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Non-Intercalating Poisons

Another category of topoII poisons is known as non-intercalating poisons. The main non-intercalating topo II poisons are etoposide, teniposide, and fluoroquinolone. These non-intercalating poisons specifically target prokaryotic type II topoisomerases in DNA by actively working against them by blocking transcription and replication [1]. Studies have shown that non-intercalating poisons play an important role in confining TopII DNA covalent complexes[2]. This occurs via a mutation in the topoII-DNA covalent complex, the DNA strand that are protein linked are found and broken and cells undergo apoptosis[3]. Etoposide, a semi-synthetic derivative of epipodophyllotoxin is commonly used to study this apoptotic mechanism.

  1. Etoposide
  2. Teniposide
  3. Fluoroquinolone.

Discovery of podophyllotoxins

Both Etoposide and Teniposide are naturally occurring semi-synthetic derivatives of podophyllotoxins and are important anti-cancer drugs that function to inhibit TopII activity.[4]

Etoposide is synthesized from podophyllum extracts found in the North American May apple plant and the North American Mandrake plant. More specifically, Podophyllotoxins are spindle poisons that cause inhibition of mitosis by blocking mitrotubular assembly. In relation, Etoposide functions to inhibit the cell cycle progression at the pre-mitotic stage (late S and G2) by breaking strands of DNA via the interaction with DNA and TopII or by the formation of free radicals[5][6]. Etoposide has shown to be one of the most active drugs for small cell lung cancer (SCLC), testicular carcinoma and malignant lymphoma[7]. Studies have indicated that some major therapeutic activity for the drug has been found in. small cell bronchogenic carcinoma, germ cell malignancies, acute non-lymphocytic leukemia, Hodgkin's disease and non-Hodgkin's lymphoma[8]. Additionally, studies have shown when treated with Etoposide derivatives there is a anti-leukemic dose response that differ compared to the normal hematopoietic elements. Etoposide is a highly schedule-dependent drug and is typically administered orally and recommended to take twice the dosage for effective treatment. [9][10] However, with the selective dosage, Etoposide treatment is dose limiting proposing toxic effects like myelosupression (leukopenia) and primarily hematologic[11][12].Furthermore, around 20-30% of patients who take the recommended dosage can have hematologic symptoms such as alopecia, nausea, vommitting and stomatitis[13]. Despite the side effects, Etoposide has demonstrated activity in many diseases and could contribute in combination chemotherapeutic regimens for these cancer related diseases[14].

Similarly, Teniposide is another drug that helps treat leukemia. Teniposide functions very similarly to Etoposide in that they are both phase specific and act during the late S and early G2 phases of the cell cycle. However, Teniposide is more protein-bound than Etoposide. Additionally, Teniposide has a greater uptake, higher potency and binding affinity to cells compared to Etoposide. Studies have shown that Teniposide is a active anti-tumor agent and have used in clinical settings to evaluate the efficacy of Teniposide. In a study preformed by the European Organization for the Research and Treatment of Cancer (EORTC) and Lung Cancer Cooperative Group (LCCG), the results of toxicity of teniposide indicated hematologic and mild symptoms similar to Etoposide. However, the study found that the treatment outcome for patients with brain metastasis of SCLC had low survival and improvement rates.[15] 

Mutations

(LL) Although the function of TopII poisons are not completely understood there is evidence that there is differences in structural specificity between intercalating and non-intercalating poisons. It is known that the difference between the two classifications of poisons rely on their biological activity and its role in the formation of the TopII-DNA covalent complexes.[16] More specifically, this difference occurs between the chromophore framework and the base pairs of DNA.[16] As a result of their structural specificity, slight differences in chemical amplification between antibiotics are seen.[16] Thus, this provides explanation on why theses drugs show differences in clinical activity of patients.

Despite the difference in the structure specificity, they both present mutations that result in anticancer drug resistance.[16] In relation to intercalating poisons, it has been found that there are recurrent somatic mutations in the anthracyclines family.[17] Studies have shown that in DNA methyltransferase 3A (DNMT3A) the most frequent mutation is seen at arginine 882 (DNMT3AR882).[17] This mutation impacts patients with acute myeloid leukemia (AML) by initially responding to chemotherapy but relapsing afterwards.[17] The persistence of DNMT3AR882 cells induce hematopoietic stem cell expansion and promotes resistance to anthracycline chemotherapy.[17]

