Topoisomerase inhibitors are chemical compounds that block the action of topoisomerases, which are broken into two broad subtypes: type I topoisomerases (TopI) and type II topoisomerases (TopII).[1][2][3] Topoisomerase plays important roles in cellular reproduction and DNA organization, as they mediate the cleavage of single and double stranded DNA to relax supercoils, untangle catenanes, and condense chromosomes in eukaryotic cells.[1][2][3] Topoisomerase inhibitors influence these essential cellular processes. Some topoisomerase inhibitors prevent topoisomerases from performing DNA strand breaks while others, deemed topoisomerase poisons, associate with topoisomerase-DNA complexes and prevent the re-ligation step of the topoisomerase mechanism.[3] These topoisomerase-DNA-inhibitor complexes are cytotoxic agents, as the un-repaired single- and double stranded DNA breaks they cause can lead to apoptosis and cell death.[2][3] Because of this ability to induce apoptosis, topoisomerase inhibitors have gained interest as therapeutics against infectious and cancerous cells.

History

In the 1940s, great strides were made in the field of antibiotic discovery by researchers like Albert Schatz, Selman A. Waksman, and H. Boyd Woodruff that inspired significant effort to be allocated to the search for novel antibiotics.[4][5][6][7] Studies searching for antibiotic and anticancer agents in the mid to late 20th century have illuminated the existence of numerous unique families of both TopI and TopII inhibitors, with the 1960s alone resulting in the discovery of the camptothecin, anthracycline and epipodophyllotoxin classes.[8] Knowledge of the first topoisomerase inhibitors, and their medical potential as anticancer drugs and antibiotics, predates the discovery of the first topoisomerase (Escherichia. coli omega protein, a TopI) by Jim Wang in 1971.[9][10][11] In 1976, Gellert et al. detailed the discovery of the bacterial TopII DNA gyrase and discussed its inhibition when introduced to coumarin and quinolone class inhibitors, sparking greater interest in topoisomerase-targeting antibiotic and antitumor agents.[3][12] Topoisomerase inhibitors have been used as important experimental tools that have contributed to the discovery of some topoisomerases, as the quinolone nalidixic acid helped elucidate the bacterial TopII proteins it binds to.[11] Topoisomerase inhibitor classes have been derived from a wide variety of disparate sources, with some being natural products first extracted from plants (camptothecin,[10] etoposide[13]) or bacterial samples (doxorubicin,[14] indolocarbazole[15]), while others possess purely synthetic, and often accidental, origins (quinolone,[11] indenoisoquinoline[16]). After their initial discoveries, the structures of these classes have been fine tuned through the creation of derivatives in order to make safer, more effective, and are more easily administered variants.[10][11][16][17] Currently, topoisomerase inhibitors hold a prominent place among antibiotics and anticancer drugs in active medical use, as inhibitors like doxorubicin (anthracycline, TopII inhibitor[14]), etoposide (TopII inhibitor[13]), ciprofloxaxin (fluoroquinolone, TopII inhibitor[18]), and irinotecan (camptothecin derivative, TopI inhibitor[19]) were all included in the 2019 WHO Model List for Essential Medicines.[20]

Topoisomerase I inhibitors

Mechanism

TopI relaxes DNA supercoiling during replication and transcription.[21][2] Under normal circumstances, TopI attacks the backbone of DNA, forming a transient TopI-DNA intermediate that allows for the rotation of the cleaved strand around the helical axis. TopI then re-ligates the cleaved strand to reestablish duplex DNA.[22][2] Treatment with TopI inhibitors stabilizes the intermediate cleavable complex, preventing DNA re-ligation, and inducing lethal DNA strand breaks.[22][23] Camptothecin-derived TopI inhibitors function by forming a ternary complex with TopI-DNA and are able to stack between the base pairs that flank the cleavage site due to their planar structure.[24] Normal cells have multiple DNA checkpoints that can initiate the removal of these stabilized complexes, preventing cell death. In cancer cells, however, these checkpoints are typically inactivated, making them selectively sensitive to TopI inhibitors.[22][23] Non-camptothecins, such as indenoisoquinolines and indolocarbazoles, also associate with TopI itself, forming hydrogen bonds with residues that typically confer resistance to camptothecin.[24] Indenosioquinolines and indolocarbazoles also lack the lactone ring present in camptothecin, making them more chemically stable and less prone to hydrolysis at biological pH.[22]

Anticancer drugs

Camptothecins

Camptothecin (CPT) was first derived from the tree Camptotheca acuminata, native to southern China.[25][10][26] It was isolated in a United States Department of Agriculture (USDA) led search for cortisone precursors in the late 1950s and its anticancer activity explored in the early 1960s by Dr. John Hartwell and his team at the Cancer Chemotherapy National Service Center.[10] Clinical trials during the 1970s converted CPT into its sodium salt in order to increase its solubility, however, clinical trials were unsuccessful due to the compound's toxicity.[27][28][19] It was not until 1985 that Hsiang et al. deduced via topoisomerase relaxation assays that the anti-tumor activity of CPT was due to its TopI inhibitory activity.[29] Cushman et al. (2000) mentions that due to a lack of observed DNA unwinding in experiments involving CPT and the non-CPT TopI inhibitor indenoisoquinoline, they believed that these inhibitors likely did not function through a mechanism involving DNA intercalation.[16] This hypothesis has been disproved, as X-ray crystallography based models have allowed for the visualization of TopI inhibitor DNA intercalation.[30]

One of important structural feature of CPT is its planar pentacyclic ring and lactone ring (the E-ring).[31] The lactone ring is believed to create the active form of the drug, but it is often prone to hydrolysis, which causes a loss in function.[32] The discovery of CPT led to the synthesis of three currently FDA approved derivatives: topotecan (TPT), irinotecan, and belotecan.[19][33] TPT is commonly used to treat ovarian and small cell lung cancer (SCLC) while irinotecan is known to improve colon cancer.[34][19] Commonly, TPT is used in conjunction with a combination of drugs such as cyclophosphamide, doxorubicin, and vincristine.[34] It was noted that IV treatment with TPT had similar response and survival rates to oral medication.[34] Furthermore, it has been shown that TPT treatment with radiotherapy can improve survival rates of patients with brain metastases. Belotecan is a recent CPT derivative used to treat SCLC.[35] Several clinical trials on CPT derivatives such as gimatecan and silatecan continue to progress.[35] Currently, silatecan is in a phase 2 study for the treatment of gliosarcoma in adults who have not had bevacizumab treatment.[36]

