Pathway for cancer chemotherapy unveiled

A team of researchers at the School of Medicine has uncovered the mechanism by which low, frequent doses of a well-known chemotherapy drug can inhibit tumor growth.

Anthracyclines are a class of widely used chemotherapy drugs. These drugs are derived from bacteria and are also used as antibiotics. They work by damaging cellular DNA enough to prevent reproduction, eventually killing the cancer cells.

Traditionally, these drugs are given to patients in very high doses every few weeks in order to destroy the tumor cells that are growing and replicating at the time. In 2000 it was discovered that lower and more frequent doses of anthracyclines can also stop the growth of tumors but by preventing new blood vessels from forming around the tumor. How exactly the drugs worked was not known until this study from the laboratory of Gregg Semenza.

As tumors grow larger, the cancer cells in the middle of the tumor become starved for oxygen. This low oxygen state, or hypoxia, causes the concentration of a protein called hypoxia-inducible factor, or HIF-1, to rise. HIF-1 in turn activates genes that promote metastasis, help tumor cells take up more nutrients and promote cell immortality. In short, these genes are responsible for many of the lethal qualities of cancers.

HIF-1 also prompts cells to send out signals that encourage new oxygen- and nutrient-bearing blood vessels to form around the tumor in a process known as angiogenesis. In patients, high HIF-1 levels in the bloodstream have been associated with faster disease progression, metastasis and higher death rates in many cancer types.

To find the best way to inhibit HIF-1 in cancer cells, the research team tested over 3,100 different drugs on cancer cell cultures. The most potent drug they found was daunorubicin, a member of the anthracycline family. The research team uncovered exactly how daunorubicin and other anthracyclines inhibited HIF-1 by a process of elimination.

Through several experiments, they eliminated the possibility that the drugs block HIF-1 accumulation, activation or assembly. Instead, anthracycline binds to the cell's DNA. The DNA binding site for anthracyclines overlaps the binding site for HIF-1. In a game of molecular musical chairs, the presence of anthracyclines blocks perfectly good HIF-1 protein from binding and activating genes.

The research team then grew prostate tumors in mouse models. After five days, they found that in mice treated with frequent low doses of anthracyclines, the tumors either became smaller or remained the same size. There were few blood vessels going to these tumors, and the genes that promoted blood cell growth were turned off in the cancer cells. The mice in the control group had much larger tumors with many more blood vessels going to them.

It is hoped that this discovery will offer another treatment option for prostate cancer and other cancer patients, especially those who have higher levels of HIF-1 and are in greater danger of relapse. The results appear online in the Proceedings of the National Academies of Science.