Idronoxil (Phenoxodiol) is a synthetic flavonoid derivative developed by MEI Pharma for cancer treatment. Idronoxil inhibits proliferation of many cancer cell lines and induces apoptosis by disrupting FLICE-inhibitory protein, FLIP, expression and by caspase-dependent and -independent degradation of the X-linked inhibitor of apoptosis, XIAP. In addition, Idronoxil sensitizes drug-resistant tumour cells to anticancer drugs including paclitaxel, carboplatin, and gemcitabine. The antiproliferative effects of Idronoxil are associated with inhibition of plasma membrane electron transport in tumour cell lines and primary immune cells. Idronoxil displays anti-cancer activity against all forms of cancer tested in vitro and in vivo to date, using cells representative of all major forms of cancer. While having a modest ability to kill cancer cells(IC50 range between about 1-5 uM), preclinical studies point to its optimal use being to sensitize cancer cells to the toxic effects of standard therapies (chemotherapy and radiotherapy). The rationale is that a sub-lethal inhibitory effect on sphingosine kinase activity reduces the ability of the cancer cell to operate drug-resistance mechanisms and to effect repair of drug- or radiation-induced damage to DNA. In the case of cytotoxic drugs such as cisplatin, carboplatin, paclitaxel, Doxorubicin, and gemcitabine, Idronoxil is an exquisite sensitizer, increasing the cytotoxic potential of those agents by between 103 -105 times, in the process restoring sensitivity to cancer cells highly refractory to those agents.

Picropodophyllin (also known as picropodophyllotoxin (PPP)), an orally active insulin-like growth factor 1 receptor (IGF1R) inhibitor that exhibits no activity at the insulin receptor, FGFR, PDGFR or EGFR. Picropodophyllin possesses antineoplastic activity. PPP is currently tested as an orally administrated single agent treatment in an open-label combined Phase I/II clinical study in advanced cancer patients with solid tumors which progress in spite of several lines of treatment. In addition, it effectively inhibits rhambodmyosarcomas tumor proliferation and metastasis in vitro and in an animal model.

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.

Teniposide is an inhibitor of topoisomerase II with anti-cancer activity. The drug was approved by FDA under the name Vumon for the treatment of children with acute lymphoblastic leukemia.

Elliptinium is an antineoplastic agent, which was used in the treatment of metastatic breast cancer in France under the name Celiptium. The drug is known to intercalate into DNA and inhibit topoisomerase II. Several studies have demonstrated that this molecule can be oxidized, yielding a reactive electrophilic form, which is able to bind covalently to a nucleophilic biological molecule.

Sobuzoxane (MST-16), a dioxopiperazine, chelates metal cations and reduces the generation of free radicals due to metal-anthracycline complexes. It interacts with topoisomerase II and blocks the formation of topoisomerase II-DNA complex. Sobuzoxane effectively blocks cell proliferation and blocks cells in G2/M phase in selected human tumor cell lines. It protects cardiomyocytes from the cardiotoxicity induced by prolonged doxorubicin treatment. It’s indicated for treatment malignant lymphoma, is also used in adult T-cell leukemia.

Podophyllum resin is the powdered mixture of resins removed from the May apple or Mandrake, a perennial plant of the northern and middle United States. The early colonists learned of themedical properties of the root from the Indians, and it was used as a cathartic in the firstUnited States Pharmacopoeia (1820). The resin, podophyllin, was first separated from Podophyllum by John King in 1835. Between 1863 and 1942, podophyllin was reported to be a cathartic, purgative, deobstruent, vermifuge, hydragogue, cholagogue, choleretic, andexpectorant.Itwas recommended, either alone or in combination with other herbs, for diseases of the liverandkidneys, for scrofula, syphilis, gonorrhea, obstructed menstruation, urinary obstruction, dropsy, and coughs. Currently Podophyllum resin is used as a medication to treat genital warts and plantar warts, including in people with HIV/AIDS. Common side effects include redness, itchiness, and pain at the site of use. Severe side effects may include vomiting, abdominal pain, confusion, bone marrow suppression, and diarrhea. It is not recommended for more than a small area at a time. Use during pregnancy is known to be dangerous to the baby.

Etoposide (trade name Etopophos) is a semisynthetic derivative of podophyllotoxin that exhibits antitumor activity. It has been in clinical use for more than two decades and remains one of the most highly prescribed anticancer drugs in the world. The primary cytotoxic target for etoposide is topoisomerase II. This ubiquitous enzyme regulates DNA under- and over winding, and removes knots and tangles from the genome by generating transient double-stranded breaks in the double helix. Etoposide kills cells by stabilizing a covalent enzyme-cleaved DNA complex (known as the cleavage complex) that is a transient intermediate in the catalytic cycle of topoisomerase II. The accumulation of cleavage complexes in treated cells leads to the generation of permanent DNA strand breaks, which trigger recombination/repair pathways, mutagenesis, and chromosomal translocations. If these breaks overwhelm the cell, they can initiate death pathways. Thus, etoposide converts topoisomerase II from an essential enzyme to a potent cellular toxin that fragments the genome. Although the topoisomerase II-DNA cleavage complex is an important target for cancer chemotherapy, there also is evidence that topoisomerase II-mediated DNA strand breaks induced by etoposide and other agents can trigger chromosomal translocations that lead to specific types of leukemia. Etopophos (etoposide phosphate) is indicated in the management of the following neoplasms: Refractory Testicular Tumors-and for Small Cell Lung Cancer. The in vitro cytotoxicity observed for etoposide phosphate is significantly less than that seen with etoposide, which is believed due to the necessity for conversion in vivo to the active moiety, etoposide, by dephosphorylation. The mechanism of action is believed to be the same as that of etoposide.

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.