Non-camptothecins

Despite the clinical success of the many CPT derivatives, they require long infusions, have low water solubility, and possess many side effects such as temporary liver dysfunction, severe diarrhea, and bone marrow damage.[28] Additionally, there has been an increase in observed single point mutations that have shown to prompt TopI resistance to CPT.[37] Therefore, three clinically relevant non-CPT inhibitors, indenoisoquinoline, phenanthridines, and indolocarbazoles, are currently being considered by the FDA as possible chemotherapies.[19] Among the non-CPT inhibitors, indolocarbazoles have shown the most promise. These inhibitors have unique advantages compared with the CPT. First, they are more chemically stable due to the absence of the lactone E-ring.[19] Second, indolocarbazoles attach to TopI at different sections of the DNA. Third, this inhibitor expresses less reversibility than CPT.[38] Therefore, they require shorter infusion times because the TopI inhibitor complex is less likely to dissociate.[19][38] Currently, several other indolocarbazoles are also undergoing clinical trials.[39] Other than indocarbazoles, topovale (ARC-111) is considered one of the most clinically developed phenanthridine. They have been promising in fighting colon cancer, but have shown limited effectiveness against breast cancer.[40]

The first member of the indolocarbazole family of topoisomerase inhibitors, BE-13793C, was discovered in 1991 by Kojiri et al.[15] It was produced by a streptomycete similar to Streptoverticillium mobaraense, and DNA relaxation assays revealed that BE-13793C is capable of inhibiting both TopI and TopII.[15] Soon after, more indolocarbazole variants were found with TopI specificity.[41]

Cushman et al. (1978) details the discovery of the first indenoisoquinoline, indeno[1,2-c]isoquinoline (NSC 314622), which was made accidentally in an attempt to synthesize nitidine chloride, an anticancer agent that does not inhibit topoisomerases.[16][38][42] Research on the anticancer activity of indenoisoquinoline ceased until the late 90s as interest grew for CPT class alternatives.[16] Since then, work on developing effective derivatives has been spearheaded by researchers like Dr. Mark Cushman at Purdue University and Dr. Yves Pommier at the National Cancer Institute.[16][43][44] As of 2015, indotecan (LMP-400) and indimitecan (LMP-776), derivatives of indeno[1,2-c]isoquinoline, were in phase one clinical trials for the treatment of relapsed solid tumors and lymphomas.[45][46]

Topoisomerase II inhibitors

Mechanism

TopII forms a homodimer that functions by cleaving double stranded DNA, winding a second DNA duplex through the gap, and re-ligating the strands.[2]  TopII is necessary for cell proliferation and is abundant in cancer cells, which make TopoII inhibitors effective anti-cancer treatments.[2][23] In addition, some inhibitors, such as quinolones, fluoroquinolones and coumarins, are specific only to bacterial type 2 topoisomerases (TopoIV and gyrase), making them effective antibiotics.[47][48][7] Regardless of their clinical use, TopoII inhibitors are classified as either catalytic inhibitors or poisons. TopoII catalytic inhibitors bind the N-terminal ATPase subunit of TopoII, preventing the release of the separated DNA strands from the TopII dimer.[49] The mechanisms of these inhibitors are diverse. For example, ICRF-187 binds non-competitively to the N-terminal ATPase of eukaryotic TopoII, while coumarins bind competitively to the B subunit ATPase of gyrase.[7][49] Alternatively, TopoII poisons generate lethal DNA strand breaks by either promoting the formation of covalent TopII-DNA cleavage complexes, or by inhibiting re-ligation of the cleaved strand.[23] Some poisons, such as doxorubicin, have been proposed to intercalate in the strand break between the base pairs that flank the TopII-DNA intermediate.[50] Others, such as etoposide, interact with specific amino acids in TopII to from a stable ternary complex with the TopII-DNA intermediate.[51]

Antibiotics

Aminocoumarins

Aminocoumarins (coumarins and simocyclinones) and quinolones are the two main classes of TopII inhibitors that function as antibiotics.[48] The aminocoimarins can be further divided into two groups:

  1. Traditional coumarin
  2. Simocyclioners

The coumarins group, which includes novobiocin and coumermycin, are natural products from the Streptomyces species and target the bacterial enzyme DNA gyrase (TopII).[7][48] Mechanistically,  the inhibitor binds in the B subunit of the gyrase (gyrB) and prevents ATPase activity.[52][7][48] This is attributed to the drug creating a stable conformation of the enzyme, which exhibits a low affinity for ATP which is needed for DNA supercoiling.[7] It is proposed that the drug functions as a competitive inhibitor. Thus, at high concentrations, ATP outcompetes the drug.[7] One limitation of traditional coumarins is gyrB ability to confer antibiotic resistance due to mutations and as a result decrease the inhibitor's ability to bind and induce cell death.[48][53]

Simocyclinones are another class of TopII antibiotics but differ from aminocoumarins in that they are composed of both aminocoumarins and a polyketide element. They also inhibit DNA gyrase's ability to bind to DNA instead of inhibiting ATPase activity, and produces several antibiotic classes.[30] These antibiotics are further divided into two group: actinomycin A and actinomycin B.[30] It was shown that both actinomycin A and actinomycin B were highly effective in killing gram-positive bacteria. Although simocyclinones are effective antibiotics, research has shown that one strain of aimocyclioners, S. antibioticus, cause streptomyces to produce antibiotics.[54]

Quinolones

Quinolones are amongst the most commonly used antibiotics for bacterial infections in humans, and are used to treat illness such as urinary infections, skin infections, sexually transmitted diseases (STD), tuberculosis and some anthrax infections.[53][30][10] The effectiveness of quinolones is proposed to be from chromosome fragments, which initiate the accumulation of reactive oxygen species that leads to apoptosis.[53] Quinolones can be divided into four generations:

  1. First generation: nalidixic acid[11]
  2. Second generation: cinoxacin, norfloxacin, ciprofloxacin[11]
  3. Third generation: levofloxacin, sparfloxacin[11]
  4. Fourth generation: moxifloxacin[11]

The first quinolone was discovered in 1962 by George Lesher and his co-workers at Sterling Drug (now owned by Sanofi) as an impurity collected while manufacturing chloroquine, an antimalarial drug.[13][55][47] This impurity was used to develop nalidixic acid, which was made clinically available in 1964.[13] Along with its novel structure and mechanism, nalidixic acid's gram negative activity, oral application, and relatively simple synthesis (qualities common among quinolones), showed promise.[55][11] Despite these features, it was relegated to solely treat urinary tract infections because of its small spectrum of activity.[13][55][11] The newer generation of drugs are classified as fluoroquinolones due to the addition of a fluorine and a methyl-piperazine, which allows for improved gyrase targeting (TopII).[10] It is proposed that this added fluorine substituent aids in base stacking during fluoroquinolone intercalation into TopII cleaved DNA by altering the electron density of the quinolone ring.[56] The first member of the fluoroquinolone subclass, norfloxacin, was discovered by Koga and colleagues at the pharmaceutical company Kyorin in 1978.[11] It was found to possess higher anti-gram negative potency than standard quinolones, and showed some anti-gram positive effects.[55] Both its blood serum levels and tissue penetration abilities proved to be poor, and it was overshadowed by the development of ciprofloxacin, a fluoroquinolone with a superior spectrum of activity.[47] Fluoroquinolones have proven to be effective on a wide array of microbial targets, with some third and fourth generation drugs possessing both anti-Gram positive and anti-anerabic capabilities.[11]

