06b Microtubule Assembly Inhibitors Camarero Flashcards Preview

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Flashcards in 06b Microtubule Assembly Inhibitors Camarero Deck (18)
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1
Q

What are the functions of Microtubules and Actin/Intermediate Filaments?

A

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

2
Q

What are the general characteristics of Microtubule Assembly Inhibitors?

A

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

3
Q

What is the main drug class of microtubule assembly inhibitors used?

A

Plant alkaloids

4
Q

What are the sub-classes of Plant Alkaloids?

A

Vinca alkaloids. Taxanes

5
Q

What are the Vinca Alkaloids used?

A

Vinblastine. Vincristine. Vinorelbine

6
Q

What are the Taxanes used?

A

Paclixatel. Docexatel

7
Q

What are Vinca Alkaloids used for?

A

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

8
Q

What is the MOA of Vinca Alkaloids?

A

Bind to tubulin dimers (a, B), inhibiting assembly of microtubule structures and resulting in mitotic arrest at metaphase

9
Q

How are Vinca Alkaloids administered?

A

Always Intravenously (Vinorelbine can also be administered PO). Should NEVER be administered into the spinal canal d/t irreversible neurological damage (~100% mortality rate)

10
Q

What are the general characteristics of Vinca Alkaloids?

A

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)

11
Q

What are the toxicities and side-effects associated with Vinca Alkaloids?

A

N/V. Alopecia. Bone marrow suppression (Vinblastine). Peripheral neuritis (Vincristine). Granulocytopenia (Vinorelbine). Vinorelbine has lower neurotoxicity than Vincristine

12
Q

What is the MOA of Taxanes?

A

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

13
Q

What are Taxanes used to treat?

A

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)

14
Q

How are Taxanes administered?

A

By Intravenous infusion, either in 3 weeks cycle or weekly

15
Q

How are Taxanes metabolized/excreted?

A

Mostly metabolized in the liver. Fecal and renal excretion

16
Q

What are the toxicities and side-effects associated with Taxanes?

A

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

17
Q

What is a general summary of Vinca Alkaloids function and cancer target?

A

Disruption of microtubule by binding tubulin (a, B); stop cell cycle during mitosis - Lymphomas, Hodgkin’s disease, acute leukemia, non-small lung cancer

18
Q

What is a general summary of Taxans function and cancer target?

A

Stabilize microtubules preventing their depolymerization; stops cell cycle mitosis - lung, ovarian, breast cancer