Taxanes

Question 1

Name of drug

Answer 1

Paclitaxel

Question 2

Mechanism of action

Answer 2

Paclitaxel

1. Unlike other tubulin-targeting drugs, such as colchicine, that inhibit microtubule assembly, paclitaxel stabilizes the microtubule polymer and protects it from disassembly.
2. stimulates MT polymerisation at high concentrations and therefore formation of inappropriate microtubule structures. This causes G2M blockade and prolonged activation of the mitotic checkpoint triggers apoptosis or reversion to the G0-phase of the cell cycle without cell division
3. Paclitaxel induces expression of Bax which is pro-apoptotic and phosphorylation at Bcl-2 which is anti apoptotic.

Paclitaxel-treated cells have defects in mitotic spindle assembly, chromosome segregation, and cell division. Chromosomes are thus unable to achieve a metaphase spindle configuration. This blocks the progression of mitosis and

Question 3

Metabolism

Answer 3

Spratlin, et al 2006
Metabolised by CYP450 enzymes, forming hydroxy metabolites

Paclitaxel exhibits non-linear pharmacokinetics in that it has a disproportionate increase in the maximal plasma concentration (Cmax) and area under the concentration curve (AUC) as the dose increased, suggesting saturation of elimination at higher concentrations of paclitaxel. Therefore at high dose above threshold, high xposure due to limited celarance and therefore toxicity

Paclitaxel is bound to proteins in plasma, tissues, andtubulins. In addition, paclitaxel has an affinity for distribution in specific tissue types. Kidney, lung, spleen, and third space fluid, including ascitic and pleural fluid, have been found to have the highest tissue concentrations. Most impressive though is the high distribution found in liver and tumor tissues.

Question 4

Drug resistance

Answer 4

1. MDR1 a P-glycoprotein, an ATP dependent efflux pump that pumps many foreign substances out of cells, either via over expression of the MDR1 gene causing paclitaxel resistance or via polymorphic variants in MDR1
2. Tubulin mutations
3. Chromosomal instability: Chromosomal instability (CIN), which comprises changes in chromosome number and structure, is the most common form of genomic instability. Over expression of CIN genes (that is, genes that are involved in maintaining the genomic integrity of the cell) e.g. NEK2, which encodes a serine/threonine mitotic kinase that has roles in spindle formation and chromosome segregation

Question 5

Tumor types

Answer 5

Ovarian cancer, breast cancer, lung cancer, Kaposi sarcoma, cervical cancer, and pancreatic cancer.

Question 6

Toxicity

Answer 6

The most concerning side effects of paclitaxel are myelosuppression, particularly neutropenia, and neuropathy.