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New cancer drugs affect specific cellular targets

According to the American Cancer Society, last year, 147,000 new cases of colorectal cancer were detected and 57,100 patients died of the disease in the United States. Colorectal cancer was the second largest cause of cancer-related mortality behind lung cancer in the country. Although early diagnosis through screening and surveillance has steadily decreased mortality, a considerable number of patients suffer from metastatic or advanced disease in which cure is not possible and the treatment is largely palliative. Chemotherapy medications, such as Camptosar and Oxaliplatin, which were introduced within the past few years, are effective and have roughly doubled the survival from one year to approximately two years. Chemotherapy, however, releases a lethal assault on cancer cells and also some surrounding normal cells, which leads to undesirable side effects.

Research into cell biology in the postgenomic era has uncovered basic pathways of cell division, proliferation and programmed cell death. It has also revealed the mechanisms of new blood vessel formation and cellular growth and death signals that are necessary to stimulate growth and programmed death of malignant cells.

Based upon this knowledge, specific targets have been identified and exploited for the purpose of developing new drugs to treat cancer. Because they are directed to specific targets, there is minimal exposure to normal tissues and consequently minimal side effects.

Some of these drugs are already in the market, and several are in the pipeline at various stages of testing. Initial results are very encouraging. In the following paragraphs, each one will be briefly mentioned and described.

Avastin is an antagonist of the Vascular Endothelial Growth Factor (VEGF). This growth factor is essential for the formation of new blood vessels, through which the tumors derive their blood supply and nutrition. Avastin and other antiangiogenesis agents work by cutting off the blood supply and starving the tumors to death. In clinical trials, Avastin demonstrated a prolongation of life in treated patients with metastatic colorectal cancer. It is on file for approval with the FDA and is expected to be approved and commercially made available for treatment of patients in a month or two.

The Wall Street Journal recently carried a story of a 65-year-old man with colon cancer that had spread to the liver. He was told by his doctors that he would die within a year. On treatment with Avastin, he is not only alive after 22 months but has a documented tumor shrinkage and is leading a normal life. The idea that interruption of blood supply to tumors can be used therapeutically, first conceived in 1930s, is now coming to fruition.

Erbitux is an anti-EGFR (Epidermal Growth Factor Receptor). These growth factor receptors are present on the surface of the cancer cells. These receptors are the main portals of entry for the growth signals, which, when interrupted, lead to growth arrest of tumors. Its initial application to the FDA was turned down because of concerns of the way the research was conducted. This was the insider trading scandal involving Martha Stewart.

An exceptional story is that of a 65-year-old woman with colon cancer that had spread to the liver, abdomen and pelvis. Her doctors had given her three months to live. She was treated with Erbitux on a clinical trial. Two years later, the patient is in complete remission to the point that no tumor was visible on a PET scan.

In clinical studies, Erbitux shrank tumors in 11 percent of patients on its own and 23 percent of patients when combined with Camptosar, a chemotherapy drug in current use for metastatic colorectal cancer. Erbitux is pending FDA approval and is expected to pass soon.

The next drug for colorectal cancer that could soon become available is currently labeled as PTK787/ZK222584. It is similar to Avastin in its mechanism of action but differs in that it is orally administered while Avastin is given by intravenous infusion. Patient accrual for the clinical trial will be complete by 2004 and should be in the market by 2006.

Iressa is approved for treatment of lung cancer. It is similar to Erbitux in that it inhibits the receptors that cover the growth signals to the cell. Velcade is yet another drug in clinical trials for metastatic colorectal cancer. It belongs to a new class of drugs that inhibit proteasome by disrupting pathways that growth and programmed death signals traverse. It is already approved for treatment of multiple myeloma, a malignant disease of the bone marrow.

Two other drugs that inhibit the EGFRs, as Erbitux and Iressa do, are ABX-EGF and Tarceva. Another new drug, Tezacitabine, inhibits tumor growth by interrupting with DNA replication. All these are in clinical trials, which should mature in the next couple of years.

It appears that there will be a number of new drugs that will become available for the treatment of advanced colorectal cancer in the very near future. Obviously, some patients will tolerate certain drugs better than others, and some drugs will work better in some patients than others.

Studying the genetic profiles of individual patients might allow the oncologists to pick and choose the most efficient drug with the least likelihood of toxicity for a given patient.

Additionally, drugs that work well in the metastatic setting where the tumors have gathered mass and become entrenched might work even better if given in earlier stages of the disease. This hypothesis, however, needs to be tested in clinical trials.

All in all, the postgenomic revolution in genetics and molecular medicine hold a lot of potential for smart and safe drug development for cancer and other diseases.

_ Dr. V. Upender Rao, FACP, practices at the Cancer and Blood Disease Center in Lecanto.

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