Q. What is Onrigin™ (laromustine) and how does it work?
Q. In what clinical trials is Onrigin™ (laromustine) being evaluated?
Q. What is Triapine® and how does it work?
Q. What is the status of Triapine® clinical trials?
A: Onrigin™ (laromustine), formerly Cloretazine® (VNP40101M) is a novel cytotoxic agent that works by damaging DNA. Onrigin™ (laromustine) releases the DNA chloroethylating agent 90CE after entering the blood stream. 90CE is capable of chloroethylating the O6 position of guanine residues, ultimately resulting in an interstrand DNA cross-link. Interstrand DNA cross-links are difficult to be repaired and are toxic to cells. Onrigin™ (laromustine) demonstrated a broad spectrum of anticancer activity in preclinical studies, including activity in selected cell lines resistant to other alkylating agents such as BCNU, cyclophosphamide and melphalan. In preclinical studies, Onrigin™ (laromustine) has been combined with other anticancer agents such as cytarabine (Ara-C). In addition, Onrigin™ (laromustine) or its metabolite has been shown to be capable of crossing the blood brain barrier in preclinical models.
A: Onrigin™ (laromustine) is being evaluated for the treatment of acute myelogenous leukemia (AML) in a pivotal Phase 2 trial in elderly de novo poor-risk AML. In addition, four clinical trials of Onrigin™ (laromustine) are underway in: (i) elderly AML and myelodysplastic syndrome (MDS) in combination with cytarabine; (ii) AML and MDS in combination with standard remission-induction therapy; (iii) brain tumors in combination with temozolomide; and (iv) advanced hematologic malignancies in combination with hematopoietic cell transplantation.
A: Triapine® is a small molecule that inhibits an enzyme, ribonucleotide reductase, necessary for the synthesis of DNA. Synthesis of DNA is necessary for cancer cells to replicate; therefore inhibition of the ribonucleotide reductase enzyme prevents cancer cells from dividing in the body. Disruption of DNA synthesis in some cancer cells will also cause their death.
DNA synthesis is also involved in repairing damage to cancer cells that have been treated with many of the standard cancer chemotherapy agents, which work by damaging DNA. The ability of cancer cells to rapidly repair DNA damage is one reason that cancer cells become resistant to standard chemotherapy agents. Because Triapine® inhibits DNA synthesis, it can inhibit DNA repair, and therefore it may be able to increase the antitumor effects of many of the common anticancer drugs. Experiments conducted by Vion and Yale scientists have shown that Triapine® can increase the antitumor effects of standard cancer agents such as cisplatin, cyclophosphamide, and etoposide in mouse tumor models.
A: Triapine® is being evaluated in clinical trials sponsored by the National Cancer Institute. Search “Triapine” at www.clinicaltrials.gov for a list of trials.