Medical Pharmacology Chapter 33-34:  Anticancer Drugs

• Natural Products:  Microtubule Antagonists

  • Taxanes:

    • Overview:

      • Taxanes represent a group of microtubule-stabilizing agents.⁹ 

        • These compounds were identified in bark extract from the yew tree, Taxus breifolia.

          • Taxus brevifolia¹⁰

            Attribution:  Hollinger, J "Pacific Yet, Taxus brevifolia, 2005-09-08, Panjab Creek, Blue Mts., WA. https://commons.wikimedia.org/wiki/File:Taxus_brevifolia_Blue_Mts_WA.jpg

          •  

            "Pacific Yew (Taxus brevifolia)"¹¹

            Attribution: Mutch R Pacific Yew (Taxus breifolia), Lookout  Creek, H.J. Andrews Forest, Oregon, USA https://www.youtube.com/watch?v=CXNwz0WQpkQ (5/2011) Robert Mutch Youtube Channel:  https://www.youtube.com/channel/UCesg82de1ACYcWc1FYuvbDQ

          • The initial agent, paclitaxel was found to exhibit anticancer activity in carcinoma cell lines nearly 50 years ago (1971).

        • Certain other compounds, related to paclitaxel, were derived from Taxus baccata, such as docetaxel.⁹  

           

          • Taxus bacca (European Yew)^11,3

            Attribution:  Muséum de Toulouse [CC BY-SA 4.0 (https://creativecommons.org/licenses/by-sa/4.0)] Descouens D Aril of the European yew 10 August 2012 https://commons.wikimedia.org/wiki/File:Taxus_baccata_MHNT.jpg

             

          • Taxus bacata, an example from the United Kingdom¹²

            Attribution: Slater D Taxus baccata https://www.youtube.com/watch?v=li7g-CesCrk Duncan Slater Youtube Channel:  https://www.youtube.com/channel/UCSgXojJsK6C_CyIgNWRD39A

      • A mechanism of taxane resistance that utilizes the P-glycoprotein efflux pump may limit the effectiveness in the clinical setting of docetaxel and paclitaxel.⁹  

        • Taxanes represent a group of microtubule-stabilizing agents.

          • These compounds were identified in bark extract from the yew tree, Taxus breifolia.

            • Paclitaxel is actually synthesized by a fungus (Taxomyces andreanae) residing in the bark of the Pacific yew.⁸

            • For commercial production a semisynthetic approach is used.⁸

          • Certain other compounds, related to paclitaxel, were derived from Taxus baccata, such as docetaxel.

          • However, carbazitaxel was developed which inhibited the 5'-triphosphate-dependent P-glycoprotein efflux pump.⁹

            • Carbazitaxel (Jevtana) was approved (2014) for treating endocrine-resistant prostate cancer.⁸

      • Mechanisms of Action:

        • Paclitaxel has been shown to bind to the inside of the microtubule lumen, binding to sites different from the :

          • (1) Exchangeable GTP site

          • (2) Colchicine site

          • (3) Podophyllotoxin  site

          • (4) Vinca alkaloid site.⁹ 

        • As a group the taxanes not only change tubulin dissociation rate constants (both ends), resulting in both dynamic instability and reduced "treadmilling" ^9,13

          • Treadmilling describes a process in which one end of the microtubule filament increases in length concurrent with the other end shrinking.

            • These actions result in a filament section seemingly "moving" across the cytosol.

              The effect occurs because protein subunits at one end of the filament are removed while subunits are added to the other end of the same time.¹³

               

              • "Actin Treadmilling Mechanism"¹⁴

                Dylan L "A figure depicting an actin filament treadmilling over time. "This figure assumes that the critical concentration at the positive end is less than the critical concentration at the negative end and that the cytosolic subunit concentration is in between the positive and negative  end critical concentration." 20 November, 2016 https://commons.wikimedia.org/wiki/File:Actin_Treadmilling_Mechanism_.jpg Attribution:  Dylan L [CC BY-SA 4.0 (https://creativecommons.org/licenses/by-sa/4.0)]

            • Taxane microtubule binding causes mitotic arrest at the G2/M transition resulting in cell death.⁹

              • The G₂ phase, a second subphase of interphase directly precedes mitosis.

                • The G₂ phase (or Gap 2 phase) follows normal completion of S phase when cellular DNA is replicated.

                • Prophase onset begins with G2 phase ending.

                • Prophase is the first phase of mitosis characterized by cellular chromatin condensation into chromosomes.¹⁶

                • The G2/M DNA damage checkpoint prevents mitosis initiation until damage DNA is repaired following replication.

                  • Cells entering mitosis carrying a defective G2/M status will proceed to apoptosis (cell death) following cell division.¹⁷

          • Taxanes may induce cancer cell death by other mechanisms.⁸ 

            • For example, in breast cancer intratumoral paclitaxel levels appear to induce mitotic arrest.

            • However, at clinical doses paclitaxel promotes abnormal chromosomal segregation which results in daughter cells having abnormal chromosomal numbers thus inducing cell death.

            • Other anticancer effects associated with taxanes include activation of apoptotic pathways.⁸

        • Clinical Uses:

          • Paclitaxel was initially approved for treating ovarian cancer following first-line or subsequent chemotherapy.⁹ 

            • Later, paclitaxel was approved for:

              • Advanced breast cancer (after anthracycline-based protocols)

              • Advanced ovarian cancer in a protocol including a platinum-based agent

              • Second-line AIDS-related Kaposi's sarcoma

              • Frst-line non-small cell lung cancer treatment (in combination with cisplatin)

            • In "off-label" settings, paclitaxel is frequently used for treating cancer of:

              • Unknown origination

              • Bladder cancer

              • Esophageal cancer

              • Gastric cancer

              • Head and neck cancer and

              • Cervical cancers.⁹