While there has not been enough research on specific mutations occurring among non-intercalating poisons, some studies have presented data regarding resistance to etoposide specifically in human leukemia cells (HL-60).[18] R Ganapathi et. al. reported that the alteration in activity of TopII as well as a reduced drug accumulation effect tumor cell resistance to epipodophyllotoxins and anthracyclines.[19] It has been proposed that the level of TopII activity is an important factor to drug sensitivity.[20] This study also indicated that hypophosophylation of TopII in HL-60 cells when treated with calcium chelator (1,2-bis-(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid acetoxymethyl ester) resulted in a > 2-fold reduction in etoposide-induced TOPO II-mediated DNA cleavable complex formation.[19] Thus indicating a plausible relationship between etoposide drug resistance and hypophosphorylation of HL-60 cells.[19] Additionally, a study reported by Yoshihito Matsumoto et. al. showed an incidence of mutation and deletion in TopIIα mRNA of etoposide and m-amsacrine (mAMSA)-resistant Cell Lines.[21] TopIIα showed a decrease in activity and expression and an increase of multidrug resistance protein (MRP) levels. As a result, this diminished the intracellular target to etoposide and other TopII poisons.[21] Furthermore, it was found that phosphorylation of TopIIα from the resistant cells was more hypophsophorylated compared to the parental cells as well as loss of phosphorylation sites located in the C-terminal domain.[21] It was determined there was cross-resistance to TopII poisons.[21] Scientist have suggested and argued against that the phosphorylation sites located outside of the C-terminal domain is what promotes the high activation of TopII or that the C-terminal region has a negative effect on TopII activity and can be altered via phosphorylation or truncation.[22][23] 

Catalytic Inhibitors

(LL) Catalytic inhibitors are the other main identification of TopII inhibitors. Common catalytic inhibitors are Bisdioxopiperazine compounds and sometimes act competitively against TopII poisons. They function to target enzymes inside the cell thus inhibiting genetic processes such as DNA replication, and chromosome dynamics.Additionally, catalytic poisons can interfere with ATPase and DNA strand passageways leading to stabilization of the DNA intermediate covalent complex. Because of these unique functions, research has suggested that bis(2,6-dioxopiperazines) could potentially solve issues with cardiac toxicity caused by anti-tumor antibiotics. Furthermore, in preclinical and clinical settings, bis(2,6-dioxopiperazines) is used to reduce the side effects of TopII poisons. Common catalytic inhibitors that target TopII are Dexrazoxane, Novobiocin, Merbarone and Anthrycycline aclarubicin.

  1. Dexrazoxane
  2. Novobiocin
  3. Merbarone
  4. Anthrycycline aclarubicin

Dexrazoxane also known as ICRF-187 is currently the only clinically approved drug used in cancer patients to target and prevent anthrycycline mediated cardiotoxicity as well as prevent tissue injuries post extravasation of anthrocyclines. Dexrazoxane functions to inhibit TopII and its effects on iron homeostasis regulation. Dexrazoxane is a bisdioxopiperazine with iron-chelating, chemoprotective, cardioprotective, and antineoplastic activities.

Novobiocin is also known as cathomycin or albamycin or streptonivicin is an aminocoumarin antibiotic compound that functions to bind to DNA gyrase and inhibits ATPase activity. It acts as a competitive inhibitor and specifically inhibits Hsp90 and TopII. Novobiocin has been investigated and used in metastatic breast cancer clinical trials as well as non-small lung cancer cells as well as treatments for psoriasis when combined with nalidixic acid. Additionally, it is regularly used as a treatment for infections by gram-positive bacteria. Novobiocin is derived from coumarin and the structure of novobiocin is similar to that of coumarin.

