Triapine®What Is It and How Does It Work?
1. What is Triapine and how does it work?
Answer: 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.
( A Phase 1 clinical trial was conducted at the University of Miami and the Arizona Cancer Research Center. )
Triapine has very potent effects on the RR enzyme, more so than 2 approved anti-cancer agents that work at least in part by inhibiting the RR enzyme. Triapine was able to inhibit the growth of some cancer cell lines that were resistant to the approved anti-cancer agents. It was active against a number of tumors in mouse models, and had activity equal to Taxol, one of the most effective anti-cancer agents available today, in one mouse tumor model.
DNA synthesis is 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 can be predicted to increase the anti-tumor effects of many of the common anti-cancer drugs. Experiments conducted by Vion and Yale scientists have shown that Triapine can indeed increase the anti-tumor effects of standard cancer agents such as cisplatinum, cyclophosphamide, and etoposide in mouse tumor models.
2. Why does Triapine have greater effects on cancer cells than normal cells?
Answer: Normal rapidly dividing cells in the bone marrow and gastrointestinal tract also require DNA synthesis and are likely to be affected by the administration of Triapine. However, normal cells have the capacity to halt their growth temporarily until the effects of Triapine have worn off, and therefore avoid or minimize the damage done by the interruption of DNA synthesis. Cancer cells, on the other hand, have lost the control mechanisms on division, and continue to try to divide even though DNA synthesis has been impaired. When cancer cells attempt to divide in the setting of incomplete replication of the DNA, they cause themselves severe damage and ultimately die.
Like all anti-cancer agents, Triapine will cause some toxicity to normal cells, but the effects on cancer cells should be greater. This differential effect is referred to as the therapeutic ratio. In several mouse tumor models, Triapine was very well-tolerated and had good anti-tumor effects.
3. What is the status of Triapine clinical trials?
Answer: Triapine is currently in phase 1 clinical trials. These are studies designed to determine the highest dose that can be given with tolerable toxicity. The first trial which gave Triapine by a 2 hour infusion every 4 weeks was recently completed, and showed that high serum concentrations could be reached for short periods without significant toxicity.
The experiments conducted in test tubes and animal models predict that the anti-tumor effects for Triapine increase as the duration of cancer cells to Triapine is increased. Because of the latter observation, the other phase 1 trials are designed to give Triapine for 4-5 days in a row, every 3-4 weeks. In one trial, the Triapine is given for 2 hours daily for 5 days in a row, every 4 weeks. More information on this study can be found in the NCI cancer information service. A second study will open in the near future and is designed to give the Triapine by a continuous intravenous infusion for 96-hours, every 3 weeks.
*** POSTED JUNE 27, 2001 ***