Breast cancer researchers find potential in new combination of existing cheaper drugs


Breast cancer researchers find potential in new combination of existing cheaper drugs


Scientists in the UK and Finland have discovered that a new combination of the chemotherapy drug doxorubicin and the bone-protecting drug zoledronic acid, both of which are considerably cheaper than herceptin, stopped breast cancer tumors growing in mice. Experts suggest that since both drugs are already in use, and if the combination proves effective and safe in human clinical trials, it should not take as long for it to be available as a new treatment for patients.

The study, which was funded by the Breast Cancer Campaign, was the work of Dr Penelope Ottewell and Dr Ingunn Holen from Sheffield University's School of Medicine and Biomedical Sciences, plus other colleagues at Sheffield University and also at the University of Kuopio in Finland. It is published in the 11 August 2008 issue of the Journal of the National Cancer Institute, JCNI.

Breast cancer is usually treated with a combination of drugs including chemotherapy to stop tumors growing, and in cases of advanced cancer, patients take a bisphosphonate to stop bone loss and protect against pain and weakness.

In their background information the researchers said that "test tube" experiments had already shown zoledronic acid enhanced the antitumor effects of chemotherapy drugs, so they decided to see what effect it would have in living mouse models, either on its own, together, or in sequence with the chemotherapy agent doxorubicin.

For the study, the researchers induced breast cancer tumors in mice by injecting them with human breast cancer cells and then after 7 days they injected them every week for 6 weeks with either (1) saline, or (2) doxorubicin, or (3) zoledronic acid, or (4) doxorubicin and zoledronic acid, or (5) zoledronic acid followed 24 hours later by doxorubicin, or (6) doxorubicin followed 24 hours later by zoledronic acid. There were about 8 or 9 mice in each treatment group.

Ottewell, Holen and colleagues then assessed the effect of the various treatments on tumor growth using a range of methods, including measuring tumor volume and rate of programmed tumor cell death (apoptosis). They also assessed the effect on bone.

The results showed that:

  • Treatment with doxorubicin or zoledronic acid alone, or zoledronic acid followed by doxorubicin 24 hours later, did not significantly decrease tumor volume compared with saline.
  • Treatment with doxorubicin plus zoledronic acid produced significantly smaller final tumor volumes than doxorubicin alone, zoledronic alone, or zoledronic acid followed 24 hours later by doxorubicin.
  • However, treatment with doxorubicin followed 24 hours later with zoledronic acid, "almost completely abolished tumor growth".
  • Tumors from mice treated with doxorubicin followed by zoledronic acid showed more evidence of apoptosis or programmed cell death (using presence of caspase-3-positive cells as a measure) than tumors from mice treated with saline, with zoledronic acid alone, or with zoledronic acid followed by doxorubicin.
  • The treatment induced increase in programmed cell death was mirrored by a decrease in the cancer positive marker Ki-67.
  • There was no evidence of bone disease in any of the treatment groups as measured by microcomputed tomography and analysis of bone histology.
The authors concluded that:

"Sequential treatment with Dox [doxorubicin] followed by Zol [zoledronic acid] elicited substantial antitumor effects in subcutaneous breast tumors in vivo, in the absence of bone disease."

The researchers suggested that if these results are replicated in humans in clinical settings, it could dramatically improve survival rates for thousands of women currently having breast cancer treatment in the UK alone.

Holen, who led the project, said that:

"Our work - using a model system - has shown that treatment with the chemotherapy agent doxorubicin followed by zoledronic acid kills breast tumours."

Holen explained that the results suggested that patients "may benefit the most if these two drugs are given in this particular order", and the team is looking forward to "the results of a large breast cancer trial later this year to confirm our findings. This method of treatment could then quickly be incorporated into clinical practice."

Chief Executive of Breast Cancer Campaign, Pamela Goldberg, said:

"The results of this study are very encouraging and could change the way breast cancer patients are treated. The good news is the two treatments used in this study are relatively inexpensive and already used in the clinic. Therefore we should quickly see the benefits giving women the best possible chance of beating breast cancer."

Breast cancer is the most common cancer in the UK, where about 46,000 new cases are diagnosed every year.

"Antitumor Effects of Doxorubicin Followed by Zoledronic Acid in a Mouse Model of Breast Cancer.",

Penelope D. Ottewell, Hannu Mönkkönen, Mark Jones, Diane V. Lefley, Robert E. Coleman, and Ingunn Holen

Journal of the National Cancer Institute, Advance Access published on August 11, 2008.

DOI 10.1093/jnci/djn240.

Click here for Abstract.

Sources: JNCI abstract, Sheffield University.


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