  1. ^ Nitiss, John L. (2009-5). "Targeting DNA topoisomerase II in cancer chemotherapy". Nature reviews. Cancer. 9 (5): 338–350. doi:10.1038/nrc2607. ISSN 1474-175X. PMC 2748742. PMID 19377506. {{cite journal}}: Check date values in: |date= (help)
  2. ^ Nitiss, John L. (2009-5). "Targeting DNA topoisomerase II in cancer chemotherapy". Nature reviews. Cancer. 9 (5): 338–350. doi:10.1038/nrc2607. ISSN 1474-175X. PMC 2748742. PMID 19377506. {{cite journal}}: Check date values in: |date= (help)
  3. ^ Nitiss, John L. (2009-5). "Targeting DNA topoisomerase II in cancer chemotherapy". Nature reviews. Cancer. 9 (5): 338–350. doi:10.1038/nrc2607. ISSN 1474-175X. PMC 2748742. PMID 19377506. {{cite journal}}: Check date values in: |date= (help)
  4. ^ Imbert, T. F. (1998-03). "Discovery of podophyllotoxins". Biochimie. 80 (3): 207–222. doi:10.1016/s0300-9084(98)80004-7. ISSN 0300-9084. PMID 9615861. {{cite journal}}: Check date values in: |date= (help)
  5. ^ Sinkule, J. A. (1984-03). "Etoposide: a semisynthetic epipodophyllotoxin. Chemistry, pharmacology, pharmacokinetics, adverse effects and use as an antineoplastic agent". Pharmacotherapy. 4 (2): 61–73. doi:10.1002/j.1875-9114.1984.tb03318.x. ISSN 0277-0008. PMID 6326063. {{cite journal}}: Check date values in: |date= (help)
  6. ^ Clark, Peter I.; Slevin, Maurice L. (1987-04-01). "The Clinical Pharmacology of Etoposide and Teniposide". Clinical Pharmacokinetics. 12 (4): 223–252. doi:10.2165/00003088-198712040-00001. ISSN 1179-1926.
  7. ^ "Food and Drug Administration (FDA)", SpringerReference, Berlin/Heidelberg: Springer-Verlag, retrieved 2020-12-13
  8. ^ Vogelzang, N. J.; Raghavan, D.; Kennedy, B. J. (1982-01). "VP-16-213 (etoposide): the mandrake root from Issyk-Kul". The American Journal of Medicine. 72 (1): 136–144. doi:10.1016/0002-9343(82)90600-3. ISSN 0002-9343. PMID 6277188. {{cite journal}}: Check date values in: |date= (help)
  9. ^ Sinkule, J. A. (1984-03). "Etoposide: a semisynthetic epipodophyllotoxin. Chemistry, pharmacology, pharmacokinetics, adverse effects and use as an antineoplastic agent". Pharmacotherapy. 4 (2): 61–73. doi:10.1002/j.1875-9114.1984.tb03318.x. ISSN 0277-0008. PMID 6326063. {{cite journal}}: Check date values in: |date= (help)
  10. ^ Clark, Peter I.; Slevin, Maurice L. (1987-04-01). "The Clinical Pharmacology of Etoposide and Teniposide". Clinical Pharmacokinetics. 12 (4): 223–252. doi:10.2165/00003088-198712040-00001. ISSN 1179-1926.
  11. ^ Sinkule, J. A. (1984-03). "Etoposide: a semisynthetic epipodophyllotoxin. Chemistry, pharmacology, pharmacokinetics, adverse effects and use as an antineoplastic agent". Pharmacotherapy. 4 (2): 61–73. doi:10.1002/j.1875-9114.1984.tb03318.x. ISSN 0277-0008. PMID 6326063. {{cite journal}}: Check date values in: |date= (help)
  12. ^ Vogelzang, N. J.; Raghavan, D.; Kennedy, B. J. (1982-01). "VP-16-213 (etoposide): the mandrake root from Issyk-Kul". The American Journal of Medicine. 72 (1): 136–144. doi:10.1016/0002-9343(82)90600-3. ISSN 0002-9343. PMID 6277188. {{cite journal}}: Check date values in: |date= (help)
  13. ^ Sinkule, J. A. (1984-03). "Etoposide: a semisynthetic epipodophyllotoxin. Chemistry, pharmacology, pharmacokinetics, adverse effects and use as an antineoplastic agent". Pharmacotherapy. 4 (2): 61–73. doi:10.1002/j.1875-9114.1984.tb03318.x. ISSN 0277-0008. PMID 6326063. {{cite journal}}: Check date values in: |date= (help)
  14. ^ Sinkule, J. A. (1984-03). "Etoposide: a semisynthetic epipodophyllotoxin. Chemistry, pharmacology, pharmacokinetics, adverse effects and use as an antineoplastic agent". Pharmacotherapy. 4 (2): 61–73. doi:10.1002/j.1875-9114.1984.tb03318.x. ISSN 0277-0008. PMID 6326063. {{cite journal}}: Check date values in: |date= (help)
