Medical Pharmacology Chapter 33-34:  Anticancer Drugs

• Natural Products: 

  • Topoisomerase Inhibitors:

    • Overview:

      • Mechanism of DNA Topoisomerases¹²

        "(a) The mechanism of type I DNA topoisomerase. The enzymes nick a single strand of DNA (pink) and form a phosphodiester bond between the enzyme tyrosine group (Y) in the phosphate group of the DNA. This makes the duplex DNA at the head of the nicking to rotate freely and follow by resealing of the nicking. (b) Mechanism of the type II DNA topoisomerase. The enzymes cleaved both strands of a DNA duplex (G-segment) and pass a second intact duplex DNA (T-segment) through the transient break using 2 ATPs for the strand passage." Attribution: Ai Lan (Fig 1) https://www.researchgate.net/figure/a-The-mechanism-of-type-I-DNA-topoisomerase-The-enzymes-nick-a-single-strand-of-DNA_fig1_262743163; original source material:  Chan MK Fadzil NA Chew AL Khoo BY New molecular biologist perspective and insight: DNA topoisomerases production by recombinant DNA technology for medical laboratory application and pharmaceutical industry. Electronic Journal of Biotechnology 16(6) 2013) http://www.ejbiotechnology.info/index.php/ejbiotechnology/article/viewFile/v16n6-6/1801

       

      • Topoisomerases:  The extended length of the human genome involving long polymers with double-stranded DNA molecules winding around each other present a topological challenge both during replication and in preparation for transcription. ¹¹

        • Resolution of complex geometric: topological requirements utilize a set of enzymes, the topoisomerases.

        • These enzymes allow for proper nuclear and mitochondrial genomic functionality and stability.¹¹

        • The reader is directed to reference 11 for details concerning topoisomerase chemical and biophysical characteristics.¹¹

      • Topoisomerase Classification and Actions:

        • There are six topoisomerases in human cells:^{10, 11} 

          • TOP1-type IB

          • TOP1MT (mitochondrial topoisomerase; gene located in the cell nucleus); type IB

          • TOP3α type IA

          • TOP3β type IA

          • TOP2α type IIA

          • TOP2β type IIA

        • TOP1 and TOP2A represent to topoisomerase genes found associated with cellular proliferation and have been noted as amplified in cancers.¹¹

          • For example, the elevated expression of the TOP2A gene in cancers is also noted in other genes that promote cellular division such as ERBB2, encoding a component of the epidermal growth factor receptor (EGFR) family of receptor tyrosine kinases.^11,13.

            • ERBB2 associated malignancies represented a target for EGFR inhibitors in, for example, lung adenocarcinomas and breast cancer.

          • An example of TOP1 gene coamplification is noted with the SRC, oncogene protein kinase).¹¹

        • Topoisomerases function through forming covalent in reversible cleavage or breaks in the DNA backbone.

          • This process involves formation of a "topoisomerase cleavage complex" or TOPcc.¹¹

          • Furthermore, anticancer topoisomerase inhibitors function by "trapping" TOPcc thus inactivating topoisomerases at the point of DNA cleavage.

            • This mechanism of action extends across the range of topoisomerase inhibitors as these agents fit into DNA breaks sites of the topoisomerase cleavage complex.¹¹

              • TOP1 is the biological target of the anticancer drugs topotecan and irinotecan, derivatives of the alkaloid camptothecin.

                 

                • Cleavage Complex for Topoisomerase I illustratating inhibition sites for the anticancer agents Topotecan (Hycamtin) and Irinotecan (Onivyce, Camptosar)¹¹

                  Attribution: Thomas A Pommier A Chapter 14 Topoisomerase Inhibitors in:  Cancer Chemotherapy, Immunotherapy and Biotherapy Principles and Practice Chabner BA Longo DL, eds 6e Wolters Kluwer 2019.11 Adapted from Fig 14.2 A (reference 11)

                •  

                  Cleavage Complex for Topoisomerase II¹¹

                  Adapted from Fig 14.2 A (reference 11) Thomas A Pommier A Chapter 14 Topoisomerase Inhibitors in:  Cancer Chemotherapy, Immunotherapy and Biotherapy Principles and Practice Chabner BA Longo DL, eds 6e Wolters Kluwer 2019.11

              • TOP2:¹⁰ 

                • TOP2 inhibitors are classified as DNA intercalators as well as non-intercalators, the epipodophyllotoxin related compounds.¹⁰  

                  • These agents trap TOP2cc (topoisomerase cleavage complexes); however, DNA intercalators at somewhat higher concentrations inhibit TOP2cc through DNA intercalation, destabilizing TOP2 DNA-binding.

                    • Due to intercalation, these anticancer agents exhibit several effects associated with DNA processing including nucleosome destabilization and helicases and polymerase enzyme inhibition.

                    • Examples of drugs classified as intercalators and non-intercalators include:

                      • Doxorubicin (anthracycline, Adriamycin)

                      • Daunorubicin (anthracycline,Cerubidine)

                      • Epirubicin (anthracycline, Ellence)

                      • Idarubicin (anthracycline, Idamycin)

                      • Mitoxantrone (anthracenedione, Novantrone)

                      • Dactinomycin (anthracenedione, Cosmegen)

                      • Etoposide (epipodophyllotoxin, Vepesid)

                      • Teniposide (epipodophyllotoxin, Vumon).¹⁰