[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.
[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.
[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.
[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.
[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.
[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.
[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.
[36] 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.
[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.
[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] 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.
[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.
[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.
[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.
[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.
[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][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.
[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.
[17] Currently, there are four main anthracyclines in medical use: Idarubicin is able to pass through cell membranes easier than daunorubicin and doxorubicin because it possesses less polar subunits, making it more lipophilic.
[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.
[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.
[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] 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.
[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.
[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.
Synthetic lethality with the topoisomerase inhibitor irinotecan appears to occur when given to cancer patients with deficient expression of the DNA repair gene WRN.