Gemcitabine is a nucleoside analog used as chemotherapy. It is marketed as Gemzar® by Eli Lilly and Company. Gemcitabine inhibits thymidylate synthetase, leading to inhibition of DNA synthesis and cell death. Gemcitabine is a prodrug so activity occurs as a result of intracellular conversion to two active metabolites, gemcitabine diphosphate and gemcitabine triphosphate by deoxycitidine kinase. Gemcitabine diphosphate also inhibits ribonucleotide reductase, the enzyme responsible for catalyzing synthesis of deoxynucleoside triphosphates required for DNA synthesis. Finally, Gemcitabine triphosphate (diflurorodeoxycytidine triphosphate) competes with endogenous deoxynucleoside triphosphates for incorporation into DNA. Gemcitabine is indicated for the treatment of advanced ovarian cancer that has relapsed at least 6 months after completion of platinum-based therapy; metastatic ovarian cancer; inoperable, locally advanced (Stage IIIA or IIIB), or metastatic (Stage IV) non-small cell lung cancer; and locally advanced (nonresectable Stage II or Stage III) or metastatic (Stage IV) adenocarcinoma of the pancreas.

Resolvin E1 (RvE1 or RX-10001) is a trihydroxy eicosapentaenoic acid metabolite that has a role as an anti-inflammatory agent and a human xenobiotic metabolite. This compound binds to leukotriene B4 (BLT-1) on neutrophils and to ERV-1/ChemR23 on monocyte/macrophages. Resolvin E1 has been shown to reverse experimental periodontitis and dysbiosis in rats. Furthermore, in a murine model of Alzheimer’s disease, Resolvin E1 (in combination with lipoxin A4) decreased neuroinflammation. Resolvin E1 was also suggested as a potential therapeutic target for psoriasis. A phase I clinical trial to test drug safety in healthy volunteers has been completed in 2009.

CG-200745 is a novel inhibitor of histone deacetylases (HDACs), initially developed by CrystalGenomics, Inc for treatment of various hematological and solid cancers. Combinations of CG-200745 with SN38 (the active form of irinotecan), or oxaliplatin were more effective than the agents alone when used to inhibit the growth of HCT116 cells. The protein expressions of acetyl-H3, p21, caspase-3, -8, and -9, PARP, and XIAP were affected in a time- and dose-dependent manner in HCT116 cells treated with the CG-200745 alone or combined CG-200745 and SN-38. In HCT116 xenografts, the HDACI CG-200745 in combination with irinotecan dramatically inhibited tumor growth without showing additive toxicity.

Rubitecan [Orathecin™] is a topoisomerase I inhibitor extracted from the bark and leaves of the Camptotheca acuminata tree, which is native to China. Rubitecan is an oral compound being developed for the treatment of pancreatic cancer and other solid tumours by SuperGen. Rubitecan binds to and inhibits the enzyme topoisomerase I and induces protein-linked DNA single-strand breaks, thereby blocking DNA and RNA synthesis in dividing cells; this agent also prevents repair of reversible single-strand DNA breaks.

CEP-11981 is an orally bioavailable inhibitor of vascular endothelial growth factor receptor (VEGFR) and Tie2 receptor tyrosine kinases with potential antiangiogenic and antineoplastic activities. Preclinical studies have shown that CEP-11981 exhibits promising permeability, metabolic stability, and pharmacokinetic properties across multiple species. Studies of pharmacologic activity across angiogenesis assays, animal tumor models, and human tumor models have shown sustained, dose-related antiangiogenic and antitumor inhibition. In clinical trals CEP-11981 administration leads to disease stabilization in patients with recurrent or refractory solid tumors. Despite acceptable tolerability of CEP-11981 at the MTD, further development by the sponsor has ceased.

CBP-501 is a chemically modified duodecapeptide and an analog of M-phase inducer phosphatase 3 (CDC25C) that increase cisplatin influx into tumor cells through an interaction with calmodulin enhancing cisplatin cytotoxicity, and affects cell cycle progression by abrogating DNA repair at the G2 checkpoint. CBP501 selectively inhibits the kinases MAPKAP-K2, C-TAK1, and CHK1 in vitro. Cell lines exposed to CBP501 plus bleomycin show a dose-dependent reduction of phosphorylated Ser216 on CDC25C. In addition to these effects on the G2 checkpoint, CBP501 also increases platinum concentration and DNA-platinum adduct formation in tumor cells through binding with calmodulin. In an in vitro panel testing the sensitivity of several tumor-derived cell lines to CBP501 in combination with a variety of anti-cancer agents, the combination of CBP501 with cisplatin was particularly effective against all four mesothelioma cell lines tested. Unfortunately, CBP-501 does not improve the efficacy of standard chemotherapy for malignant pleural mesothelioma.