Taxanes and Platinum Drugs in Cancer Treatment

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Taxanes
The taxanes are a group of drugs that includes paclitaxel (Taxol®) and docetaxel (Taxotere®). Taxanes have a unique way of preventing the growth of cancer cells by affecting cell structures called microtubules, which play an important role in cell function. In normal cell growth, pre-existing microtubules, which support cell shape and act as “highways” for transport of materials inside the cell, are completely rearranged into a machine called the spindle when a cell starts dividing. Once the cell stops dividing, the spindle disappears and a microtubule network reappears. These rearrangements require rapid microtubule disassembly and reassembly. Taxanes stop microtubules from breaking down and rearranging properly. In addition, they cause too many microtubules to form and to form in the wrong places. All this prevents cancer cells from growing and dividing in an efficient manner [see 'Animation' video].

Paclitaxel
Paclitaxel is a compound that was originally isolated from the bark of the Pacific yew tree (Taxus brevifolia). Early research using paclitaxel was limited due to difficulties in obtaining sufficient quantities of the drug. The amount of paclitaxel in yew bark is small, and extracting it is a complicated and expensive process. In addition, bark collection is restricted because the Pacific yew is a limited resource located in forests that are home to the endangered spotted owl.

As demand for paclitaxel grew, NCI, in collaboration with other government agencies and the pharmaceutical company Bristol-Myers Squibb, worked to increase the availability and find other sources of paclitaxel besides the bark of the Pacific yew tree. This work led to the production of a semi-synthetic form of paclitaxel which is prepared from precursor chemicals called baccatins. These chemicals were derived from the needles and twigs of the European or Himalayan yew tree (Taxus bacatta), which is a renewable resource. The Food and Drug Administration (FDA) approved the semi-synthetic form of paclitaxel for use with cancer patients in the spring of 1995. This form of paclitaxel has now replaced the drug derived from the bark of the Pacific yew tree.

In 1984, NCI began clinical trials that looked at paclitaxel’s safety and how well it worked to treat certain cancers. In December 1992, the FDA approved the use of paclitaxel for initial or first line ovarian cancer that was resistant to treatment. Paclitaxel was later approved as initial treatment for ovarian cancer in combination with the platinum drug cisplatin. Women with epithelial ovarian cancer are now generally treated with surgery followed by a taxane and a platinum drug.

The FDA has also approved paclitaxel for the treatment of breast cancer that recurs within six months after adjuvant chemotherapy, or that has spread to nearby lymph nodes or other parts of the body. Paclitaxel is also used for other cancers, including AIDS-related Kaposi’s sarcoma and lung cancer. Paclitaxel is now being used to such a wide extent that sales of the drug exceeded $1.5 billion in 2001.

Side effects of paclitaxel include hypersensitivity reactions such as flushing of the face, skin rash, or shortness of breath. Patients often receive medication to prevent hypersensitivity reactions before they take paclitaxel. Paclitaxel can also cause temporary damage to the bone marrow. Bone marrow damage can cause a person to be more susceptible to infection, anemia, and bruise or bleed easily. Other side effects may include joint or muscle pain in the arms or legs; diarrhea; nausea and vomiting; numbness, burning, or tingling in the hands or feet; and loss of hair. Nevertheless, for many patients with cancer, the benefits outweigh the risks associated with this drug.

Docetaxel
Docetaxel, a compound that is similar to paclitaxel but developed later than paclitaxel, is also used to treat cancer. Docetaxel, like the semi-synthetic paclitaxel, comes from the needles of the yew tree. The FDA has approved docetaxel to treat advanced breast, lung, and ovarian cancer. While docetaxel is similar to paclitaxel, its pharmacokinetics, toxicity profile and other factors are different from paclitaxel. Additionally, docetaxel can cause fluid retention. This can result in shortness of breath, swelling of hands or feet, or unexplained weight gain. Before receiving docetaxel, patients are often given medication to prevent fluid retention.

Researchers continue to look for new and better ways to use taxanes to treat cancer. They are studying paclitaxel in combination with other anticancer drugs to treat many different types of cancer, including lymphoma and cancers of the head and neck, breast, esophagus, stomach, bladder, prostate, endometrium (uterus), and cervix. In addition, researchers are studying ways to overcome some cancers’ resistance to paclitaxel. Clinical trials are also in progress to test the effectiveness of docetaxel, alone or in combination with other anticancer drugs, for several types of cancer, including cancers of the head and neck, prostate, breast, lung, and endometrium.

Platinum Drugs
Platinum, a metal, is the 78th element in the periodic table of elements and has long been known to chemists. It began to reach Europe in the middle of the 18th century from Spanish colonies in South America. Today it is used in jewelry, electrical contacts, thermometers, and catalysts. Cisplatin was first made in an Italian laboratory in the middle of the 19th century. Its use in medicine stems from the experiments of Barnett Rosenberg, a physicist working on the effects of electric fields on cell growth at Michigan State University in the mid-1960s. This led to the clinical introduction of cisplatin as an anti-cancer agent.

Platinum drugs cause cell death by the formation of chemical cross-links in DNA that interfere with DNA replication and transcription which, in turn, leads to cell death. However, a more precise mechanism of action of existing platinum drugs needs to be elucidated. Because metal-based drugs are likely to be readily transformed in the body by oxidation and chemical substitution reactions, the administered form of the platinum compound is unlikely to be the active form of the drug. During the past few years, sensitive nuclear magnetic resonance (NMR) methods for studying the chemical and biochemical transformations of platinum drugs have been developed in the hopes of advancing our understanding of mechanism and activity. Current research is aimed at the design of new platinum compounds that would be active against a wide range of cancers and have few toxic side effects.

Cisplatin (Platinol®, Bristol-Myers Squibb), the first platinum analogue, was introduced approximately 20 years ago and is still widely used. Cisplatin was followed by carboplatin (Paraplatin®, Bristol-Myers Squibb), and most recently by oxaliplatin (Eloxatin®, Sanofi-Synthelabo).

Cisplatin and carboplatin have similar efficacy profiles. Cisplatin has a well-established spectrum of activity in lung, ovarian, and germ cell tumors while carboplatin is used extensively to treat ovarian and lung cancers. Oxaliplatin is currently approved for the treatment of colorectal cancer.

Cisplatin and carboplatin have some undesirable side effects and toxicities and, in addition, many solid tumors that initially respond to platinum-based therapy become resistant, and disease recurs. Platinum resistance presents significant challenges in the treatment and management of many solid tumors. While damage to the nerves and damage to the kidneys are the main dose-limiting toxicities observed following cisplatin treatment, suppression of bone marrow activity is most significant following carboplatin treatment. Carboplatin is known to cause cumulative dose-related toxicity that results in slow bone marrow recovery. Peripheral nerve damage is the most prominent and best documented side effect in patients treated with oxaliplatin.

These three drugs are also widely used in combination therapies for numerous solid tumors including ovarian, lung, testicular, bladder, colorectal, gastric, head and neck and melanoma cancers. Worldwide total platinum drug sales (including the aforementioned drugs and several newer ones in early phase clinical trials) are estimated to reach $1 billion in 2002.

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