Currently, the US Food and Drug Administration (FDA) has updated the public on eight new-generation fluoroquinolones: moxifloxacin, delafloxacin, ciprofloxacin, ciprofloxacin extended-release, gemifloxacin, levofloxacin, and ofloxacin.[18] It was observed that the new fluoroquinolones can cause hypoglycemia, high blood pressure, and mental health effects such as agitation, nervousness, memory impairment and delirium.[57][18]

Although quinolones are successful as antibiotics, their effectiveness is limited due to accumulation of small mutations and multi-drug efflux mechanisms, which pump out unwanted drugs out of the cell.[10] In particular, smaller quinolones have shown to bind with high affinity in the multi-drug efflux pump in Escherichia coli and Staphylococcus aureus.[58][59][19] Despite quinolones ability to target TopII, they can also inhibit TopIV based on the organisms and type of quinolone.[10] Additionally, the discovery of mutations in the gyrB region is hypothesized to cause quinolone-based antibiotic resistance.[10][60] Specifically, the mutations from aspartate (D) to asparagine (N), and Lysine (K) to glutamic acid (E) are believed to disrupt interactions, leading to some loss of tertiary structure.[10][60]

Mechanically, the since disproven, Shen et al. (1989) model of quinolone inhibitor binding proposed that, in each DNAgyrase-DNA complex, four quinolone molecules associate with one another via hydrophobic interactions and form hydrogen bonds with the bases of separated, single stranded segments of DNA.[11][61][56] Shen et al. based their hypothesis on observations regarding the increased affinity and site specificity of quinolone binding to single stranded DNA compared to relaxed double stranded DNA.[61] A modified version of the Shen et al. model was still regarded as a likely mechanism in the mid to late 2000s,[11][62] but X-ray crystallography-based models of inhibitor-DNA-TopII complex stable intermediates developed in 2009 have since contradicted this hypothesis.[63][56] This newer model suggests that two quinolone molecules intercalate at the two DNA nick sites created by TopII, aligning with a hypothesis proposed by Leo et al. (2005).[64][56][47]

Anticancer therapeutics

Intercalating poison

TopII inhibitors have two main identification: poisons and catalytic inhibitors.[65][62] TopII poisons are characterized by their ability to create irreversible covalent bonds with DNA.[62] Furthermore, TopII poisons are divided into two groups: intercalating or non-intercalating poisons.[62][8] The anthracycline family, one of the most medically prevalent types of intercalating poisons, are able to treat a variety of cancer due to its diverse derivations and are often prescribed in combination with other chemotherapeutic medications.[14][62]

The first anthracycline (doxorubicin) was isolated from the bacteria Streptomyces peucetius in the 1960s.[14][17] Anthracyclines are composed of a core of four hexane rings, the central two of which are quinone and hydroquinone rings. A ring adjacent to the hydroquinone is connected to two substituents, a daunosamine sugar and a carbonyl with a varying side chain.[17] Currently, there are four main anthracyclines in medical use:

  1. Doxorubicin
  2. Daunorubicin (doxorubicin precursor)
  3. Epirubicin (a doxorubicin stereoisomer)
  4. Idarubicin (a daunorubicin derivative)[17]

Idarubicin is able to pass through cell membranes easier than daunorubicin and doxorubicin because it possesses less polar subunits, making it more lipophilic.[17][66] It is hypothesized that doxorubicin, which possesses a hydroxyl group and a methoxy group not present in idarubicin, can form hydrogen bonding aggregates with itself on the surface of phospholipid membranes, further reducing its ability to enter cells.[66]

Despite the success of these poisons, they have been shown that interaction poisons have a few limitations including 1) little inhibitor success of small compounds 2) anthracyclines' adverse effects such as membrane damage and secondary cancers due to oxygen-free radical generation 3) congestive heart failure.[62] The harmful oxygen free radical generation associated with the use of doxorubicin and other anthracyclines stems, in part, from their quinone moiety undergoing redox reactions mediated by oxido-reductases, resulting in the formation of superoxide anions, hydrogen peroxide, and hydroxyl radicals.[17][14] The mitochondrial electron transport chain pathway containing NADH hydrogenase is one potential instigator of these redox reactions.[17] The reactive oxygen species produced by interactions like this can interfere with cell signaling pathways that utilize protein kinase A, protein kinase C and calcium/calmodulin-dependent protein kinase II (CaMKII), a kinase integral in controlling calcium ion channels in cardiomyocites.[14]

Non-intercalating poisons

Another category of TopII poisons is known as non-intercalating poisons. The main non-intercalating TopII poisons are etoposide and teniposide. These non-intercalating poisons specifically target prokaryotic TopII in DNA by blocking transcription and replication.[62] Studies have shown that non-intercalating poisons play an important role in confining TopII-DNA covalent complexes.[62] Etoposide, a semi-synthetic derivative of epipodophyllotoxin is commonly used to study this apoptotic mechanism and include:

  1. Etoposide
  2. Teniposide

Both etoposide and teniposide are naturally occurring semi-synthetic derivatives of podophyllotoxins and are important anti-cancer drugs that function to inhibit TopII activity.[67] 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.[13][68] Etoposide has shown to be one of the most active drugs for small cell lung cancer (SCLC), testicular carcinoma and malignant lymphoma. 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.[69] Additionally, studies have shown when treated with etoposide derivatives there is an 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.[13][68] However, with the selective dosage, etoposide treatment is dose limiting proposing toxic effects like myelosupression (leukopenia) and primarily hematologic.[13][69] 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.[13]

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.[70] However, teniposide is more protein-bound than etoposide.[70] Additionally, teniposide has a greater uptake, higher potency and greater binding affinity to cells compared to etoposide. Studies have shown that teniposide is an active anti-tumor agent and have been used in clinical settings to evaluate the efficacy of teniposide.[70] In a study performed 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.[70] However, the study found that the treatment outcome for patients with brain metastasis of SCLC had low survival and improvement rates.[70]

Mutations

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.[71] More specifically, this difference occurs between the chromophore framework and the base pairs of DNA.[71] As a result of their structural specificity, slight differences in chemical amplification between antibiotics are seen.[71] Thus, this provides explanation on why theses drugs show differences in clinical activity in patients.[71]

