AntiCancer - II

With antibiotics we can exploit the differences between bacterial and human cells to treat the infection. With chemotherapeutics, cancer cells are so similar to normal human cells, that selective toxicity is not really possible to attain. This brings us to the topic of Chemotherapy Toxicity.

Chemotherapy Toxicity:

1. Normal cells in the body that tend to be injured the most due to chemotherapy are those which have a high growth fraction. This is the limiting element to chemotherapy drug use.

2. Chemotherapeutic drugs lack selective toxicity.

3. Catch 22 of chemotherapy – Most of the drugs used have condierable toxicity yet in order for them to be effective they have to be used long enough to destroy all of the tumor cells present in the body. If even one cell is left over, it can proliferate and produce another tumor. So you have to find a balance between the duration of drug use and the eradication of the cancer.

4. Specific tissue toxicities due to chemotherapy:

• Bone marrow

• GI Tract

• Hair follicles

• Reproductive toxicity

Other Toxicities:

• Hyperuricemia – Increased uric acid in blood. Can be treated with allopurinol and large amount of fluid. Allopurinol works by inhibiting xanthine dehydrogenase which is needed in uric acid synthesis.

• Local injury from extravasation of vesicants. If a given chemotherapeutic drug were to come into contact with the skin due to a leaky IV it could cause burning and necrosis. Make sure the IV is securely in place.

Strategies used in Chemotherapy:

1. Intermittent Chemotherapy: Method of giving chemotherapeutic drugs in intervals. It is beneficial only if the patient’s normal cell population can recover quicker than the cancer cell population.

2. Combination Therapy: This multi-drug therapy is used more frequently today. Advantages to this method include increased numbers of killed cancer cells, reduced injury to normal cells, and supression of drug resistance. There are several requirements for its use.

• Each drug has to be effective if given independently

• Each drug should have a different mechanism of action from the other drugs being used.

• Minimal overlapping toxicities should exist between the drugs.

The specific combinations of drugs are decided empirically.

3.) Risks involved in chemotherapy must be weighed against the benefits when deciding a course of treatment. One tool used for this is the Karnofsky Performance Scale, which takes into account the stage of the illness, the possibility of cure, and other factors.

Problems with Chemotherapy and treating Cancer:

There are several problems that we have to deal with in the treatment of cancer:

1. 100% cell kill is required. If there is one remaining tumor cell after treatment, hte cancer is not cured and can reestablish itself.

2. The kinetics of cancer chemotherapy are always first order. This means that a certain dosage of the drug kills a constant fraction of cells as opposed to killing an absolute number of cells. (i.e. In order to kill off 50% of 1000 cells you have to use the same dosage that you would use to kill of 50% of 100 cells.) This is problematic because this dosage may not be tolerated by the patient.

3. Detection. The smallest tumor detectable is approximately 1 cm in size or 109 cells. This is a lot of cells and means that approximately 30 divisions have already taken place. If detection is late the tumor has a better chance of having metastasized. These larger tumors are often less responsive to chemotherapy. (Think about recruitment as a strategy to deal with this.)

4. Resistance to chemotherapy may develop by several mechanisms.

• Decrease in the amount of drug uptake by cancer cells

• Increase in the amount of drug removed by cancer cells. (Transporters.)

• Decrease in drug activation – certain drugs require activation by the liver in order for them to work.

• Decrease in target molecule sensitivity – this is cause by mutation in the molecule targeted by the drug

• Increase in DNA repair ability of the cell via an increased expression of DNA repairing enzymes.

Supportive Therapy:

1. Anti-emetics. Nausea and vomiting are major problems with cancer chemotherapy. The nausea and vomiting experienced by these patients cannot be compared to what one experiences when one has a stomach flu or a bacterial infection. When these patients say they would rather die, believe them. But don’t kill them. Give them anti-emetics. Anti-emetics not only make the patients feel better, but they improve compliance.

2. G-CSF 1 (granulocyte - colony stimulating factor) and GM-CSF (granulocyte macrophage – colony stimulating factor). These stimulate bone marrow growth and reduce leukopenia. This is important in reducing infection.

Category: Pharmacology Notes