DNA topoisomerases as molecular targets for anticancer drugs

Figures & data

Table 1. Types and subfamilies of topoisomerases

Type of topoisomerase	Subfamily	Subunit structure	Domains of life
I	IA	Monomer Heterodimer—reverese gyrase isolated from Methanopyrus kandleri	Bacteria, Archaea, Eukarya
	IB	Monomer	Eukarya and some viruses
	IC	Monomer	Archaea (Methanopyrus genus)
II	IIA	Heterotetramer - prokaryotic Top IIA Homodimer – eukaryotic Top IIA	Eukarya, Bacteria
	IIB	Heterotetramer	Archaea, Bacteria

Figure 1. General mechanism of action of topoisomerase I (a) Top I binds to the DNA, (b) single-strand DNA (in blue) splitting, (c) controlled rotation of free DNA strand (in red), (d) religation of cleaved DNA strand.

Figure 2. General mechanism of action of topoisomerase II (a) topoisomerase binds to the G-segment, (b) Top IIA- G-segment complex binds to T-segment, (c) Two ATP molecules are attached to the resulting complex, (d) G-segment cleavage in presence of Mg²⁺ ions, (e) T-segment transport through the created gap, (f) T-segment release and religation of G-segment broken strands and (g) hydrolysis of ATP molecules and release of the G-segment.

Table 2. Clinically relevant topoisomerases inhibitors

Drug	Class	Molecular target	Date and country of approval	Application
Topotecan	Camptothecins	Top IB	1996–U.S.A.	Treatment of metastatic ovarian cancer, relapsed platinum-SCLC, recurrent or persistent cervical cancer
Irinotecan			1994–Japan	Treatment of colon cancer
Belotecan			2003–South Korea	Treatment of NSCLC and ovarian cancer
Etoposide	Epipodophyllotoxins	Top IIA	1983–U.S.A.	Treatment of SCLC, lymphomas (including non-Hodgkin’s lymphomas), AML, testicular and ovarian cancer
Teniposide			1992–U.S.A.	Treatment of childhood ALL, glioma, central nervous system tumours and bladder cancer
Doxorubicin	Anthracyclines		1974–U.S.A.	Treatment of various types of cancer i.a. ovarian, lung, gastric and breast cancers, multiple myeloma, thyroid cancer, Hodgkin’s and non-Hodgkin’s lymphoma, paediatric cancers and sarcoma
Epirubicin			1999–U.S.A.	Mainly in the treatment of advanced breast cancer
Valrubicin			1998–U.S.A.	Intravesical treatment of patients with BCG-refractory carcinoma in situ
Mitoxantrone	Anthracenediones		1987–U.S.A.	Treatment of acute leukaemia, lymphoma, prostate and breast cancer
Amsacrine	Acridines		1983–Canada	Treatment patients with AML and refractory ALL

Table 3. Selected topoisomerase inhibitors under clinical investigation

Compound	Study purpose	Clinical trial status	Clinical trial identification number
Namitecan	Determination of the pharmacokinetic profile and dose finding of the compound in treatment of patients with solid tumours	Phase I completed	NCT01748019
CZ-48	Examination the safety of CZ-48 administered orally	Recruitment of patients for the phase I trial	NCT02575638
AR-67	Application of AR-67 in the treatment of patients with refractory or metastatic solid malignancies	Phase I completed	NCT00389480
		Phase I completed	NCT01202370
	AR-67 application in the treatment of patients with recurrence of glioblastoma multiforme or gliosarcoma	Unknown	NCT01124539
Gimatecan	Safety, tolerance and pharmacokinetics study of the compound in fallopian tube cancer, advanced ovarian epithelial cancer or primary peritoneal cancer	Recruitment of patients for the phase I trial	NCT04029909
Edotecarin	Evaluatation the effectiveness of edotecarin with cisplatin in the treatment of advanced or metastatic solid tumours	Phase I completed	NCT00072332
	Determination of the effectiveness of treatment of women with chemoresistant locally advanced or metastatic breast cancer	Phase II completed	NCT00070031
LMP400	Application of the LMP400 and LMP776 in the treatment of adults with relapsed solid tumours and lymphomas	Phase I completed	NCT01051635
LMP776
Genz-644282	Determination of the safety and tolerability of the compound	Phase I completed	NCT00942799
F14512	Evaluation of the maximum tolerated dose and the efficacy of combined therapy (F14512 and cytarabine) in patients (≥60 years old) with AML	Phase II completed	2012-005241-20 (EudraCT number)
Amrubicin	Application of amrubicin plus pembrolizumab in the treatment of refractory SCLC	Phase II is ongoing	NCT03253068
	The use of amrubicin for the treatment of relapsed or refractory thymic malignancies	Phase II completed	NCT01364727
	Potent application of the amrubicin in the therapy of HER2-negative metastatic breast cancer	Phase I completed	NCT01033032
Amrubicin	The use of amrubicin in combination therapy with cyclophosphamide for the treatment of advanced solid organ malignancies	Phase I completed	NCT00890955
Aldoxorubicin	Aldoxorubicin application in the treatment of glioblastoma	Phase II completed	NCT02014844
	The use of aldoxorubicin in the therapy of soft tissue sarcomas	Phase III completed	NCT02049905
	Application of combination therapy (aldoxorubicin plus gemcitabine) in the treatment of metastatic solid tumours	Phase I completed	NCT02235688
	Determination of the safety and efficacy of the standard chemotherapy in combination with aldoxorubicin and other drugs compared to standard chemotherapy in patients with locally advanced or metastatic pancreatic cancer	Recruitment of patients for the phase I trial	NCT04390399
Vosaroxin	Application of vosaroxin with azacitidine in treating older patients with AML	Recruitment of patients for the phase II trial	NCT03338348
	The use of vosaroxin in the treatment of patients with myelodysplastic syndromes	Phase I is ongoing	NCT01913951
Vosaroxin	Evaluation of combination therapy (vosaroxin with infusional cytarabine) in therapy of untreated AML	Phase II is ongoing	NCT02658487

Figure 3. Chemical structure of camptothecin.

Figure 4. Chemical structures of camptothecins.

Figure 5. Chemical structures of noncamptothecins.

Figure 6. Chemical structure of etoposide.

Figure 7. Chemical structures of epipodophyllotoxins.

Figure 8. Chemical structures of doxorubicin.

Figure 9. Chemical structure of anthracyclines.

Figure 10. Chemical structure of mitoxantrone.

Figure 11. Chemical structure of amsacrine.

Figure 12. Chemical structure of vosaroxin.

Figure 13. Chemical structure of dexrazoxane.

Figure 14. Chemical structure of merbarone.