Despite the difference in structural specificity, they both present mutations that result in anticancer drug resistance[71] In relation to intercalating poisons, it has been found that there are recurrent somatic mutations in the anthracyclines family.[72] Studies have shown that in DNA methyltransferase 3A (DNMT3A) the most frequent mutation is seen at arginine 882 (DNMT3AR882).[72] This mutation impacts patients with acute myeloid leukemia (AML) by initially responding to chemotherapy but relapsing afterwards.[72] The persistence of DNMT3AR882 cells induce hematopoietic stem cell expansion and promotes resistance to anthracycline chemotherapy.[72]

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).[73] 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.[14] It has been proposed that the level of TopII activity is an important determination factor in drug sensitivity.[74] This study also indicated that hypophosphorylation 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 TopII-mediated DNA cleavable complex formation.[14] Scientists have indicated that this could be a plausible relationship between etoposide drug resistance and hypophosphorylation of HL-60 cells.[14] 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.[75] 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.[75] 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.[75] Other sources have seen this same trend and have reported hyperphosphorylation of TopII in etoposide-resistant cells and that the TopIIα located in these etoposide-resistant cells have a mutation at the amino acid residues Ser861-Phe.[74]

Catalytic inhibitors

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.[76] Additionally, catalytic poisons can interfere with ATPase and DNA strand passageways leading to stabilization of the DNA intermediate covalent complex.[77] 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.[78] Furthermore, in preclinical and clinical settings, bis(2,6-dioxopiperazines) is used to reduce the side effects of TopII poisons.[78] 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.[79][80] Dexrazoxane functions to inhibit TopII and its effects on iron homeostasis regulation.[80] Dexrazoxane is a bisdioxopiperazine with iron-chelating, chemoprotective, cardioprotective, and antineoplastic activities.[81]

Novobiocin is also known as cathomycin, albamycin or streptonivicin and is an aminocoumarin antibiotic compound that functions to bind to DNA gyrase and inhibits ATPase activity.[82] It acts as a competitive inhibitor and specifically inhibits Hsp90 and TopII.[83] Novobiocin has been investigated and used in metastatic breast cancer clinical trials, non-small lung cancer cells and treatments for psoriasis when combined with nalidixic acid. Additionally, it is regularly used as a treatment for infections by gram-positive bacteria.[84] Novobiocin is derived from coumarin and the structure of novobiocin is similar to that of coumarin.

Synthetic lethality with deficient WRN expression

Synthetic lethality arises when a combination of deficiencies in the expression of two or more genes leads to cell death, whereas a deficiency in expression of only one of these genes does not. The deficiencies can arise through mutations, epigenetic alterations or inhibitors of the genes. Synthetic lethality with the topoisomerase inhibitor irinotecan appears to occur when given to cancer patients with deficient expression of the DNA repair gene WRN.

The analysis of 630 human primary tumors in 11 tissues shows that hypermethylation of the WRN CpG island promoter (with loss of expression of WRN protein) is a common event in tumorigenesis.[85] WRN is repressed in about 38% of colorectal cancers and non-small-cell lung carcinomas and in about 20% or so of stomach cancers, prostate cancers, breast cancers, non-Hodgkin lymphomas and chondrosarcomas, plus at significant levels in the other cancers evaluated. The WRN protein helicase is important in homologous recombinational DNA repair and also has roles in non-homologous end joining DNA repair and base excision DNA repair.[86]

A 2006 retrospective study, with long clinical follow-up, was made of colon cancer patients treated with the topoisomerase inhibitor irinotecan. In this study, 45 patients had hypermethylated WRN gene promoters and 43 patients had unmethylated WRN promoters.[85] Irinotecan was more strongly beneficial for patients with hypermethylated WRN promoters (39.4 months survival) than for those with unmethylated WRN promoters (20.7 months survival). Thus, a topoisomerase inhibitor appeared to be especially synthetically lethal with deficient WRN expression. Further evaluations have also indicated synthetic lethality of deficient expression of WRN and topoisomerase inhibitors.[87][88][89][90][91]

