Flashcards in 06b Microtubule Assembly Inhibitors Camarero Deck (18):
What are the functions of Microtubules and Actin/Intermediate Filaments?
Determine cell shape and are involved in the intracellular movement of organelles. Originating from centrosomes they form the mitotic spindle. Microtubules appear as rigid hollow rods around 25nm in diameter: assembled from tubulin, a dimer globular protein consisting of two monomers (a, B tubulin) with very similar structures
What are the general characteristics of Microtubule Assembly Inhibitors?
They promote depolymerization or stabilization of the microtubules. Resulting in mitotic arrest at metaphase, dissolution of the mitotic spindle, and interference with chromosome segregation or; interfere with the normal breakdown of microtubules during cell division
What is the main drug class of microtubule assembly inhibitors used?
What are the sub-classes of Plant Alkaloids?
Vinca alkaloids. Taxanes
What are the Vinca Alkaloids used?
Vinblastine. Vincristine. Vinorelbine
What are the Taxanes used?
What are Vinca Alkaloids used for?
Used for treating a variety of cancers, including lymphoblastic leukemia, breast carcinoma, Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma, soft-tissue sarcomas, osteogenic sarcoma, and brain tumors
What is the MOA of Vinca Alkaloids?
Bind to tubulin dimers (a, B), inhibiting assembly of microtubule structures and resulting in mitotic arrest at metaphase
How are Vinca Alkaloids administered?
Always Intravenously (Vinorelbine can also be administered PO). Should NEVER be administered into the spinal canal d/t irreversible neurological damage (~100% mortality rate)
What are the general characteristics of Vinca Alkaloids?
Distribute widely throughout many tissues in the body and binds readily to leukocytes and platelets. Do not cross the BBB. Metabolized in the liver by cytochrome P450. Mostly biliary/fecal excretion (~10% renal)
What are the toxicities and side-effects associated with Vinca Alkaloids?
N/V. Alopecia. Bone marrow suppression (Vinblastine). Peripheral neuritis (Vincristine). Granulocytopenia (Vinorelbine). Vinorelbine has lower neurotoxicity than Vincristine
What is the MOA of Taxanes?
Promote the assembly of microtubules and stabilize their formation by inhibiting depolymerization (inhibit cell-cycle during mitosis). Paclitaxel also induces apoptosis in cancer by binding to anti-apoptotic Bcl-2 (B-cell leukemia 2) and thus arresting its function. Paclitaxel also induces the expression of tumor necrosis factor-alpha and inhibits angiogenesis
What are Taxanes used to treat?
Patients with lung, ovarian, breast cancer, ahead and neck cancer, and advanced forms of Kaposi's sarcoma. Docetaxel is approved for treatment of locally avanced, or metastatic breast or non small-cell lung cancer (after the failure of anthracyclic chemotherapy)
How are Taxanes administered?
By Intravenous infusion, either in 3 weeks cycle or weekly
How are Taxanes metabolized/excreted?
Mostly metabolized in the liver. Fecal and renal excretion
What are the toxicities and side-effects associated with Taxanes?
Toxicity is correlated to dose rather than prolonged usage. Similar toxicities but Docexatel considered 1.3-12 times more toxic than Paclitaxel. Bone marrow depression (neutropenia, thrombocytopenia). Neurotoxicity (peripheral neuropathy). Fluid retention
What is a general summary of Vinca Alkaloids function and cancer target?
Disruption of microtubule by binding tubulin (a, B); stop cell cycle during mitosis - Lymphomas, Hodgkin's disease, acute leukemia, non-small lung cancer