Why Do Powerful Cancer Drugs Fail?

It’s a sad story that everyone is familiar with: A patient takes one or more well-known cancer drugs, and they work – for a while. However, after the respite, the cancer comes roaring back, this time impervious to the once powerful effects of the cancer drugs. Many people would view the disease’s return with resignation and hope that some other intervention can help.

But does it have to be this way? Instead of waving the white flag, it might pay to examine how the cancer was able to resist treatment. That might be knowledge used to allow the cancer drugs to keep fighting.

Such is the focus of research by Dr. Robert Ladner, a professor at the University of Southern California (USC). Dr. Ladner and co-workers are interested in the widely used agent 5-fluorouracil (5-FU). This drug leads to the blockage of the natural conversion of deoxyuridine monophosphate (dUMP) in the body to deoxythymidine monophosphate (dTMP). As a result, dUMP builds up. One reason 5-FU is bad news for rapidly dividing, DNA-hungry cancer cells is that dUMP is enzymatically converted to deoxyuridine triphosphate (dUTP), which is “mistakenly” taken up into DNA, causing damage.¹

Dr. Ladner and colleagues set out to help shed light on why, exactly, cancer cells develop resistance to 5-FU. They found that resistance to 5-FU in cancer cells correlates with increased production of the enzyme dUTPase, which converts dUTP back to dUMP. In other words, before dUTP can enter into DNA and throw a wrench into the works, resistant cancer cells knock it back down to dUMP.

Rather than just being a point of interest, the discovery of the role of dUTPase in resistance may highlight how it might be possible to prevent malignant cells from circumventing the effects of cancer drugs. In the case of 5-FU, Dr. Ladner and co-workers are developing ways to inhibit dUTPase. Dr. Ladner’s research has recently been supported by a donation of $500,000 from the Moore for Kids Foundation.^{2, 3}

Although the development of new cancer drugs is vital, there is hope, thanks to work like this at USC, that the old standbys can be assisted so that they can continue to attack this disease, even in the face of resistance. Researchers who are part of the battle and are interested in outsourcing oncology are welcome to explore the oncology resources available from Scientist. Fight on!