Nursing Pharmacology Chapter 33-34:  Anticancer Drugs

• Natural Products:  Microtubule Antagonists

  • Epothilones:

    • Overview:

      • Epothilones were originally obtained from Sorangium cellulosum, a mycobacterium.^10,11 

        • Sorangium cellulosum¹¹

          "Sorangium cellulosum, vegative cells. "Phase contrast microscopy; 1550x. "Individual cells measure 0.9-1.0 x 3-6 um."11

        • These agents comprise a new class of anticancer agents based on their anti-tubulin properties.

          • Epothilones are cytotoxic both by enhancing tubulin polymerization and by increasing microtubule stability.

            • Increased microtubule stability caused by epothilone administration results in cell-cycle arrest (at the G2/M transition point) and apoptosis (programmed cell death).

              • 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.¹²

                • 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.¹³

        • Compared to taxanes, another antineoplastic natural product group, the epothilones exhibit greater potency. 

          • Whereas for both vinca alkaloids and taxanes, elevated expression of P-glycoprotein which enhances drug efflux, epothilone cytotoxicity is not affected by P-glycoprotein levels.

            • Epothilone cytotoxicity is not only insensitive to P-glycoprotein levels but appears also insensitive to taxane resistance due to beta-tubulin overexpression or mutations.

      • Several natural or semi-synthetic epothilones have been described including epothilone B (naturally occurring) and aza-epothilone B (a.k.a. ixabepilone (Ixempra), epothilone D (semisynthetics).

        • Sagopilone is an example of fully synthetic derivative.¹⁰    

    • Ixabepilone (Ixempra for injection)

       

      • Ixabepilone in Patients with Aggressive Breast Cancer¹⁵

        Attribution: Seidman AD:  On Ixabepilone in Patients with Aggressive Breast Cancer https://www.youtube.com/watch?v=26gTXqmx_ZE (3/2016) OncLiveTv Youtube Channel:  https://www.youtube.com/channel/UC3aRpa3CR_w4JrxYv_r_pDg

    • Clinical Use:

      • Ixabepilone (Ixempra) has been FDA approved for treating breast cancer.¹⁰    

        • Ixabepilone is effective even in patients who had previously received docetaxel or paclitaxel.

        • Ixabepilone (Ixempra) is typically administered as combination treatment with capecitabine in individuals either with locally advanced or metastatic breast cancer. ¹⁴    

          • (1) resistant to: anthracycline + taxane combination treatment

          • (2) cancer exhibiting taxane resistance and

          • (3) for patients in which anthracycline treatment is contraindicated.

      • Ixabepilone (Ixempra) may be used as monotherapy in treating breast cancer (metastatic or locally advanced) in which tumors exhibit resistance to anthracyclines, capecitabine and taxane or demonstrate refractoriness to these agents.¹⁴   

    • Toxicity:

      • Primary toxicities associated with ixabepilone involve neutropenia and peripheral neuropathy.¹⁰    

        • Other toxicities include diarrhea, emesis, nausea.

        • When administered in combination with capecitabine, enhanced toxicity has been observed in settings of liver function impairment.¹⁴ 

    • Drug Elimination:

      • Ixabepilone undergoes hydrolysis which constitutes the primary elimination mechanism.

        • Active metabolites have not been identified.¹⁰