Monday March 23 2009
Mice's tumours grew after exposure to low doses of anti-cancer drug
“A type of drug designed to stunt tumour growth has actually been found to fuel cancer if given at too low a dose,” BBC News reported. It said the experimental drug cilengitide, aimed at inhibiting cancer growth by targeting the tumour's blood vessels, actually stimulated the growth of cancers when given in low doses. It said that the cancer drugs Avastin and Sutent act in a similar way but have been proven to work and were not covered in this research.
This surprising discovery was made in a laboratory study of cilengitide in mice. Cilengitide has not yet been licensed for use in patients, and is still in its experimental phase where it has proven to be of limited effectiveness so far. The researchers say that these results could explain why these trials have not been as promising as hoped.
Where did the story come from?
The research was carried out by Dr Andrew Reynolds and colleagues from the Adhesion and Angiogenesis Laboratory and Centre for Tumour Biology, Queen Mary University of London, and other institutions in the UK and France. Several researchers were supported by grants from different sources, including Cancer Research UK, the Bartholomew’s and The Royal London Charitable Foundation, Breakthrough Breast Cancer, and the Portuguese Foundation for Science and Technology.
The study was published in the peer-reviewed medical journal Nature Medicine.
What kind of scientific study was this?
This laboratory study focused on cilengitide, which is a type of angiogenesis inhibitor (a substance that inhibits the growth of new blood vessels). Cilengitide is an experimental drug, and is currently in phase 1 and 2 clinical trials. It is being tested as a treatment for cancer, usually in combination with chemotherapy. It is being targeted at a range of cancers, including non-small-cell lung cancer, and head and neck cancer. According to the BBC news report, some people with brain tumours respond to high doses of cilengitide, but the drug is not effective for most cancer patients.
Angiogenesis inhibitors are designed to stop tumours growing by cutting off their blood supply. According to the researchers, drugs such as cilengitide inhibit integrin molecules called ανβ5 and ανβ3, which are partly responsible for regulation of angiogenesis (growth of blood vessels). They also act directly on the tumours. The researchers say that although the drug has been tested in human studies, there is little evidence that it is effective in treating human cancers, apart from some gliomas (brain tumours). In this study, the researchers investigated the reasons behind the apparent failure of the ανβ5/ανβ3 inhibitors.
The researchers used two tumour models that are known to be unresponsive to integrin inhibitor therapy. Mice were injected with cancer cells and their response to treatment with two different ανβ5/ανβ3 inhibitors was assessed. The researchers monitored how much of the dose of ανβ5/ανβ3 inhibitors that remained in the mice’s bodies after treatment. The researchers then assessed whether different doses had different effects on tumour growth and angiogenesis.
They also assessed the effects of two drugs, cilengitide and S36578, in mice that were not able to produce the β3 or β5 integrins. Further investigations were carried out using aortic rings of mice (isolated rings of mouse aortas) which are often used to explore the mechanisms of angiogenesis. In these in vitro experiments, the researchers explored the precise effects of the inhibitors on cells. They assessed the effects of the inhibitors on angiogenesis that is stimulated by VEGF (vascular endothelial growth factor, which are proteins important in the stimulation of new blood supply to tissues).
Further experiments explored how the inhibitors interacted at a molecular level with various growth factors in cells. The researchers also explored the effects of varying doses, similar to what would happen during chemotherapy when the dose is high at the start of treatment and then tapers off as the body gets rid of the drug.
What were the results of the study?
The researchers found that certain melanomas and lung carcinomas had enhanced growth in mice with low blood concentrations of ανβ5/ανβ3 inhibitors (both S36578 and cilengitide), compared to mice treated with a placebo drug. The inhibitors also appeared to promote tumour vascularisation (growth of blood vessels).
Mice that were given higher concentrations of the inhibitors had similarly sized tumours to those from mice treated with placebo. The increased vascularisation and growth was seen only in tumours, not in healthy mouse skin. Other melanomas (A375 tumours) were sensitive to treatment with high doses of the inhibitors, but their growth and vascularisation was promoted by low doses. In mice that did not produce the β3 or β5 integrins, low concentrations of inhibitors did not promote the growth of tumour cells.
Assessment in cancer cell cultures found that the inhibitors did not promote tumour growth directly, but instead acted on cancer cells that expressed αν integrins (e.g. tumour endothelial cells). Low doses of the inhibitors did not promote the growth of tumour cells in culture. The researchers also discovered that exposure to low doses of inhibitors counteracted the positive effects of high doses.
What interpretations did the researchers draw from these results?
The researchers conclude that low concentrations of ανβ5/ανβ3 inhibitors can stimulate tumour growth and vascularisation in mice. They suggest that there is a need to re-evaluate the dosage and administration of these integrin inhibitors in the clinic. For example, the way that these drugs are given to cancer patients. They say that if they are given brief infusions twice weekly, the concentrations of drug in the plasma falls to low levels between doses, and tumour growth and angiogenesis may be enhanced.
They believe that the phenomenon represents a “major mechanism compromising the efficacy of” these drugs, and that their use should consequently be re-evaluated.
What does the NHS Knowledge Service make of this study?
This laboratory study has further explored the mechanisms behind the action of ανβ5/ανβ3 inhibitors, including cilengitide, a drug currently being trialled as a treatment for some human cancers. Results with cilengitide to date have not been overly positive, although some people with brain tumours appear to respond. One question with this animal study is whether the results can be applied to human cancers.
However, the findings are important and may lead to further research into how treatment with these types of ανβ5/ανβ3 integrin inhibitors may be given to patients with cancer. The researchers say that their results suggest that it would be better to maintain high concentrations of the inhibitors in plasma, and to avoid low concentrations. This, they say, may be achieved through a pump-based system of administration, which is currently being tested in a trial of cilengitide.
Researchers will be interested in these findings, which have given important details about how different doses of the drug work. These findings could influence how the drug is delivered in future trials. Further research is needed, however, and the results of the study assessing prolonged infusion using a pump-based system will be eagerly awaited.
The study only assessed the effects of two inhibitors of angiogenesis that work by inhibiting ανβ5/ανβ3 integrins – S36578 and cilengitide. Cilengitide is at an early stage of development and has so far only been used to treat human cancers in phase I and phase II clinical trials.
According to the news reports, Avastin and Sutent, which act in a similar way, have been proven to work and were not covered in this research. These drugs are in fact VEGF inhibitors, therefore their method of preventing angiogenesis is slightly different to the ανβ5/ανβ3 integrin inhibitors. Avastin and Sutent are not covered by this research.