Ethidium is a DNA intercalating agent first discovered as and used as a veterenary trypanocide. A bromide salt is commonly used as a fluorescent tag in molecular biology. The fluorescene of ethidium bromide increased 21 fold upon binding to double-stranded RNA, 25 fold upon binding double stranded DNA. Because of the binding to DNA, ethidium bromide is a powerful inhibitor of DNA polymerase.

Pibrozelesin (KW-2189) is a semisynthetic water-soluble derivative of the antineoplastic antibiotic duocarmycin B2. Activated by carboxyl esterase, pibrozelesin alkylates DNA by binding to adenine-thymine (A-T)-rich sequences in the minor groove of DNA, thereby inhibiting DNA replication and inducing apoptosis. KW-2189 induced DNA strand breaks in H69 cells in a concentration-dependent manner. DNA cleavage is one of the major mechanisms of KW-2189-mediated cytotoxicity. KW-2189 showed evidence of anti-tumor activity in hepatocellular carcinoma (HCC). However, because of significant and prolonged hematologic toxicity, when given as a single dose every 6 weeks, further development of this drug in HCC is not possible. Pibrozelesin had been in phase II clinical trial for the treatment of advanced malignant melanoma and advanced renal cell carcinoma. No activity in metastatic renal cell carcinoma was demonstrated and the lack of significant antitumor activity in advanced malignant melanoma treatment was shown.

Amonafide L-malate (AS1413, Xanafide) is a DNA intercalator and topoisomerase II inhibitor that induces apoptosis by disrupting chromatin organisation independently of ATP. This is different from classical topoisomerase II inhibitors which induce apoptosis by causing extensive DNA damage. Amonafide L-malate is also able to evade P-glycoprotein and related transporters that contribute to multi-drug resistance. AS1413 had orphan drug status in both the U.S. and the E.U. for the treatment of AML and also received Fast Track status from the U.S. FDA for the treatment of secondary AML. Amonafide L-malate was originated by Xanthus Pharmaceuticals. It was added to Antisoma's pipeline through the acquisition of Xanthus Pharmaceuticals, Inc. in June 2008. Antisoma discontinued development of Amonafide L-malate after data from the open-label, international Phase III ACCEDE trial in over 420 patients showed that 600 mg/m 2 IV amonafide for 5 days plus cytarabine missed the primary endpoint of significantly improving initial remission rate, defined as the proportion of patients who achieve CR or CRi, vs. daunorubicin plus cytarabine.

Asulacrine, also known as CI-921, an inhibitor of topoisomerase II, participated in clinical trials phase II for the treatment of cancer. In spite of the positive and promising results, this drug showed the toxicity, phlebitis that blocks its implementation in the future.

Amonafide L-malate (AS1413, Xanafide) is a DNA intercalator and topoisomerase II inhibitor that induces apoptosis by disrupting chromatin organisation independently of ATP. This is different from classical topoisomerase II inhibitors which induce apoptosis by causing extensive DNA damage. Amonafide L-malate is also able to evade P-glycoprotein and related transporters that contribute to multi-drug resistance. AS1413 had orphan drug status in both the U.S. and the E.U. for the treatment of AML and also received Fast Track status from the U.S. FDA for the treatment of secondary AML. Amonafide L-malate was originated by Xanthus Pharmaceuticals. It was added to Antisoma's pipeline through the acquisition of Xanthus Pharmaceuticals, Inc. in June 2008. Antisoma discontinued development of Amonafide L-malate after data from the open-label, international Phase III ACCEDE trial in over 420 patients showed that 600 mg/m 2 IV amonafide for 5 days plus cytarabine missed the primary endpoint of significantly improving initial remission rate, defined as the proportion of patients who achieve CR or CRi, vs. daunorubicin plus cytarabine.

Datelliptium is a DNA-intercalating agent, an analog of a natural alkaloid ellipticine. The compound was active in vivo against a variety of murine solid tumors. In a phase I clinical trial no objective complete or partial responses were observed in patients with solid tumors or lymphoma treated with datelliptium.

Teloxantrone (also known as DuP 937) was developed as an anthrapyrazole intercalator that inhibits DNA synthesis. Teloxantrone interacts with topoisomerase II, thereby inhibiting DNA replication and repair, as well as RNA and protein synthesis. The drug participated in phase II clinical trials in colorectal carcinoma, in non-small cell lung cancer, in metastatic malignant melanoma. However, these studied apparently were discontinued.

Ditercalinium is the antineoplastic agent. Ditercalinium itself is not a natural product, however, it is derived from the natural product 5,11-dimethyl-6H-pyrido-[4,3- b]carbazole (ellipticine) that was isolated in 1959. It is a rare example of a noncovalent DNA-binding ligand that forms bisintercalation complexes via the major groove of the double helix. Ditercalinium selectively recognizes certain GC-rich sequences in DNA. It preferentialy binds with antiparallel quadruplex sequence d(AG(3)[T(2)AG(3)](3)). Ditercalinium chloride can deplete mitochondrial DNA in both mouse and human cells. Ditercalinium chloride inhibits human DNA polymerase gamma activity as efficiently as does ethidium bromide. Ethidium bromide distributes diffusely in the mitochondria of HeLa cells, while ditercalinium chloride distributes granularly and hence may be strongly associated with mitochondrial DNA.

Prospidium is a diazoniadispiro(5.2.5.2)hexadecane derivative patented by All-Union Scientific-Research Chemical-Pharmaceutical Institute as an antitumor agent that does not inhibit hematopoiesis. In preclinical models, The injection of Prospidium to thyroidectomized and hypophysectomized rats inhibited tumor growth to a greater extent than in intact rats. Larynx and lung cancer, lymphogranulomatosis, leucosis, etc. can be successfully treated with Prospidium at doses of 60-120 mg daily.