Chemotherapy and DNA

A large number of adjuvant chemotherapy drugs are also DNA damaging agents. When the drug is transported across the cell barrier, it interacts either directly with DNA (cisplatin, 5-FU), or it interferes with cellular machinery for maintenance of DNA quality (camptothecin, topotecan). A few others such as taxol are even more indirect, instead hitting the "structural" parts of the cell which hold it up or together. But in general, the chemotherapy drugs damage DNA in some way.
If you read what is adjuvant chemotherapy in this blog, you will find that these drugs hurt all cells. Understanding that the way they work is by damaging DNA, also makes it obvious why these drugs are hurting all cells. But importantly, because cancer cells are dividing rapidly, they must continually make DNA so are susceptible to the DNA damaging agents.

Most interesting are the class of drugs for adjuvant chemotherapy known as the topoisomerase inhibitors. Topoisomerase is a cellular machinery that winds and unwinds DNA as it's about to be replicated. DNA exists as a double helix, but must be "opened up" so that it can replicate and divide into two for each daughter cell. The topoisomerase inhibitors are drugs which interfere with the topoisomerase preventing it from winding or unwinding the DNA effectively. As a result, the DNA of the cells become damaged due to incorrect unwinding and winding.

There is also an very interesting compound known as "cisplatin", which contains the metal platinum. It is a very "simple" drug in the sense that it contains an atom of platinum, surrounded by just a two nitrogens and two chlorines. The other compounds mentioned have much more complicated chemical formulas and structures. Their complex structures give them the ability to break DNA by mimicking it, or by specifically shutting down proteins and enzymes that maintain DNA integrity. But the cisplatin is slightly different. The platinum atom has a structure which allows it to draw in atoms from other molecules. In particular, when placed near a DNA molecule, the platinum atom draws in DNA atoms and bends it. Breaks in the DNA is thought to occur when it is bent by platinum. The cisplatin family has spawned a series of other platinum compounds such as oxaliplatin with various additives that enhance its cancer killing ability. However, for some reason certain patients become resistant to platinum therapy. While nothing can prevent cisplatin from binding to DNA, the cancer cells likely evolve DNA repair strategies or short-circuit the cell-death processes which generally lead to destruction of cancer cells.

The resistance of cisplatin adjuvant chemotherapy can be potentially overcome with other types of drugs such as taxol.

Neoadjuvant chemotherapy for breast cancer

This site is called adjuvant chemotherapy, meaning chemo in addition to whatever surgical procedure is used to remove the breast or colon or what not cancer in patients. What is neoadjuvant chemotherapy? In certain cases, a patient will have an outsized growth, while not metastatic (i.e. it hasn't yet "spread"), is just so big that it's too hard to remove by surgery alone. It may have bulged into tissue that's surrounding it, and removal would incur great damage because of the need to excise lots of tissue around any one particular tumor. This is where neoadjuvant chemotherapy comes in. The latin word "neo" means new, and in this case, for a new tumor one is targeting it with chemo before hitting it with surgery. The purpose of this is to attempt to shrink the tumor. Of course, any patient who undergoes neoadjuvant chemotherapy is still going to suffer from chemotherapy side effects such as sickness and hairloss and fatigue. Success with this kind of therapy is if the tumor shrinks, and then becomes easier for the surgeon to remove. For a patient, this is probably a harrowing time, since any patient who has cancer probably wants to get the thing excised as soon as possible. Now with the physician telling him or her to wait out a few months taking chemotherapy must be nerve wracking. Basically, the idea is to get the tumor to shrink.

There are certain kinds of breast cancer for which neoadjuvant chemotherapy is indicated. For example, inflammatory breast cancer (IBC) is characterized by inflammation of breast tissue, and growth in sheets rather than solid masses. This makes the cancer difficult to localize for surgical removal, and as such, drugs would be most suitable for treating this type of disease manifestation. Some symptoms of IBC are given by:

* Changes in skin surface of breast, such as localized thickening
* Extra warmth, due to blood vessels dilating in response to inflammation
* Pain, sharp or dull
* Color changes of the areola
* Itchiness
* Sudden swelling, sometimes a cup size in a few days
* Erythema, with texture like skin of an orange
* Nipple retraction
* Nipple discharge

Worse still, IBC may not be detectable via traditional imaging methods such as ultrasound or mammography because of its diffuse, nonsolid nature. Physicians are usually advised to be cautious in interpreting imaging of breasts that have the above associated symptoms. A needle biopsy may show more definitive results than using ultrasound or mammograms. Finally, IBCs have been known to progress to more aggressive cancers at a higher rate than solid mass tumors. This is not well understood, but is thought to be due to the complex nature of the inflammation. Inflammation of tissues is usually associated with deranged signaling processes of the cells, which can trigger changes that lead to cancer metastasis. Metastasis is the dreaded "spread" of the cancer from its primary site to far, secondary sites. For example, a tumor in the breast may break off in pieces and lodge itself in the lungs, giving rise to lung cancer. Such metastatic cancers are difficult to treat with surgery, and one must rely completely on the efficacy of neoadjuvant chemotherapy in wiping them out.