Chemotherapy

Here I want to talk about chemotherapy, its pros and cons. In this type of cancer treatment, we give drugs mostly intravenously. As you know, within seven seconds they are going to get to virtually every cell in the body. The good thing about chemotherapy is that we don’t need a target. This is why it has become so important in metastatic cancer. We don’t need to know where the cancer cells are hiding, the drugs will get there. However, it is very toxic and it isn’t good for handling tumor bulk.

There are a couple of things about this treatment that you need to know. There is something called the Goldie-Coldman hypothesis. This is a huge mathematical concept that I have no idea what is about. I know, however, what Doctors Goldie and Coldman found out. They found out that chemotherapy would fail even in very small numbers of cells unless you go the whole way and get all the possible metastatic cells. You cannot back off and get the same result.

If you’re getting a bad result with surgery or radiation you can always back off for the patient to rest and pick up again. In chemotherapy, however, if you don’t finish the course of treatment because of toxicity, then the patient is very likely to have a lot of resistant cells that escaped through natural selection. You’ll get the most resistant cells.

Goldie and Coldman also say that it’s very unlikely you’re going to be able to do the job with one drug. We usually don’t use one drug. We use multiple drugs so that we can lower the toxicity of each one. We try to get drugs with different toxicities. Maybe we use one that works maybe depressing the bone marrow, which is a bad thing. We may use another that has another toxicity and you get a synergistic effect that kills the cells you want to kill and not make the patient so sick.

Ideally we use eight or ten drugs, but we generally use two or three and try to get the patient to complete the whole cycle. Just about the time things are really getting bad for the patient we back off and pick up again later. These cycles are timed to try to get the cancer cells when they just caught their breath and started to multiply again. Meanwhile, normal cells have probably recovered pretty well.

It is very hard to measure the effectiveness of the treatment unless you have some tumor you can see. The most important type of chemotherapy is the category called adjuvant therapy. Adjuvant cancer therapy has a very specific definition. It means that it is given to a patient in whom we cannot prove that they have metastasis, but we highly suspect it.

What we found out is that if you wait until there are enough tumor cells to produce symptoms it is usually too late to get the best results from any treatment. If you move in to a patient who has microscopic metastasis, you’re going to get the best result. How do we know who that patient is?

Adjuvant therapy, therefore, is defined as drug therapy given to a patient without proven metastasis but who we think has a very high likelihood of having them. Doctors do all the studies they can and say to the patient: “Look, it is likely that you’re cured, but we’ve got a lot of bad biologic markers. We would do you a lot of good if we do the chemotherapy now, before this comes back three years down the road.”

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Cancer Treatment

We’ve seen what cancer is and what we think causes it. What about cancer treatment? How do we treat and cure this fearsome disease? There are three ways to treat cancer: surgery, radiation and chemotherapy. Surgery is by far the most common cancer treatment. Removal of a tumor that is localized can cure cancer. Much of cancer surgery in recent years has become conservative of the surrounding tissue.

Radiation is used in cancer treatment on localized regions that can’t be removed in surgery. This might be in a very diffuse area, for example. It also might be useful to shrink a tumor that is up against a vital organ and the surgeon is afraid of damaging that organ. Radiation damages DNA, it causes both strands of DNA to be broken. The amounts of radiation used are small from the military viewpoint, but quite large from the medical one. Let’s illustrate this. The lifetime exposure to radiation of a typical person on Earth is about 0.12 gray (a physical unit). During the course of radiation treatment, the tumor itself gets 50 gray over five weeks. That’s 400 times the lifetime dose.

The third method of cancer treatment is called chemotherapy. It is used when tumors have spread over the body, because when you put a drug in the blood system, it will be distributed everywhere. Typical chemotherapy uses drugs that kill all dividing cells, including the tumor. There are side effects to chemotherapy. Normal tissues get affected, like bone marrow, cells in the intestines and skin.

A wide array of drugs that block cell division have been isolated and are used. Some are natural products we get from plants, others we build in the laboratory.

A Real Life Case

This is a real case involving cancer treatment with chemotherapy. John first noted that he tired easily at the gym. It got worst over several weeks. When he began to have shortness of breath even when he walked from room to room, he decided to see his physician. When his doctor looked at a drop of blood under the microscope, he saw many white blood cells. A blood sample was sent to laboratory, and they confirmed that he had over 200000 white blood cells per milliliter. This is 40 times normal. An hematologist looked at bone marrow as well as the blood and found a lot of immature white blood cells. In addition, he saw an abnormality: a funny looking chromosome called the “Philadelphia chromosome”. The diagnosis: chronic myelogenous leukemia.

No one knows how, but in this disease, the DNA in two chromosomes inside an immature white blood cell is cut and spliced. Two chromosomes exchange material, so that part of two genes that are ordinarily on separate chromosomes come to be right beside one another. The shuffled chromosome that was seen in John’s white blood cells was first noticed by scientists in Philadelphia in 1960, that’s where it got its name. White blood cells carrying this strange chromosome are stimulated to divide very rapidly. This is why they found this huge number of cells in John.

John was first treated with standard chemotherapy. He was given drugs designed to kill any reproducing cell. One of the drugs bound to DNA. A second one blocked the assembly of amino-acids. A third drug blocked the mechanism that partitions chromosomes to new cells. These drugs have bad side effects on other dividing cells. Using this conventional cancer treatment, John’s white blood cell count went down from 200000 per milliliter to 80000 per milliliter. This is still 16 times normal, however.

The drugs that John took blocked cell division all over the body. They were non-specific. John’s oncologist now tried a new approach: a specific drug. In the 1990’s, the molecular biology of this type of leukemia was described in detail. The new gene found in the Philadelphia chromosome was sequenced, and its protein product was studied. The protein turned out to be a terrific cell-division stimulant. It causes cells to divide without control.

Next, chemists at a drug company went into the laboratory and designed a brand new substance: a chemical that would specifically bind to and inactivate this new gene product in the tumor cells. At the University of Oregon, Dr. Brian Druker coordinated a clinical trial in which patients with chronic myelogenous leukemia were given this drug; to test for its safety and then its effectiveness. Patients like John, whose blood concentration of white blood cells was still high, were given the new drug and the result was spectacular. In John’s case, his white blood cell count went down to a normal 5400 per milliliter. He was cured.

The development of this drug, which is called Gleevec, is a great example of a new molecular approach to cancer treatment. The aim is to find out precisely what’s going wrong in a tumor cell and design rational treatments on this basis.

Precise molecular descriptions of the chemical biology of cancer are leading to new drug treatment for cancer and targeted chemotherapies.

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