ANTIMICROTUBULES PHL 417

ANTIMICROTUBULE AGENTS

1. Vinca Alkaloids Vinblastine Vincristine Vinorelbine

Vinca Alkaloids They are plant alkaloids extracted from Periwinkle plant (Vinca Rosa) 3 3

Vinca Alkaloids Mechanism of Action They act by binding to  and  tubulin and inhibit its polymerization into microtubules leading to preventing spindle formation in mitosing cells. Resulting in mitotic arrest at metaphase, dissolution of the mitotic spindle, and interference with chromosome segregation. CCS agents- M phase Derived from the vinca rosea, the periwinkle plant Microtubules are an important part of the cytoskeleton and the mitotic spindle “Spindle Poison”

Vinca alkaloid Mechanism of resistance 1- Pleiotropic drug resistances i.e. cross- resistant to a wide range of chemically dissimilar agents: vinca alkaloid, epidophyllotoxin, anthracyclines and colchicine. Due to: High level of P-glycoprotein 2- Mutation in either  and  tubulin that prevent effective binding of vinca alkaloids

Vinca alkaloid Therapeutic uses Vincristine Vinblastine Vinorelbine With prednisone for remission of Acute Leukemia Lymphomas and Systemic Hodgkin’s disease Non-small cell lung cancer

Vinca alkaloid Side effects Vincristine Vinblastine Vinorelbine Hair loss Neuromuscular abnormalities parathesia -Myelosupression -GIT ulceration - Granulocytopenia

2. Taxanes Paclitaxel (Taxol) Docetaxel Alkaloid esters derived from the bark of ash tree (Taxus brevifolia). The taxanes are a group of drugs that includes paclitaxel (Taxol®) and docetaxel (Taxotere®) These agents are mainly used to treat breast cancer

Taxanes (cont.) Mechanism of Action Taxanes enhance assembly of microtubules and stabilize them against depolymerization. It binds to tubulin (at a site distinct from that used by vinca alkaloids) and promotes assembly of microtubules giving non-functional microtubule network. Taxanes have a unique way of preventing the growth of cancer cells: they affect cell structures called microtubules, which play an important role in cell functions. In normal cell growth, microtubules are formed when a cell starts dividing. Once the cell stops dividing, the microtubules are broken down or destroyed. Taxanes stop the microtubules from breaking down; cancer cells become so clogged with microtubules that they cannot grow and divide

Taxanes (cont.) Toxicity Paclitaxel Neutropenia, thrombocytopenia Peripheral neuropathy Docetaxel Bone marrow suppression Neurotoxicity Fluid retention Side Effects of Paclitaxel For example, paclitaxel can cause hypersensitivity (allergic) 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. The bone marrow is the soft, sponge-like tissue in the center of large bones that produces blood cells, which fight infection, carry oxygen, and help prevent bleeding by causing blood clots to form. Bone marrow damage can cause a person to be more susceptible to infection, anemia (a condition in which the number of red blood cells is below normal), 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. Side Effects of Docetaxel The side effects of docetaxel are similar to those related to paclitaxel. Additionally, docetaxel can cause fluid retention, which is the accumulation of fluid in the body. 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.