A synthetic purineanalog is a drug that mimics a building block of DNA to become incorporated into the DNA of disease-causing cells, subsequently interfering with DNA synthesis. This class of medication has found clinical applications in the treatment of blood cancers and viral infections.
- Purines and PurineAnalogs
- DNA is encoded in four molecules called nucleosides. Two of these nucleosides are derived from a single carbon ring compound called pyrimadine, and the other two are derived from a larger, two-ringed compound called purine. Adenine and guanine, the purine-derived bases, are collectively referred to simply as the "purine" bases; a synthetic purineanalog is an artificially synthesized molecule that is similar to one of these bases but crucially different. Synthetic pyrimadineanalogs also exist and have therapeutic properties somewhat different from those of the purineanalogs.
Mechanism of Action
- Synthetic purine nucleosides, once incorporated into replicating DNA, interfere with the activity of one or more enzymes that continue the replication process. The anti-cancer activity of these drugs depends on the fact that cancer cells grow faster than healthy cells and therefore take up more of the DNA-inhibiting analog than healthy cells. The enzymes found in cancer cells may also have mutations that make them less selective than those in healthy cells. Purineanalogs active as anti-virals can take advantage of enzymatic differences between human cells and viruses for improved specificity. Since these drugs slow down DNA synthesis in the diseased cells but do not reverse the disease, synthetic purineanalogs are typically used in combination with other therapies.
Cancer Therapy
- Fludarabine and cladribine are synthetic purineanalogs in which one carbon atom has been replaced by a fluorine or chlorine atom. This substitution allows them to be incorporated into DNA but disrupts further replication of the DNA. These drugs are used in the treatment of lymphomas and leukemias. Although several candidates have been tested, no synthetic purineanalog has yet been effective in treatment of solid tumors.
Viral Infections
- All natural nucleosides have an attached sugar group that is instrumental in the nucleoside's proper incorporation into DNA. Several synthetic purineanalogs in which the sugar group has been altered are effective at inhibiting replication of viral DNA. Acyclovir and its newer siblings valaciclovir and famciclovir are effective at treating herpes simplex virus (HSV). Ganciclovir is used to treat certain opportunistic infections in AIDS patients, while defovir is a standard treatment for hepatitis B infection. Tenofovir is one of several antiviral purineanalogs used as part of anti-HIV treatment regimens; many more are under development.
Toxicity
- Synthetic purineanalogs are a vitally important class of drugs for treating conditions that do not have other effective treatments. However, the side effects of these DNA-inhibiting compounds can be serious and include problems with the nervous system, heart muscle, liver and pancreas. This multi-system response appears to be due to damage to the mitochondria, where energy for the cell is generated.