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Targeting the Lifelines of Cancer
Whether we are considering chemotherapy, targeted therapies, or hormone therapies, most cancer-fighting medicines converge on the lifelines of a cancer cell-namely, its communications network. Like the normal cells from which they are derived, cancer cells rely heavily on their ability to communicate in order to function. They send and receive signals from nearby cancer cells as well as from surrounding healthy cells in order to survive and grow. Our cells have evolved a highly specialized communications network that is made up of a large and complex network of interacting molecules: signals dart around furiously as they might on a computer chip. Cancer cells co-opt critical nodes on this chip in the form of molecules that increase the signals to grow, spread, and resist death. As scientists identify these crucial molecules, drugs can be designed to block their function and shut down a line of communication. If this line is vital, the cancer cell may implode and die.
Both normal and cancer cells are protected from the outside world by a layer of fat called the lipid membrane. This membrane separates the watery environment of the inside of a cell from the rest of the body. Embedded within the lipid shield are tiny proteins called receptors that often span its width. Many millions of receptors on the cell surface function like antennae, picking up signals from the surrounding environment and transmitting them to the inner world of the cell on the other side of the lipid layer. Each type of receptor can be stimulated by only one or a few molecules, much as a lock can be opened by only one key.
Once a surface receptor becomes activated, it initiates a cascade of signals (think of falling dominoes) that travel through the cell to reach the destination, the DNA. These communications transmissions are a form of chemical energy that is passed like a baton in a relay race from one signaling molecule to the next. Ultimately, the final molecule in the relay heads to the DNA finish line, where it latches onto the double helix and modifies what DNA directs the cell to do; DNA responds by send ing out new commands that ramify back throughout the cell. The DNA may signal the cell to duplicate itself to increase the size of a tumor, spread to a new location to form a metastasis, or stay alive despite the body’s effort to eradicate it. The goal of cancer treatments is to disrupt this flow of information in the cancer cell, ultimately causing it to die. The three main components of the cancer communications system can be thought of as residing at different levels of a cancer cell: surface receptors at the outer layer, internal signaling molecules on the inside, and DNA embedded in the deepest part of a cell. Each component serves as a target for modern-day cancer-fighting drugs:
- Chemotherapy blocks DNA from functioning properly.
- Targeted therapies block surface receptors and/or signaling molecules from communicating their signals.
- Hormone therapies prevent estrogen or testosterone from generating growth signals in the cancer cell.
Each type of therapy works in a specific way to disrupt cell communication. Even though only one type carries the name targeted, each does seek out and attach to particular targets in the cell; even chemotherapy drugs attack specific regions of the DNA. Whereas targeted therapies are designed to block known targets, many chemotherapy drugs were originally discovered based primarily on their cancer-fighting properties before their targets in the cell were identified. It is because the targets of chemotherapy are so large (a cell’s entire DNA) and exist in nearly every cell of the body that chemotherapy tends to cause more side effects than targeted therapies.
Because many genetic derangements affect most cancers, often several pathways in the communications network must be disrupted to force a cancer cell to shut down. Accordingly, many patients are being treated with chemotherapy plus one or more targeted therapies to achieve a result superior to either type of therapy alone. As always, the most appropriate therapy depends on the specific cancer, the treatments that have already been used, and the medical condition of the patient.
Chemotherapy
Chemotherapy drugs represent a diverse collection of chemicals that have been proven effective in treating cancer. Each type of cancer responds to different chemotherapy drugs, although some drugs can be effective against many cancers. More than half of all chemotherapy drugs come from nature or are derivatives of natural compounds. For example, doxorubicin (Adriamycin) is made by a fungus, paclitaxel (Taxol) and docetaxel (Taxotere) come from the Pacific yew tree, and irinotecan (Camptosar) was isolated from a Chinese ornamental plant.
