National Anti-vivisection Society

 

National Antivisection Society

Case study: research using mice funded by Cancer Research UK

Posted: 13 December 2011. Updated: 17 April 2012

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Massie, C. E. et al, (2011) “The androgen receptor fuels prostate cancer by regulating central metabolism and biosynthesis”, The EMBO Journal, vol. 30, pp: 2719 – 2733

Cancer Research UK

Xenograft tumours were generated in mice using a human prostate cancer cell line as part of a study into androgen receptor (AR) regulated genes and their roles in prostate cancer. Four groups of four mice (total = 16) were injected three times weekly and the subsequent growth of tumours monitored.

Repetition:

The authors of the current paper state that “In the course of preparing this manuscript another group reproduced our finding that CAMKK2 is an important downstream effector of the AR, selecting CAMKK2 from published expression array data on a candidate basis.” The other group also recommended CAMKK2 as a potential therapeutic target for prostate cancer, however gained their results using human cellular models of prostate cancer, (1) in contrast to the current authors.

Species differences and awareness of them:

Despite the increasing use of rodents to model human diseases such as cancer, fundamental biological differences exist between rodents and humans. None of these species differences were acknowledged in this study. The rat’s basal metabolic rate for example, is around seven times higher than that of humans, which has important consequences in terms of levels of mutagens that are produced as by-products of normal metabolism (2) Other researchers noted that “Many carcinogens are activated or neutralized quite differently in mouse and human liver” and that “there are subtle differences with respect to physiology and tissue architecture that can alter tumour phenotype drastically” (3) Neither species differences nor the limitations of the data, regarding extrapolating the results to humans have been mentioned.

Current available treatments:

The main treatments for prostate cancer currently include hormone therapy, radiotherapy, surgery, and chemotherapy. Other treatments include cryotherapy and high intensity focussed ultrasound (4)

Animal suffering:

All 16 animals were initially injected with prostate cancer cells to generate xenograft tumours. After this, the mice were divided into four groups, and two of the groups were castrated. All the animals were subsequently injected three times per week, with one of two chemicals to assess the impacts of these agents on tumour growth. Images within the paper show a time-series of tumour growth over a 5 week period, monitored using bioluminescence. Tumour growth has the potential to significantly impact an animal’s welfare. For example, the Office of Animal Care and Use (U.S. National Institutes of Health) state that a tumour burden greater than 10% of the body weight or exceeding 20mm in diameter in an adult mouse could constitute an endpoint in a study (5)

The mice were also injected for blood plasma studies, and their blood was then sampled 9 times following the initial injection. The high frequency of this blood sampling, associated handling stress and the possible effects this may have had on the animals is not considered.

Alternative advance techniques

A 2004 study used human prostate tissues obtained from therapeutic or diagnostic procedures, (6) demonstrating that research in this field without animals is possible, and highly informative.

Poor experimental planning:

Mice were injected for blood plasma studies either into the body cavity or into the vein. The reason for the different sampling approach and its possible impact on results is not explained. The authors state that “A complete understanding of the function of CAMKK2 in prostate cancer will clearly depend on improved in vivo and in vitro models”, a clear acknowledgement of the weaknesses of their model.

Disease context:

Cancer is a common condition, and more than one in three people will develop some form of cancer during their lifetime. The most common types of cancer in the UK include breast, prostate, lung, bowel, bladder and uterine cancer. (7&8)

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References:

1.Frigo, D.E. et al. (2010) “CaM kinase kinase β-mediated activation of the growth regulatory kinase AMPK is required for androgen-dependent migration of prostate cancer cells”, Cancer Research, e.10.1158/0008-5472.CAN-10-2581
2.Ames, B.N. et al. (1993) “Oxidants, antioxidants, and the degenerative diseases of ageing”, PNAS, vol. 90, 7915-7922.
3.Rangarajan, A. and Weinberg, R.A. (2003) “Comparative biology of mouse versus human cells: modelling human cancer in mice”, Nature Reviews, vol. 3, 952-959.
4.http://www.nhs.uk/Conditions/Cancer-of-the-prostate/Pages/Treatment.aspx - Accessed 10/10/11.
5.http://oacu.od.nih.gov/arac/endpoints.pdf - Accessed 03/10/11.
6.Holzbeierlein, J. et al. (2004) “Gene Expression Analysis of Human Prostate Carcinoma during Hormonal Therapy Identifies Androgen-Responsive Genes and Mechanisms of Therapy Resistance”, American Journal of Pathology, vol. 164, 1, 217-227
7.http://www.nhs.uk/conditions/cancer/Pages/Introduction.aspx - Accessed 04/10/11.
8.http://www.macmillan.org.uk/Cancerinformation/Aboutcancer/Whogetscancer.aspx - Accessed 10/10/11.

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