References

  1. 1 2 Cooper GM (2019). The Cell: A Molecular Approach Eighth Edition. Oxford University Press. p. 222. ISBN 9781605357072.
  2. 1 2 3 4 5 6 7 Nelson DL, Cox MM (2017). Lehninger Principles of Biochemistry Seventh Edition. W. H. Freeman and Company. pp. 963–971. ISBN 9781464126116.
  3. 1 2 3 4 5 Delgado JL, Hsieh C, Chan N, Hiasa H (2018-01-31). "Topoisomerases as anticancer targets". Biochemical Journal. 475 (2): 373–398. doi:10.1042/BCJ20160583. ISSN 0264-6021. PMC 6110615. PMID 29363591.
  4. ↑ Waksman SA, Woodruff HB (1940). "The Soil as a Source of Microorganisms Antagonistic to Disease-Producing Bacteria*1". Journal of Bacteriology. 40 (4): 581–600. doi:10.1128/jb.40.4.581-600.1940. ISSN 0021-9193. PMC 374661. PMID 16560371.
  5. ↑ Bush K (December 2010). "The coming of age of antibiotics: discovery and therapeutic value: Origins of antibiotic drug discovery". Annals of the New York Academy of Sciences. 1213 (1): 1–4. doi:10.1111/j.1749-6632.2010.05872.x. PMID 21175674. S2CID 205935691.
  6. ↑ Chevrette MG, Currie CR (March 2019). "Emerging evolutionary paradigms in antibiotic discovery". Journal of Industrial Microbiology & Biotechnology. 46 (3–4): 257–271. doi:10.1007/s10295-018-2085-6. ISSN 1367-5435. PMID 30269177. S2CID 52889274.
  7. 1 2 3 4 5 6 7 Di Marco A, Cassinelli G, Arcamone F (1981). "The discovery of daunorubicin". Cancer Treatment Reports. 65 (Suppl 4): 3–8. ISSN 0361-5960. PMID 7049379.
  8. 1 2 Marinello J, Delcuratolo M, Capranico G (2018-11-06). "Anthracyclines as Topoisomerase II Poisons: From Early Studies to New Perspectives". International Journal of Molecular Sciences. 19 (11): 3480. doi:10.3390/ijms19113480. ISSN 1422-0067. PMC 6275052. PMID 30404148.
  9. ↑ Buzun K, Bielawska A, Bielawski K, Gornowicz A (2020-01-01). "DNA topoisomerases as molecular targets for anticancer drugs". Journal of Enzyme Inhibition and Medicinal Chemistry. 35 (1): 1781–1799. doi:10.1080/14756366.2020.1821676. ISSN 1475-6366. PMC 7534307. PMID 32975138.
  10. 1 2 3 4 5 6 7 8 9 10 11 Wall ME (1998). "Camptothecin and taxol: Discovery to clinic". Medicinal Research Reviews. 18 (5): 299–314. doi:10.1002/(SICI)1098-1128(199809)18:5<299::AID-MED2>3.0.CO;2-O. ISSN 1098-1128. PMID 9735871. S2CID 41392556.
  11. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 Mitscher LA (2005-06-14). "Bacterial Topoisomerase Inhibitors: Quinolone and Pyridone Antibacterial Agents". ChemInform. 36 (24): 559–92. doi:10.1002/chin.200524274. ISSN 0931-7597. PMID 15700957.
  12. ↑ Gellert M, Mizuuchi K, O'Dea MH, Nash HA (1976-11-01). "DNA gyrase: an enzyme that introduces superhelical turns into DNA". Proceedings of the National Academy of Sciences. 73 (11): 3872–3876. Bibcode:1976PNAS...73.3872G. doi:10.1073/pnas.73.11.3872. ISSN 0027-8424. PMC 431247. PMID 186775.
  13. 1 2 3 4 5 6 7 8 9 10 Sinkule JA (March 1984). "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. S2CID 31424235.
  14. 1 2 3 4 5 6 7 8 9 Benjanuwattra J, Siri-Angkul N, Chattipakorn SC, Chattipakorn N (January 2020). "Doxorubicin and its proarrhythmic effects: A comprehensive review of the evidence from experimental and clinical studies". Pharmacological Research. 151: 104542. doi:10.1016/j.phrs.2019.104542. PMID 31730804. S2CID 208060979.
  15. 1 2 3 Kojiri K, Kondo H, Yoshinari T, Arakawa H, Nakajima S, Satoh F, Kawamura K, Okura A, Suda H, Okanishi M (1991). "A new antitumor substance, BE-13793C, produced by a streptomycete. Taxonomy, fermentation, isolation, structure determination and biological activity". The Journal of Antibiotics. 44 (7): 723–728. doi:10.7164/antibiotics.44.723. ISSN 0021-8820. PMID 1652582.
  16. 1 2 3 4 5 6 Cushman M, Jayaraman M, Vroman JA, Fukunaga AK, Fox BM, Kohlhagen G, Strumberg D, Pommier Y (October 2000). "Synthesis of New Indeno[1,2- c ]isoquinolines: Cytotoxic Non-Camptothecin Topoisomerase I Inhibitors". Journal of Medicinal Chemistry. 43 (20): 3688–3698. doi:10.1021/jm000029d. ISSN 0022-2623. PMID 11020283.
  17. 1 2 3 4 5 6 7 McGowan JV, Chung R, Maulik A, Piotrowska I, Walker JM, Yellon DM (February 2017). "Anthracycline Chemotherapy and Cardiotoxicity". Cardiovascular Drugs and Therapy. 31 (1): 63–75. doi:10.1007/s10557-016-6711-0. ISSN 0920-3206. PMC 5346598. PMID 28185035.
  18. 1 2 3 Research Cf (2019-04-15). "FDA reinforces safety information about serious low blood sugar levels and mental health side effects with fluoroquinolone antibiotics; requires label changes". FDA.
  19. 1 2 3 4 5 6 7 8 Li F, Jiang T, Li Q, Ling X (2017-12-01). "Camptothecin (CPT) and its derivatives are known to target topoisomerase I (Top1) as their mechanism of action: did we miss something in CPT analogue molecular targets for treating human disease such as cancer?". American Journal of Cancer Research. 7 (12): 2350–2394. ISSN 2156-6976. PMC 5752681. PMID 29312794.
  20. ↑ World Health Organization Model List of Essential Medicines, 21st List, 2019. Geneva: World Health Organization; 2019. Licence: CC BY-NC-SA 3.0 IGO.
  21. ↑ Sinha BK (1995-01-01). "Topoisomerase Inhibitors". Drugs. 49 (1): 11–19. doi:10.2165/00003495-199549010-00002. ISSN 1179-1950. PMID 7705211. S2CID 46985043.
  22. 1 2 3 4 Pommier Y (2009-07-08). "DNA Topoisomerase I Inhibitors: Chemistry, Biology, and Interfacial Inhibition". Chemical Reviews. 109 (7): 2894–2902. doi:10.1021/cr900097c. ISSN 0009-2665. PMC 2707511. PMID 19476377.