These drugs were found mainly through an extensive and ongoing effort of the National Cancer Institute to screen compounds made by plants, bacteria, fungi, and marine life for their cancer-fighting properties. A number of other chemotherapies have been rationally constructed by scientists to interfere with known mechanisms of cell growth. Still others have been discovered by serendipity.
Most chemotherapy drugs work by damaging DNA. They do so through a variety of mechanisms too complex to discuss here. Examples include doxorubicin, carboplatin, cisplatin, oxaliplatin, Cytoxan, 5-FU, fludarabine (Fludara), gemcitabine (Gemzar), and capecitabine (Xeloda).
Mainly, the drugs chemically attack DNA, like metal to a magnet, causing the double helix to break; they may also interfere with the cell’s DNA repair machinery, leading to further fragmentation of the genetic code. If the DNA, the cell’s molecular brain trust, sustains extensive damage, then the cell commits suicide or undergoes apoptosis. Some chemotherapy drugs do not affect DNA but instead target a different cell structure called microtubules to prevent a cell from multiplying. One of the most important signals that DNA communicates is for a cell to divide or multiply (by a process called mitosis). This is the process by which one cell becomes two; it is the grist for the mill of cancer growth. For this to occur, the DNA duplicates itself to form two copies; each copy goes to the opposite ends of the cell. Next, the cell splits down the middle, and two newly minted cells pinch apart from each other; an analogy would be the twisting of a long balloon to make two halves, which magically separate and seal at their ends to make two balloons.
This complicated process is dependent on a cell component called microtubules, long fibers that push the DNA to opposite poles of a cell and pull the two newly forming cells apart. Drugs like paclitaxel (Taxol) and docetaxel (Taxotere) prevent the push and pull of the microtubules and freeze the cell in place; the result is cancer cell death. The ability of chemotherapy drugs to preferentially kill cancer cells rather than normal cells rests with the fact that more cells are dividing in a cancerous tumor than in the other tissues of the body. As a result, cancer DNA and microtubules are more susceptible to chemotherapyinduced damage. For example, chemotherapy given for cancer that has spread to the lungs or liver will affect the cancer there but not likely damage the surrounding lungs or liver; in fact, normal organ function may improve if the damaging effects of the cancer are diminished. Chemotherapy drugs may work in other ways to eliminate cancer cells. One way is by reducing the blood flow to a tumor (called angio-genesis inhibition, discussed below). This effect is associated with frequently administered drugs, such as daily pills or weekly intravenous injections. Blood flow to the tumor is reduced when the blood vessel– forming cells that feed it are killed; like cancer cells, these cells are also busy multiplying, building a blood supply for the cancer.
The modern era of chemotherapy
Talking about chemotherapy is like talking about the weather: on any given day, in any part of the world, there can be perfect calm or there may be a blizzard.
When discussing the side effects of chemotherapy, just as when discussing the weather, it is important to avoid generalizations and not lump all chemotherapy together. The specific drugs, doses, and schedules in which chemotherapy is given as well as the patient’s constitution determine how well it is tolerated. Whereas some chemotherapy regimens are very hard on the body, others are compatible with normal routines. Before receiving chemotherapy, patients are usually given fact sheets describing the possible (likely and less likely) side effects of each medicine as well as the opportunity to meet with an oncology nurse to talk about what to expect.
Fears about chemotherapy drugs can cause great anxiety among those about to undergo treatment. A great deal of misinformation exists about their side effects. Some of this is a holdover from days long gone when cancer patients receiving chemotherapy frequently experienced nausea and vomiting as well as a greatly diminished ability to prevent certain infections. We are now in the modern era of chemotherapy, in which many of the most severe side effects have been greatly improved by a host of medications. My intent is not to minimize the serious side effects that chemotherapy can sometimes cause and about which there is ample information. My goal is to clarify the misconceptions about chemotherapy that I frequently hear from new patients in my oncology practice.
If you are undergoing chemotherapy treatments, I recommend reading the pamphlet Chemotherapy and You, available free from the National Cancer Institute. It contains helpful information on managing the side effects of chemotherapy.