With more than 200 different types affecting humans, cancer is among the leading causes of mortality worldwide. However, one-third of cancer deaths are preventable. According to the American Cancer Society, there are an estimated 14.5 million child and adult cancer survivors in the United States, the majority of whom are older than age 50 and have survived either breast or prostate cancer. All told, two-thirds of patients with invasive cancer will now survive at least 5 years.

Analysis of the DNA of various cancers has already ushered in targeted therapy and should ultimately lead to earlier diagnoses. Let's take a closer look.

In the genes

Picture a stepladder with 3 billion steps. The sides of this ladder are made of sugar phosphate. The steps of the ladder are made up of the paired molecules adenine, thymine, guanine, and cytosine. Adenine is always paired with thymine. Guanine is always paired with cytosine. These four continue on in random order to make up the 30,000 genes in human DNA. The ladder winds and coils upon itself to finally form the X-shaped chromosomes that float around in the nuclei of cells. DNA dispatches messenger RNA from the nucleus into the remainder of the cell to create proteins and conduct the cell's business.

Cancers begin with the mutation of genes. There can be a point mutation where a single molecule is inserted or deleted; this disrupts the normal sequence of the neighboring steps. More significantly, there can be mutations at the chromosome level, such as when chromosomes 9 and 22 are abnormally fused together. The body has repair genes in place that are constantly at work either repairing defective genes or directing mutated cells to undergo cell death (apoptosis) if the defects can't be fixed.

One such tumor-suppressor gene is TP53, which writes code for the p53 protein. If the TP53 coding gene becomes mutated, then there are subtle changes in the shape of the p53 protein that prevent it from properly doing its repair work. Thus, the mutated cell can continue to replicate itself unchecked. Mutation of the TP53 gene plays a role in over half of all cancers. The APC gene is another tumor-suppressor gene that can lead to a severe form of colon cancer if mutated.

There are other genes that, when mutated, send abnormal growth signals to cells, allowing for proliferation of cancers. Hundreds of these oncogenes have been identified. One such oncogene is HER2, which plays a role in one-fourth of all breast cancers. When mutated, the oncogene RAS codes for the tyrosine kinase protein that sends strong growth signals to cancer cells.

Telomeres are protective segments that cover the ends of chromosomes and help preserve the DNA. They're made of thymine-thymine-adenine-guanine-guanine-guanine sequences that are repeated up to 3,000 times. Shortened telomeres are associated with a higher risk of chromosome mutation. Around 25 ladder steps are lost naturally each year during division of the cell. Oxidative damage from air pollution, tobacco smoking, and obesity can accelerate the loss of segments. Regular physical activity, adequate fiber intake, and intake of antioxidant foods containing vitamin C, E, and beta-carotene are associated with longer telomere segments.

In the cells

As a group of cancer cells reaches the size of a breadcrumb, it uses the vascular endothelial growth factor to begin growing its own blood vessels to ensure its growth. Although these aren't exactly the same as normal blood vessels, they're successful in delivering oxygen and nutrients to the tumor. The targeting drug bevacizumab was developed to block the development of such vessels. Many adverse reactions are possible with this drug and its benefits haven't yet materialized in terms of prolonged patient survival. It's believed that this agent will show potential when used in combination with other drug types.

There are many traditional chemotherapy agents that are designed to bond to the DNA in cancer cells and render it ineffective. This destroys (lyses) the cancer cell. Some of these agents are mercaptopurine, gemcitabine, fluorouracil, and cisplatin. Other agents, such as vincristine and docetaxel, lyse the cancer cell by interfering with the function of the tubule and spindle structures that make duplication of the cell possible. Topoisomerase is an enzyme that assists in the functioning of the cancer cell's DNA. Drugs that block this enzyme include irinotecan and doxorubicin.