  23. 1 2 3 4 Pommier Y, Leo E, Zhang H, Marchand C (2010-05-28). "DNA Topoisomerases and Their Poisoning by Anticancer and Antibacterial Drugs". Chemistry & Biology. 17 (5): 421–433. doi:10.1016/j.chembiol.2010.04.012. ISSN 1074-5521. PMC 7316379. PMID 20534341.
  24. 1 2 Pommier Y (October 2006). "Topoisomerase I inhibitors: camptothecins and beyond". Nature Reviews Cancer. 6 (10): 789–802. doi:10.1038/nrc1977. ISSN 1474-1768. PMID 16990856. S2CID 25135019.
  25. ↑ Perdue RE, Smith RL, Wall ME, Hartwell JL, Abbott BJ, Perdue RE, Smith RL, Wall ME, Hartwell JL, Abbott BJ (1970). Camptotheca acuminata Decaisne (Nyssaceae) Source of Camptothecin, an Antileukemic Alkaloid. Technical Bulletin. Vol. 1415. doi:10.22004/AG.ECON.171841.
  26. ↑ D'yakonov VA, Dzhemileva LU, Dzhemilev UM (2017), "Advances in the Chemistry of Natural and Semisynthetic Topoisomerase I/II Inhibitors", Studies in Natural Products Chemistry, Elsevier, vol. 54, pp. 21–86, doi:10.1016/b978-0-444-63929-5.00002-4, ISBN 978-0-444-63929-5, retrieved 2020-12-20
  27. ↑ Liu Y, Li W, Morris-Natschke SL, Qian K, Yang L, Zhu G, Wu X, Chen A, Zhang S, Nan X, Lee K (2015). "Perspectives on Biologically Active Camptothecin Derivatives". Medicinal Research Reviews. 35 (4): 753–789. doi:10.1002/med.21342. ISSN 1098-1128. PMC 4465867. PMID 25808858.
  28. 1 2 Cunha KS, Reguly ML, Graf U, Rodrigues de Andrade HH (2002-03-01). "Comparison of camptothecin derivatives presently in clinical trials: genotoxic potency and mitotic recombination". Mutagenesis. 17 (2): 141–147. doi:10.1093/mutage/17.2.141. hdl:20.500.11850/422901. ISSN 0267-8357. PMID 11880543.
  29. ↑ Hsiang YH, Hertzberg R, Hecht S, Liu LF (1985-11-25). "Camptothecin induces protein-linked DNA breaks via mammalian DNA topoisomerase I". The Journal of Biological Chemistry. 260 (27): 14873–14878. doi:10.1016/S0021-9258(17)38654-4. ISSN 0021-9258. PMID 2997227.
  30. 1 2 3 4 Staker BL, Feese MD, Cushman M, Pommier Y, Zembower D, Stewart L, Burgin AB (April 2005). "Structures of Three Classes of Anticancer Agents Bound to the Human Topoisomerase I−DNA Covalent Complex". Journal of Medicinal Chemistry. 48 (7): 2336–2345. doi:10.1021/jm049146p. ISSN 0022-2623. PMID 15801827.
  31. ↑ Lu A, Zhang Z, Zheng M, Zou H, Luo X, Jiang H (February 2007). "3D-QSAR study of 20 ( S )-camptothecin analogs". Acta Pharmacologica Sinica. 28 (2): 307–314. doi:10.1111/j.1745-7254.2007.00477.x. ISSN 1745-7254. PMID 17241535. S2CID 25448878.
  32. ↑ Ulukan H, Swaan PW (2002-10-01). "Camptothecins". Drugs. 62 (14): 2039–2057. doi:10.2165/00003495-200262140-00004. ISSN 1179-1950. PMID 12269849. S2CID 195692628.
  33. ↑ HOPKINS RP (1983-12-01). "Principles of Biochemistry, Seventh Edition (two volumes): General Aspects, Mammalian Biochemistry". Biochemical Society Transactions. 11 (6): 829–830. doi:10.1042/bst0110829a. ISSN 0300-5127.
  34. 1 2 3 Lynch T (1996-12-01). "Topotecan today". Journal of Clinical Oncology. 14 (12): 3053–3055. doi:10.1200/JCO.1996.14.12.3053. ISSN 0732-183X. PMID 8955649.
  35. 1 2 Hu G, Zekria D, Cai X, Ni X (June 2015). "Current status of CPT and its analogues in the treatment of malignancies". Phytochemistry Reviews. 14 (3): 429–441. Bibcode:2015PChRv..14..429H. doi:10.1007/s11101-015-9397-1. ISSN 1568-7767. S2CID 14747493.
  36. ↑ Arno Therapeutics (2014-12-08). "A Phase 2 Study of AR-67 (7-t-butyldimethylsiltyl-10-hydroxy-camptothecin) in Adult Patients With Recurrence of Glioblastoma Multiforme (GBM) or Gliosarcoma".
  37. ↑ Pommier Y, Pourquier P, Urasaki Y, Wu J, Laco GS (October 1999). "Topoisomerase I inhibitors: selectivity and cellular resistance". Drug Resistance Updates. 2 (5): 307–318. doi:10.1054/drup.1999.0102. ISSN 1368-7646. PMID 11504505.
  38. 1 2 3 Cushman M, Cheng L (September 1978). "Stereoselective oxidation by thionyl chloride leading to the indeno[1,2-c]isoquinoline system". The Journal of Organic Chemistry. 43 (19): 3781–3783. doi:10.1021/jo00413a036. ISSN 0022-3263.
  39. ↑ Long BH, Rose WC, Vyas DM, Matson JA, Forenza S (March 2002). "Discovery of antitumor indolocarbazoles: rebeccamycin, NSC 655649, and fluoroindolocarbazoles". Current Medicinal Chemistry. Anti-Cancer Agents. 2 (2): 255–266. doi:10.2174/1568011023354218. ISSN 1568-0118. PMID 12678746.
  40. ↑ Li T, Houghton PJ, Desai SD, Daroui P, Liu AA, Hars ES, Ruchelman AL, LaVoie EJ, Liu LF (2003-12-01). "Characterization of ARC-111 as a novel topoisomerase I-targeting anticancer drug". Cancer Research. 63 (23): 8400–8407. ISSN 0008-5472. PMID 14679002.
  41. ↑ Yamashita Y, Fujii N, Murakata C, Ashizawa T, Okabe M, Nakano H (1992-12-08). "Induction of mammalian DNA topoisomerase I mediated DNA cleavage by antitumor indolocarbazole derivatives". Biochemistry. 31 (48): 12069–12075. doi:10.1021/bi00163a015. ISSN 0006-2960. PMID 1333791.
  42. ↑ Cui Y, Wu L, Cao R, Xu H, Xia J, Wang ZP, Ma J (2020). "Antitumor functions and mechanisms of nitidine chloride in human cancers". Journal of Cancer. 11 (5): 1250–1256. doi:10.7150/jca.37890. ISSN 1837-9664. PMC 6959075. PMID 31956371.
  43. ↑ Huang C, Kavala V, Kuo C, Konala A, Yang T, Yao C (2017-02-17). "Synthesis of Biologically Active Indenoisoquinoline Derivatives via a One-Pot Copper(II)-Catalyzed Tandem Reaction". The Journal of Organic Chemistry. 82 (4): 1961–1968. doi:10.1021/acs.joc.6b02814. ISSN 0022-3263. PMID 28177250.
  44. ↑ "Yves Pommier, M.D., Ph.D." Center for Cancer Research. 2014-08-12. Retrieved 2020-12-13.
  45. ↑ Xu Y, Her C (2015-07-22). "Inhibition of Topoisomerase (DNA) I (TOP1): DNA Damage Repair and Anticancer Therapy". Biomolecules. 5 (3): 1652–1670. doi:10.3390/biom5031652. ISSN 2218-273X. PMC 4598769. PMID 26287259.
