if you give a drug for 2 months, and then leave it for other 2 months, and then you give another cycle, you will notice that the

patient will have a recall. And this is actually what we call the immortality of neoplastic cells; they want to proliferate more and more. Chemotherapy is a cell-cycle specific kill. Most of the chemotherapeutic agents are cell cycle specific. Meaning that they target the cell either in G1, G2, S, or M phases. Why is that? Because what happens normally in the cell is that we have nucleotides that will be included in the DNA synthesis then transcribed into mRNA which will be translated into protein. So, the point is that we 4 classes of chemotherapeutic agents: 1. Agents that will target nucleotides, by preventing their production inside the cell preventing the DNA synthesis. 2. Agents that will prevent the DNA synthesis by inhibiting the enzymes responsible for synthesizing. 3. Agents that will target the transcription process No mRNA and no protein produced for the cell to survive. 4. Agents that will target the production of proteins outside or inside the cell cycle (could be cell cycle specific or not). As you can see, most of these mechanisms are within the cell cycle and specifically within the parts of the cells that will proliferate or divide. And the quiescent cells will not be affected by this. So, what happens is that we are correlating this targeting with the growth fraction of the cells. Such that, tumors actively dividing are more susceptible to chemotherapeutic therapy.

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For example, if we want to consider leukemia, then it will be more actively dividing than brain tumors, and thus chemotherapy will be more effective in treating leukemia than brain tumors.

Within the tumor itself, we said that we have dividing and quiescent cells, so you have to know that those dividing cells are more susceptible to chemotherapy than the other types of cells. 1. 2. 3. There are 3 common examples on the actively dividing tissues in the body: Bone marrow. Mucous membranes. Hair.

By that, it's easy for you to remember the side effects of chemotherapy (most common): 1. Suppression of the bone marrow causing anemia, leukocytopenia (leading to infections) and thrombocytopenia (leading to hemorrhage). 2. Ulcerations like stomatitis and gastritis. 3. Alopecia (hair loss). We have other side effects that don't appear in all patients and don't happen acutely, including renal failure. But it takes a long time to happen (maybe 10 years or so).

Drug resistance. We have something that is called MDR (multi drug resistant) genes and proteins. It means that when the cancer becomes resistant, it will be resistant for all types of chemotherapeutic agents. It happens by forming many channels that are governed by ATP. And we know that the production of ATP is too much because the cancer
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cells are actively dividing. So, the cell will use those channels to pump the chemotherapeutic agents out.

So, cancer cells are multi-drug resistant and not one class resistant. (IMP)

Summary for the clinical uses of drugs : We rarely use combinations of drugs, because it leads to more and more side effects. But if you have to, then: - Use drugs that have synergistic or additive effects (they work by different mechanisms of actions). Example 2 drugs, one acts on nucleotide and the other one acts on the translation process. - Use drugs that have different systemic toxic effects. - Reduce the doses of each drug and the numbers of cycles given for the patient. - Keep praying that nothing bad can happen.

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-The EndGreetings to those who still have the ability to continue and give unlimitedly at the time they are the most who need!

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