Cancer cells are able to produce proteins on their surfaces that block recognition of the cancer as an invader by the body's B and T lymphocytes. Using murine technology, a specimen of the tumor can be extracted from the patient and then injected into a mouse. The mouse then grows antibodies to the tumor. The mouse antibodies are "humanized" with the addition of human DNA segments and then reinjected into the patient. These antibodies then recognize the cancer's protective proteins and signal the patient's killer T cells to attack the tumor cells.

Such immunotherapy, along with nanotechnology, allows particles of radioactive iodine to be attached to murine antibodies (see Let's go nano). The antibody portion of the molecule attaches to the cancer cell surface and the iodine 131 portion destroys the cancer cell with radiation (see Treating the treatment). This means, however, that any adjacent healthy cells are also affected by the radiation. Infused radiation can also be toxic to the kidneys. A diphtheria-like particle may also be linked to a murine antibody. The antibody attaches to the surface and the particle lyses the cancer cell.

Another immunotherapy technique involves removing the patient's T lymphocytes, redesigning them in a lab to recognize a cancer cell surface marker, and then reinfusing the T cells back into the patient. A vaccine can also be developed for not only one, but all of the markers in a given tumor based on genetic analysis.

A tumor's presence in the body will initiate a response from an intact immune system. The patient will circulate stress cytokines, such as interleukin-6, and be in a state of continuous energy expenditure even at rest. This begins the process of cachexia, which the patient will experience over time as a loss of muscle mass, anorexia, and a sharp decrease in weight. Cachexia is linked to one-third of cancer deaths. Attempts to improve the patient's food intake may increase weight and levels of adipose tissue, but won't reverse the loss of muscle. Limited improvement in lost body mass has been achieved with fish oil and celecoxib. These agents reduce the body's inflammatory response to the cancer.

DNA all the way

There are very few definitive cancer screening methods currently in place. Even the mammogram and prostate-specific antigen test have come under scrutiny. Pap smears may soon be replaced with a DNA analysis of cervical cells. Analyzing cancer DNA can lead to earlier diagnosis and help target therapy.

Treating the treatment

A general rule in chemotherapy is the dosage of a drug that produces an antitumor effect is also the dosage that will produce adverse reactions in the patient. Chemotherapy agents attack the DNA in the nucleus of rapidly dividing cancer cells, but also affect the DNA of rapidly dividing healthy cells. This brings on the familiar gastrointestinal tract symptoms, alopecia, and pancytopenia.

Patients with cancer regularly have to be premedicated with antihistamines, antacids, acetaminophen, and steroids to better tolerate a run of chemotherapy. Oral dexamethasone can be given over a period of days before therapy. Blood products or red blood cell and white blood cell growth stimulants can be given to maintain adequate blood counts. The patient will need antibiotics to reduce the risk of infection if the granulocyte count drops.

Chemotherapy agents, especially at higher dosages, activate the nausea receptor in the brain. Ondansetron can be given to block this activation. Agents such as carboplatin can be toxic to the kidneys and require the patient to remain well hydrated. The kidneys are also taxed by the massive release of potassium by cancer cells as they're destroyed. The patient may go into renal failure and require dialysis.

The newer chemotherapy drugs are designed to target the surfaces of cancer cells and spare healthy cells. These targeting agents are, in general, better tolerated but still have adverse reactions of their own. Sorafenib, which inhibits tyrosine kinase growth protein, can cause severe rash on the hands and feet, and a decrease in muscle mass. If this occurs, the dosage of the drug must be reduced or treatment delayed.

Let's go nano

A nanometer can be thought of as a billionth of a meter; 5,000 nanometers would fit around a hair strand. Nanocrystals can be injected into a tumor to enhance absorption during radiation treatment. Nanocapsules are shells covered with molecular binding sites and filled with a chemotherapy drug. The shell binds to a cancer cell, is drawn into it, and dissolves to release the drug. Nanorobots are cylinders made of synthetic DNA strands that can now recognize up to 12 different types of tumors. The bot is filled with a chemotherapy agent; once in contact with a particular type of cancer cell, the cylinder pops open to release the drug.

REFERENCES