  46. ↑ "A Phase I Study of Indenoisoquinolines LMP400 and LMP776 in Adults with Relapsed Solid Tumors and Lymphomas". 15 June 2021.
  47. 1 2 3 4 Aldred KJ, Kerns RJ, Osheroff N (2014-03-18). "Mechanism of Quinolone Action and Resistance". Biochemistry. 53 (10): 1565–1574. doi:10.1021/bi5000564. ISSN 0006-2960. PMC 3985860. PMID 24576155.
  48. 1 2 3 4 5 Hevener K, Verstak TA, Lutat KE, Riggsbee DL, Mooney JW (October 2018). "Recent developments in topoisomerase-targeted cancer chemotherapy". Acta Pharmaceutica Sinica B. 8 (6): 844–861. doi:10.1016/j.apsb.2018.07.008. ISSN 2211-3835. PMC 6251812. PMID 30505655.
  49. 1 2 Classen S, Olland S, Berger JM (2003-09-16). "Structure of the topoisomerase II ATPase region and its mechanism of inhibition by the chemotherapeutic agent ICRF-187". Proceedings of the National Academy of Sciences. 100 (19): 10629–10634. Bibcode:2003PNAS..10010629C. doi:10.1073/pnas.1832879100. ISSN 0027-8424. PMC 196855. PMID 12963818.
  50. ↑ Thorn CF, Oshiro C, Marsh S, Hernandez-Boussard T, McLeod H, Klein TE, Altman RB (July 2011). "Doxorubicin pathways: pharmacodynamics and adverse effects". Pharmacogenetics and Genomics. 21 (7): 440–446. doi:10.1097/FPC.0b013e32833ffb56. ISSN 1744-6872. PMC 3116111. PMID 21048526.
  51. ↑ Montecucco A, Zanetta F, Biamonti G (2015-01-19). "Molecular mechanisms of etoposide". EXCLI Journal. 14: 95–108. doi:10.17179/excli2014-561. ISSN 1611-2156. PMC 4652635. PMID 26600742.
  52. ↑ Lewis RJ, Singh OM, Smith CV, Skarzynski T, Maxwell A, Wonacott AJ, Wigley DB (1996-03-15). "The nature of inhibition of DNA gyrase by the coumarins and the cyclothialidines revealed by X-ray crystallography". The EMBO Journal. 15 (6): 1412–1420. doi:10.1002/j.1460-2075.1996.tb00483.x. ISSN 0261-4189. PMC 450046. PMID 8635474.
  53. 1 2 3 Anderson VE, Osheroff N (March 2001). "Type II topoisomerases as targets for quinolone antibacterials: turning Dr. Jekyll into Mr. Hyde". Current Pharmaceutical Design. 7 (5): 337–353. doi:10.2174/1381612013398013. ISSN 1381-6128. PMID 11254893.
  54. ↑ Li W, Nihira T, Sakuda S, Nishida T, Yamada Y (1992-01-01). "New inducing factors for virginiamycin production from Streptomyces antibioticus". Journal of Fermentation and Bioengineering. 74 (4): 214–217. doi:10.1016/0922-338X(92)90112-8. ISSN 0922-338X.
  55. 1 2 3 4 Li Q, Mitscher LA, Shen LL (2000). "The 2-pyridone antibacterial agents: bacterial topoisomerase inhibitors". Medicinal Research Reviews. 20 (4): 231–293. doi:10.1002/1098-1128(200007)20:4<231::AID-MED1>3.0.CO;2-N. ISSN 1098-1128. PMID 10861727. S2CID 24531327.
  56. 1 2 3 4 Laponogov I, Sohi MK, Veselkov DA, Pan X, Sawhney R, Thompson AW, McAuley KE, Fisher LM, Sanderson MR (June 2009). "Structural insight into the quinolone–DNA cleavage complex of type IIA topoisomerases". Nature Structural & Molecular Biology. 16 (6): 667–669. doi:10.1038/nsmb.1604. ISSN 1545-9993. PMID 19448616. S2CID 23776629.
  57. ↑ Wolfson JS, Hooper DC (1991-12-30). "Overview of fluoroquinolone safety". The American Journal of Medicine. Fluoroquinolones in the Treatment of Human Infection: The Role of Temafloxacin. 91 (6, Supplement 1): S153–S161. doi:10.1016/0002-9343(91)90330-Z. ISSN 0002-9343. PMID 1767803.
  58. ↑ Collin F, Karkare S, Maxwell A (November 2011). "Exploiting bacterial DNA gyrase as a drug target: current state and perspectives". Applied Microbiology and Biotechnology. 92 (3): 479–497. doi:10.1007/s00253-011-3557-z. ISSN 0175-7598. PMC 3189412. PMID 21904817.
  59. ↑ Drlica K, Hiasa H, Kerns R, Malik M, Mustaev A, Zhao X (August 2009). "Quinolones: Action and Resistance Updated". Current Topics in Medicinal Chemistry. 9 (11): 981–998. doi:10.2174/156802609789630947. ISSN 1568-0266. PMC 3182077. PMID 19747119.
  60. 1 2 Yoshida H, Bogaki M, Nakamura M, Yamanaka LM, Nakamura S (1991-08-01). "Quinolone resistance-determining region in the DNA gyrase gyrB gene of Escherichia coli". Antimicrobial Agents and Chemotherapy. 35 (8): 1647–1650. doi:10.1128/AAC.35.8.1647. ISSN 0066-4804. PMC 245234. PMID 1656869.
  61. 1 2 Shen LL, Mitscher LA, Sharma PN, O'Donnell TJ, Chu DW, Cooper CS, Rosen T, Pernet AG (1989-05-02). "Mechanism of inhibition of DNA gyrase by quinolone antibacterials: a cooperative drug-DNA binding model". Biochemistry. 28 (9): 3886–3894. doi:10.1021/bi00435a039. ISSN 0006-2960. PMID 2546585.
  62. 1 2 3 4 5 6 7 8 Nitiss JL (May 2009). "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.
  63. ↑ Wohlkonig A, Chan PF, Fosberry AP, Homes P, Huang J, Kranz M, Leydon VR, Miles TJ, Pearson ND, Perera RL, Shillings AJ (2010-08-29). "Structural basis of quinolone inhibition of type IIA topoisomerases and target-mediated resistance". Nature Structural & Molecular Biology. 17 (9): 1152–1153. doi:10.1038/nsmb.1892. ISSN 1545-9993. PMID 20802486. S2CID 24498996.
  64. ↑ Leo E, Gould KA, Pan X, Capranico G, Sanderson MR, Palumbo M, Fisher LM (2005-01-18). "Novel Symmetric and Asymmetric DNA Scission Determinants forStreptococcus pneumoniaeTopoisomerase IV and Gyrase Are Clustered at the DNA Breakage Site". Journal of Biological Chemistry. 280 (14): 14252–14263. doi:10.1074/jbc.m500156200. ISSN 0021-9258. PMID 15659402. S2CID 29092424.
  65. ↑ Atwal M, Swan RL, Rowe C, Lee KC, Lee DC, Armstrong L, Cowell IG, Austin CA (October 2019). "Intercalating TOP2 Poisons Attenuate Topoisomerase Action at Higher Concentrations". Molecular Pharmacology. 96 (4): 475–484. doi:10.1124/mol.119.117259. ISSN 0026-895X. PMC 6744389. PMID 31399497.
