Taxanes
Chemotherapy

Author: Irene scarfo
Date: 19/07/2011

Description

DESCRIPTION

The taxanes are a clinically well established anti-mitotic chemotherapy medication. They are a family of chemotherapeutic agents derived from bark of the Yew (Taxus brevifolia). In 1967, Dr. Wall and Dr. Wani discovered the first of these compounds, paclitaxel (Taxol ®) at the Research Triangle Institute, and they tested for the treatment of tumors in rodents. In December 1992, the FDA approved the use of paclitaxel for the treatment of ovarian cancer.

MOLECULAR MECHANISM

These agents, as the Vinca Alkaloids ,do not work to alter DNA structure or function. These drugs interfere with the mechanics of cell division in another way. During mitosis, the DNA of a cell is replicated and then divided into two new cells. The process involves spindle fibers, which are constructed with microtubules (formed by long chains of smaller subunits of proteins called tubulins).The main mechanism of action of this class of chemotherapy is the destruction of microtubule function. The movement of replicated chromosomes during mitosis in the cell requires both the polymerization of tubulin (α and β) to form microtubules, and the subsequent breakdown of the same. The taxanes, by binding to tubulin, are able to block the depolymerization of the spindle once formed, chromosomes are unable to move to opposite sides of the dividing cell because microtubules are not broken down. Cell division is halted, and cell death is induced.

Microtubules as a target for anticancer drugs, 2004
The effect of antimicrotubule agents on signal transduction pathways of apoptosis: a review, 1999

STRUCTURE

PHARMACOKINETIC

Taxanes are difficult to synthesize, have hepatic metabolism and biliar(90%) and renal (10%) excretion and they are usually administered intravenously (IV)

Clinical application of Taxanes is accompanied by twofold problems:

  • the availability (four trees have to be sacrificed to produce 2 g of the drug for the chemotherapy of one patient, and this is not affordable from the environmental point of view)
  • the solubilità ( paclitaxel is poorly soluble in an aqueous medium, but can be dissolved in organic solvents)
A practical method for synthesis is yet to be developed. Paclitaxel is currently formulated in a vehicle composed of 1:1 blend of Cremophor EL (polyethoxylated castor oil) and ethanol which is diluted with 5– 20-fold in normal saline or dextrose solution (5%) for administration. This formulation is stable in unopened vials for 5 years at 4 °C


RESISTENCE

Two mechanisms of acquired resistance to the taxanes have been characterized:

  • alterations of α-and / or β-tubulin:
    -Production of β-tubulin forms that have alterations in the binding site for the drugs; –
    -Production of α-and / or β-tubulin forms with altered level of the binding sites for GT
  • changes in the intracellular storage :
    -overexpression of P-glycoprotein
    -overexpression of MRP-1

P-GLYCOPROTEIN
Paclitaxel
Taxol: mechanisms of action and resistance
Taxol resistant mutants of Chinese hamster ovary cells: genetic biochemical, and cross-resistance studies

CLASSIFICATION

There are two major taxanes in clinical use:

PACLITAXEL

Paclitaxel, the first of a new class of microtubule stabilizing agents, has been hailed by National Cancer Institute (NCI) as the most significant advance in chemotherapy of the past 15–20 years. Paclitaxel was not a chance discovery but was the outcome of the investigation of over 12 000 natural compounds for anticancer activity (Appendino,1993). Paclitaxel is a diterpenoid pseudoalkaloid having molecular formula C47H51NO14, corresponding to molecular weight of 853 Da. For anti-tumor activity it is required that entire taxane molecule be present, since the ester and the tetraol formed by a low temperature cleavage of paclitaxel are found to be essentially inactive (Wall and Wani,1996). Paclitaxel was obtained in a pure form in 1969 and its structure was published in 1971, after many complexities due to its low concentration and structure complexities. Paclitaxel and its formulations(2002)

PHARMACOKINETIC

Pharmacokinetics of paclitaxel shows wide variability.

high protein binding (90%)

hepatic metabolism (CYP2C8 o CYP3A4)

biliar (90%) and renal (10%) excretion

half-life 1,3-8,6 hours (mean 5 h)

The highest concentration of the paclitaxel following a 6-h infusion in rats was found to be in lung, liver, kidney and spleen and was essentially excluded from brain and testes
Clinical pharmacology and metabolism of Taxol (paclitaxel): update 1993
Usually paclitaxel is dissolved in Cremophor EL and ethanol, as a delivery agent. A newer formulation, in which paclitaxel is bound to albumin, is sold under the trademark Abraxane.

Paclitaxel and its formulations
Novel formulations of taxanes: a review. Old wine in a new bottle?

INDICATIONS

Malignancies in which paclitaxel is used include:

  • lung, ovarian, breast cancer
  • head and neck cancer
  • and advanced forms of Kaposi’s sarcoma.

PHARMACOLOGICAL INTERACTION

Paclitaxel can be used in combination with other chemotherapy drugs. For example, in combination with cisplatin, is used as first-line treatment for non-small cell tumors of the lung. In combination with carboplatin can be used for the treatment of lung cancer and ovarian cancer. The FDA is currently very encouraging approval of paclitaxel incombination with Herceptin ® (anitcorpo monoclonal antibody) for the treatment of breast cancer.

SIDE EFFECTS

Common side effects include:

  • reduction in bone marrow function which may result in anemia
  • blood in stools or black stools
  • fast or irregular heartbeat
  • fever, chills, lower back pain
  • numbness or tingling of the hands or feet
  • mouth sores
  • painful, bloody, or difficult urination
  • swelling of the face, lips, or throat
  • nausea, vomiting, or diarrhea
  • unusual bleeding or bruising
  • wheezing or trouble breathing
  • hair loss
The drug may cause birth defects. Patients should not take this drug if they are pregnant or plan to become pregnant. Breast feeding should also be avoided by patients taking paclitaxel. Immunosuppression may lead to increased risk of infection.

STRUCTURE

3D
Wikipedia-Paclitaxel

DOCETAXEL

The mechanism of action of docetaxel (Taxotere ®) is similar to that of Pacliltaxel, which inhibits microtubule depolymerization and thus blocks the cell division process.

STRUCTURE

PHARMACOKINETIC

high protein binding (>98%)

hepatic metabolism (CYP3A4 o CYP3A5)

biliar excretion

half-life 86 hours

INDICATIONS

The malignancy for which docetaxel is administered:

  • Breast cancer (advanced or metastatic)
  • Cancer of the non-small cell lung

SIDE EFFECTS

The most common side effects are:

  • Myelosuppression
  • Fluid retention
  • Hair loss
  • Infections related to myelosuppression
  • Diarrhea
  • Skin rashes
    Treatment with docetaxel is generally accompanied by administration of steroids to prevent serious manifestations of fluid retention. Nevertheless, in most cases, the fluid retention is an effect of this type of treatment very often.

    Side effects can be serious or more variables, when docetaxel is given in combinationwith other drugs.

    the docetaxel is a strong suppressor of bone marrow function. Therefore, it is important to monitor the count of red blood cells and white blood and platelets for the duration of treatment.

    The drug may cause birth defects. Patients should not take this drug if they are pregnant or plan to become pregnant


    Wikipedia-Docetaxel
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