Temozolomide

Temozolomide (TMZ) is a chemotherapy drug often used to treat glioblastoma, the most aggressive form of cancer that begins in the brain. This cancer is extremely difficult to treat because it usually recurs even after extensive surgery, chemotherapy, and radiation.

TMZ was developed at Aston University (Birmingham, UK) more than 20 years ago. In 1999, the US Food and Drug Administration granted approval to Merck to market it under the trade name Temodar for treating glioblastoma and refractory anaplastic astrocytoma. It is available in capsule and injectable forms.

TMZ’s mode of action is alkylation, which causes serious side effects such as reduction in blood cells, weakening of the immune system, and secondary cancers. Only a small portion of administered TMZ enters the brain, making most of it free to cause problems in other parts of the body.

Now, Paul J. Hergenrother and colleagues at the University of Illinois (Urbana–Champaign) report that a modification to TMZ’s structure makes it easier for the drug to penetrate the blood–brain barrier. When the team replaced the molecule’s amide group with a methyl ketone group, the percentage of the drug that entered the central nervous system in mice increased from 8% to 69%.

In a mouse model of glioblastoma, treatment with the modified drug (K-TMZ) increased survival indefinitely. The researchers’ next step is to test K-TMZ on larger glioblastoma-affected animals.