  66. 1 2 Matyszewska D, Nazaruk E, Campbell RA (January 2021). "Interactions of anticancer drugs doxorubicin and idarubicin with lipid monolayers: New insight into the composition, structure and morphology". Journal of Colloid and Interface Science. 581 (Pt A): 403–416. Bibcode:2021JCIS..581..403M. doi:10.1016/j.jcis.2020.07.092. PMID 32771749.
  67. ↑ Imbert TF (March 1998). "Discovery of podophyllotoxins". Biochimie. 80 (3): 207–222. doi:10.1016/s0300-9084(98)80004-7. ISSN 0300-9084. PMID 9615861.
  68. 1 2 Clark PI, Slevin ML (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. PMID 3297462. S2CID 33161084.
  69. 1 2 Vogelzang NJ, Raghavan D, Kennedy BJ (January 1982). "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.
  70. 1 2 3 4 5 Postmus PE, Haaxma-Reiche H, Smit EF, Groen HJ, Karnicka H, Lewinski T, Van Meerbeeck J, Clerico M, Gregor A, Curran D, Sahmoud T, Kirkpatrick A, Giaccone G (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. 18 (19): 3400–3408. doi:10.1200/JCO.2000.18.19.3400. PMID 11013281.
  71. 1 2 3 4 5 Manfait M, Chourpa I, Sokolov K, Morjani H, Riou J, Lavelle F, Nabiev I (1993), Theophanides T, Anastassopoulou J, Fotopoulos N (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
  72. 1 2 3 4 Guryanova OA, Shank K, Spitzer B, Luciani L, Koche RP, Garrett-Bakelman FE, Ganzel C, Durham BH, Mohanty A, Hoermann G, Rivera SA (December 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.
  73. ↑ 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.
  74. 1 2 Ganapathi RN, Ganapathi MK (2013-08-01). "Mechanisms regulating resistance to inhibitors of topoisomerase II". Frontiers in Pharmacology. 4: 89. doi:10.3389/fphar.2013.00089. ISSN 1663-9812. PMC 3729981. PMID 23914174.
  75. 1 2 3 Matsumoto Y, Takano H, Kunishio K, Nagao S, Fojo T (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.
  76. ↑ Andoh T, Ishida R (1998-10-01). "Catalytic inhibitors of DNA topoisomerase II". Biochimica et Biophysica Acta (BBA) - Gene Structure and Expression. 1400 (1): 155–171. doi:10.1016/S0167-4781(98)00133-X. ISSN 0167-4781. PMID 9748552.
  77. ↑ Kerrigan D, Pommier Y, Kohn KW (1987). "Protein-linked DNA strand breaks produced by etoposide and teniposide in mouse L1210 and human VA-13 and HT-29 cell lines: relationship to cytotoxicity". NCI Monographs (4): 117–121. ISSN 0893-2751. PMID 3041238.
  78. 1 2 Andoh T (March 1998). "Bis(2,6-dioxopiperazines), catalytic inhibitors of DNA topoisomerase II, as molecular probes, cardioprotectors and antitumor drugs". Biochimie. 80 (3): 235–246. doi:10.1016/s0300-9084(98)80006-0. ISSN 0300-9084. PMID 9615863.
  79. ↑ Langer SW (2014-09-15). "Dexrazoxane for the treatment of chemotherapy-related side effects". Cancer Management and Research. 6: 357–363. doi:10.2147/CMAR.S47238. ISSN 1179-1322. PMC 4168851. PMID 25246808.
  80. 1 2 Weiss G, Loyevsky M, Gordeuk VR (January 1999). "Dexrazoxane (ICRF-187)". General Pharmacology. 32 (1): 155–158. doi:10.1016/s0306-3623(98)00100-1. ISSN 0306-3623. PMID 9888268.
  81. ↑ PubChem. "Dexrazoxane". pubchem.ncbi.nlm.nih.gov. Retrieved 2020-12-10.
  82. ↑ "Novobiocin". go.drugbank.com. Retrieved 2020-12-10.
  83. ↑ "NCATS Inxight: Drugs — NOVOBIOCIN". drugs.ncats.io. Retrieved 2020-12-10.
  84. ↑ PubChem. "Novobiocin". pubchem.ncbi.nlm.nih.gov. Retrieved 2020-12-10.
  85. 1 2 Agrelo R, Cheng WH, Setien F, Ropero S, Espada J, Fraga MF, Herranz M, Paz MF, Sanchez-Cespedes M, Artiga MJ, Guerrero D, Castells A, von Kobbe C, Bohr VA, Esteller M (2006). "Epigenetic inactivation of the premature aging Werner syndrome gene in human cancer". Proc. Natl. Acad. Sci. U.S.A. 103 (23): 8822–7. Bibcode:2006PNAS..103.8822A. doi:10.1073/pnas.0600645103. PMC 1466544. PMID 16723399.
  86. ↑ Monnat RJ (2010). "Human RECQ helicases: roles in DNA metabolism, mutagenesis and cancer biology". Semin. Cancer Biol. 20 (5): 329–39. doi:10.1016/j.semcancer.2010.10.002. PMC 3040982. PMID 20934517.
  87. ↑ Wang L, Xie L, Wang J, Shen J, Liu B (2013). "Correlation between the methylation of SULF2 and WRN promoter and the irinotecan chemosensitivity in gastric cancer". BMC Gastroenterol. 13: 173. doi:10.1186/1471-230X-13-173. PMC 3877991. PMID 24359226.
  88. ↑ Bird JL, Jennert-Burston KC, Bachler MA, Mason PA, Lowe JE, Heo SJ, Campisi J, Faragher RG, Cox LS (2012). "Recapitulation of Werner syndrome sensitivity to camptothecin by limited knockdown of the WRN helicase/exonuclease". Biogerontology. 13 (1): 49–62. doi:10.1007/s10522-011-9341-8. PMID 21786128. S2CID 18189226.
  89. ↑ Masuda K, Banno K, Yanokura M, Tsuji K, Kobayashi Y, Kisu I, Ueki A, Yamagami W, Nomura H, Tominaga E, Susumu N, Aoki D (2012). "Association of epigenetic inactivation of the WRN gene with anticancer drug sensitivity in cervical cancer cells". Oncol. Rep. 28 (4): 1146–52. doi:10.3892/or.2012.1912. PMC 3583574. PMID 22797812.
  90. ↑ Futami K, Takagi M, Shimamoto A, Sugimoto M, Furuichi Y (2007). "Increased chemotherapeutic activity of camptothecin in cancer cells by siRNA-induced silencing of WRN helicase". Biol. Pharm. Bull. 30 (10): 1958–61. doi:10.1248/bpb.30.1958. PMID 17917271.
  91. ↑ Futami K, Ishikawa Y, Goto M, Furuichi Y, Sugimoto M (2008). "Role of Werner syndrome gene product helicase in carcinogenesis and in resistance to genotoxins by cancer cells". Cancer Sci. 99 (5): 843–8. doi:10.1111/j.1349-7006.2008.00778.x. PMID 18312465. S2CID 21078795.

Bibliography

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