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.

Pelitinib (EKB-569) is a 3-cyanoquinoline pan-ErbB tyrosine kinase inhibitor with potential antineoplastic activity. Pelitinib irreversibly binds covalently to epidermal growth factor receptors, thereby inhibiting receptor phosphorylation and signal transduction and resulting in apoptosis and suppression of proliferation in tumor cells that overexpress these receptors. Pelitinib had been in phase II clinical trials for the treatment of non-small cell lung cancer and colorectal cancer. Treatment-emergent adverse events were diarrhea, abdominal pain, gastrointestinal carcinoma, intestinal obstruction and vomiting.

Pipendoxifene (ERA-923) is a selective estrogen receptor modulator with a distinct profile compared with tamoxifen. In particular, unlike tamoxifen, ERA-923 is devoid of uterotropic activity and does not stimulate the growth of endometrial tumors in the EnCa-101 (human endometrial adenocarcinoma that is continuously passaged in animals in the presence of estrogen) experimental mice model. These data may indicate that, in patients, ERA-923 will not increase the incidence of endometrial hyperplasia or cancer. ERA-923 inhibits estrogen-stimulated ER-alpha-dependent tumor growth with equal effects compared with tamoxifen in models sensitive to tamoxifen. ERA-923 partially or completely overcomes tamoxifen resistance. In vivo combination of temsirolimus and ERA-923 at certain doses and schedules completely inhibited breast carcinoma growth, while individual agents were only partially effective. Pipendoxifene had been in phase II clinical trial for the treatment of refractory metastatic breast cancer. However, this research has been discontinued.

Estrazinol is a synthetic estrogen.

Metoprine is a diaminopyrimidine folate antagonist with potential antineoplastic activity. Metoprine inhibits dihydrofolate reductase, resulting in decreased cellular folate metabolism and cell growth. Metoprine shows potent in vitro antitumor activity against several experimental tumors including methotrexate-resistant tumors. Metoprine inhibits the enzyme dihydrofolate reductase, much less effectively than methotrexate but it also inhibits histamine-N-methyltransferase, resulting in decreased histamine catabolism. S phase cells are most sensitive, whilst cells in G2 and M are least sensitive to the lethal effects of Metoprine, and a prolonged exposure to a high Metoprine concentration produces maximum cytotoxic effects. After oral administration, Metoprine has a widespread distribution and concentration in all tissues examined with the highest tissue/plasma ratios found in brain, lung, pancreas, and skin. Phase I and early Phase II clinical trials in various centers have shown activity in hypernephroma, epidermoid carcinoma arising in bronchus or head and neck, central nervous system leukemia, malignant melanoma, and mycosis fungicides. Metoprine had been in some phase II clinical trials but further studies were discontinued due to CNS and hematological toxicity.

Spiromustine is a bifunctional nitrogen alkylating agent with antineoplastic activity and lipophilic properties. Preclinical screening has shown activity against a variety of tumors, including an intracranially implanted ependymoblastoma. Alkylating activity has been demonstrated in an intracerebral glioma in the rat. Spiromustine is a cell cycle non-specific agent. Animal pharmacology studies have shown a biphasic plasma decay curve, with hepatic metabolism and excretion, an enterohepatic circulation of metabolites, and approximately 50% renal excretion of unchanged drug. Toxicology studies in mice, rats, and dogs showed that dose-related myelosuppression and neurotoxicity predominated; other organ toxicities were mild. In Phase I clinical trials Neurotoxicity was the dose-limiting toxicity presenting as alterations in cortical integrative functions (orientation, language, coordination), leading to a decrease in the level of consciousness.

Antineoplaston A10 is a piperidinedione antineoplaston with potential antineoplastic activity. Antineoplaston A10 was originally isolated from human urine but is now synthetically derived. This agent intercalates into DNA, resulting in cell cycle arrest in G1 phase, reduction of mitosis, and decreased protein synthesis. Antineoplaston A10 may also inhibit ras-oncogene expression and activate tumor suppressor gene p53, leading to cell differentiation and apoptosis. Antineoplaston A10 has been used in trials studying the treatment of glioma, sarcoma, lymphoma, lung cancer, liver cancer, and kidney cancer, among others.

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.

Porfiromycin is an N-methyl derivative of the antineoplastic antibiotic mitomycin-C initially isolated from Streptomyces ardus. Upon administration, the drug undergoes chemical or enzymatic reduction, followed by spontaneous loss of the tertiary methoxy (hydroxyl) group and formation of an aromatic indole system. Thus activated, porfiromycin generates oxygen radicals and alkylates DNA, producing interstrand cross-links and single-strand breaks at guanosine residues. Porfiromycin was tested in phase III for head and neck carcinoma, however, its development was terminated.

Fiacitabine, also known as FIAC, is a pyrimidine nucleoside, which had been in phase II clinical trilas for the treatment Cytomegalovirus infections and Herpes simplex virus infections. However, these researches have been discontinued. It was also shown the inhibitor activity of FIAC against the DNA polymerase of hepadnaviruses.