  15. ^ Postmus, Haaxma-Reiche, Smit, Groen, Karnicka, Lewinski, Meerbeeck, Clerico, Gregor, Curran, Sahmoud, Kirkpatrick, and Giaccone, Pieter E., Hanny, Egbert, Groen, Hanna, Tadeusz, Jan van, Mario, Anna, Desmond, Tarek, Anne, and Giuseppe (2000). "Treatment of Brain Metastases of Small-Cell Lung Cancer: Comparing Teniposide and Teniposide With Whole-Brain Radiotherapy—A Phase III Study of the European Organization for the Research and Treatment of Cancer Lung Cancer Cooperative Group". Journal of Clinical Oncology. Vol 18, No 19 (October 1): 3400–3408. {{cite journal}}: |volume= has extra text (help)CS1 maint: multiple names: authors list (link)
  16. ^ a b c d Manfait, M.; Chourpa, I.; Sokolov, K.; Morjani, H.; Riou, J.-F.; Lavelle, F.; Nabiev, I. (1993), Theophanides, Theophile; Anastassopoulou, Jane; Fotopoulos, Nikolaos (eds.), "Intercalating and Non-Intercalating Antitumor Drugs: Structure-Function Correlations as Probed by Surface-Enhanced Raman Spectroscopy", Fifth International Conference on the Spectroscopy of Biological Molecules, Dordrecht: Springer Netherlands, pp. 59–64, doi:10.1007/978-94-011-1934-4_18, ISBN 978-94-011-1934-4, retrieved 2020-12-15
  17. ^ a b c d Guryanova, Olga A.; Shank, Kaitlyn; Spitzer, Barbara; Luciani, Luisa; Koche, Richard P.; Garrett-Bakelman, Francine E.; Ganzel, Chezi; Durham, Benjamin H.; Mohanty, Abhinita; Hoermann, Gregor; Rivera, Sharon A. (12 2016). "DNMT3A mutations promote anthracycline resistance in acute myeloid leukemia via impaired nucleosome remodeling". Nature Medicine. 22 (12): 1488–1495. doi:10.1038/nm.4210. ISSN 1546-170X. PMC 5359771. PMID 27841873. {{cite journal}}: Check date values in: |date= (help)
  18. ^ Ganapathi, R.; Constantinou, A.; Kamath, N.; Dubyak, G.; Grabowski, D.; Krivacic, K. (1996-08-01). "Resistance to etoposide in human leukemia HL-60 cells: reduction in drug-induced DNA cleavage associated with hypophosphorylation of topoisomerase II phosphopeptides". Molecular Pharmacology. 50 (2): 243–248. ISSN 0026-895X. PMID 8700130.
  19. ^ a b c Ganapathi, R.; Constantinou, A.; Kamath, N.; Dubyak, G.; Grabowski, D.; Krivacic, K. (1996-08). "Resistance to etoposide in human leukemia HL-60 cells: reduction in drug-induced DNA cleavage associated with hypophosphorylation of topoisomerase II phosphopeptides". Molecular Pharmacology. 50 (2): 243–248. ISSN 0026-895X. PMID 8700130. {{cite journal}}: Check date values in: |date= (help)
  20. ^ Ganapathi, Ram N.; Ganapathi, Mahrukh K. (2013-08-01). "Mechanisms regulating resistance to inhibitors of topoisomerase II". Frontiers in Pharmacology. 4. doi:10.3389/fphar.2013.00089. ISSN 1663-9812. PMC 3729981. PMID 23914174.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  21. ^ a b c d Matsumoto, Yoshihito; Takano, Hiroshi; Kunishio, Katsuzo; Nagao, Seigo; Fojo, Tito (2001). "Incidence of Mutation and Deletion in Topoisomerase IIα mRNA of Etoposide and mAMSA–resistant Cell Lines". Japanese Journal of Cancer Research. 92 (10): 1133–1137. doi:10.1111/j.1349-7006.2001.tb01069.x. ISSN 1349-7006. PMC 5926608. PMID 11676865.{{cite journal}}: CS1 maint: PMC format (link)
  22. ^ Alghisi, G. C.; Roberts, E.; Cardenas, M. E.; Gasser, S. M. (1994). "The regulation of DNA topoisomerase II by casein kinase II". Cellular & Molecular Biology Research. 40 (5–6): 563–571. ISSN 0968-8773. PMID 7735331.
  23. ^ Wells, N. J.; Fry, A. M.; Guano, F.; Norbury, C.; Hickson, I. D. (1995-11-24). "Cell cycle phase-specific phosphorylation of human topoisomerase II alpha. Evidence of a role for protein kinase C". The Journal of Biological Chemistry. 270 (47): 28357–28363. doi:10.1074/jbc.270.47.28357. ISSN 0021-9258. PMID 7499337.{{cite journal}}: CS1 maint: unflagged free DOI (link)
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