Behind the Headlines

Monday September 28 2009

Chemotherapy can damage the ovaries (shown in pink)

There is a “baby hope for women on toxic cancer drugs”, according to the Daily Express. The newspaper heralds what it calls a major breakthrough by scientists whose work could “bring new hope for women who face the heartbreak of losing their fertility after toxic cancer treatment”.

The research behind this news is a laboratory study carried out by researchers at the University of Rome, largely in mice cells and live mice but also using some human bone cancer cells. The researchers investigated the complex effects of treatment a drug called cisplatin used to treat some cancers, including ovarian. They focused on its affect on mice ovaries and its interaction with imatinib, a drug used to treat leukemia and known to block some of the reactions that cisplatin activates. The scientists found that imatinib was able to prevent the death of cells that cisplatin can otherwise cause.

The findings open up an avenue for future research into the infertility that is commonly associated with chemotherapeutic treatment in women. However, any infertility treatments that can be given to women alongside their chemotherapy remain some way off, and the findings will next need to be replicated in human tissue samples. These two drugs can counter each other’s effects, so the action simultaneous treatment has on the anti-tumour effect of cisplatin will also need investigation.

 

Where did the story come from?

Drs Stefania Gonfloni and colleagues from the University of Rome and the University of Leicester carried out this study. The research was funded by Associazione Italiana per la Ricerca sul Cancro, the EU integrated projects Interaction Proteone and EPISTEM. The study was published in the peer-reviewed medical journal, Nature Medicine.

 

What kind of scientific study was this?

In this laboratory study in mice, the researchers investigated the processes involved in the death of germ cells (the cells that develop into sperm or eggs) in response to genotoxic stress. Genotoxic stress describes the negative effects a number of substances may have on DNA. Chemotherapy drugs are genotoxic and, in females, ovarian failure and infertility often result from this type of cancer treatment.

The researchers were particularly interested in a drug called cisplatin that is used to treat endometrial and ovarian cancers. As a side effect of treatment, the drug causes DNA damage that often leads to infertility in women. The research focused on exploring the mechanisms that lie behind the loss of ovarian follicles, the groups of cells that release a mature ovum during ovulation.

A protein called p63 is thought to be a key factor in germ cells being damaged by genotoxins, but the precise mechanism behind this process is not known. The p63 protein is thought to be involved in a chain of reactions, in which enzymes detect the DNA damage and communicate this to the protein, which then destroys the damaged cells. To investigate the process, researchers carried out a number of experiments on mice.

In the first stage they removed the ovaries from five-day-old mice and grew their cells (oocytes) in culture containing either cisplatin or a control drug. They then investigated the extent of DNA damage and the concentration of p63 and other enzymes in each group of cells. 

A drug called imatinib is known to inhibit the actions of an enzyme called c-Abl tyrosine kinase, which is believed to be crucial in the accumulation of p63. The researchers then investigated whether adding imatinib to the cultures would change the levels of detectable p63.

Several experiments were also carried out in human bone cancer cells (osteosarcoma cells), exposing them to genotoxins including cisplatin, and assessing the effect on levels of p63 and associated enzymes. The researchers also investigated the effects of cisplatin in live mice and then whether imatinib could protect against the damaging effects of cisplatin on the oocytes. The live mice were mated and the pups counted to assess the effects on fertility.

 

What were the results of the study?

After two hours of treatment in culture, there was no difference in the concentration of p63 between the ovarian cells with cisplatin and those with a placebo drug. Cisplatin induced death in most of the oocytes. Treatment with cisplatin led to an increase in the levels of c-Abl tyrosine kinase but the addition of imatinib abolished this effect, ultimately preventing the accumulation of p63 that would otherwise lead to cell death. As such, imatinib protected the cells from cell death.

As was the case with the mice ovarian cells, human cancer cells responded similarly to challenges with cisplatin, accumulating p63 and showing an increase in c-Abl concentration. Live mice treated with cisplatin exhibited the expected depletion of ovarian follicles, but the effect was blocked by simultaneous treatment with imatinib.

 

What interpretations did the researchers draw from these results?

The researchers conclude that although the precise details of the mechanisms that lead to cell death after treatment with cisplatin will need further investigation, their study has shown that they do rely on the activation of p63, and that this is probably dependent on the activity of c-Abl. They say that imatinib’s ability to rescue the follicles has implications for its use to “preserve female fertility during chemotherapy”.

 

What does the NHS Knowledge Service make of this study?

This laboratory study, conducted primarily in mice but also with a human cell component, has further explained the complex chemical pathways that lie behind the effects of the ovarian cancer drug cisplatin on fertility. It is too soon to say what the application of these findings might be for humans with cancer, and there are several points to highlight, some of which are discussed by the researchers:

  • It is not clear whether the anti-tumour properties of cisplatin are affected when combining it with treatment that involves imatinib.
  • The body’s use of p63 to kill cells with damaged DNA is essentially a protective action. This activity is particularly important with germ cells, as damage to their DNA would lead to developmental problems in embryos. Whether neutralising the effect of p63 would have an effect on the viability of embryos remains to be seen and was not specifically reported by the researchers.
  • It is unclear how the findings from this study in mice might be applied to human reproductive systems.

Any infertility treatments that can be given to women alongside their chemotherapy remain a long way off. However, the findings of this study have opened up an avenue for future research which might potentially contribute to a finding a viable treatment.

Links to the headlines

Baby hope for women on toxic cancer drugs. Daily Express, September 28 2009

Links to the science

Gonfloni S, Di Tella L, Caldarola S et al. Inhibition of the c-Abl–TAp63 pathway protects mouse oocytes from chemotherapy-induced death. Nature Medicine, September 27 2009 [published online]

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Edited by NHS Choices