Dr. Paul Foster, a Lecturer in Molecular Endocrinology at the University of Birmingham, is an experienced cancer researcher and pharmacologist with a strong interest in understanding how animals help advance medical research. A list of Dr. Foster’s publications can be found at the bottom of this page.
Dr. Paul Foster – Staff Profile.
Animals in Medical Research
The use of animals in scientific investigation has been traced back to several centuries BC. For instance, the writings of Aristotle (384-322 BC) and Erasitratus (304-258 BC) indicate that they had studied the anatomy of various animals. Early investigations such as these were the beginning of the basic sciences that today form the foundations for new drug development.
Until the end of the last century, experiments using living animals were carried out on domestic or easily captured wild species. The choice was usually limited and based on availability. By the end of the nineteenth century, the concept of the laboratory animal had begun to emerge as an animal deliberately chosen for its inherent suitability for the purpose; it was especially bred in captivity or obtained from its environment not merely on grounds of convenience but rather for its usefulness for the particular investigation at hand.
Tests in intact animals are necessary to understand how a drug will work in the context of the myriad metabolic and homeostatic mechanisms that are active in vivo. Screening tests are commonly conducted with in vitro systems and isolated tissues or organs to identify and, in some cases, to act as a bioassay to help purify pharmacologically active agents. However, the variable processes of absorption, distribution within the organism, metabolism to either inactive or more active products, and excretion will modulate the expression of pharmacologic activity in vivo. The only way this modulation can be estimated is by studying the new drug in intact animals.
Aside from studies of pharmacologic activity, side effects of new drugs must be identified and an initial assessment made of their risk-to-benefit ratio. Again, mechanisms of action and effects on specific organs can be studied by using in vitro techniques. However, to identify unexpected adverse effects and to estimate the dosages that may be pharmacologically active without producing unwanted effects, in vivo studies must be conducted.
For most substances, the mechanism of action will be the same in humans and other mammals. Therefore, quantitative rather than qualitative differences in response are most common. Humans may be more sensitive to some drugs than certain laboratory animals are, but in many cases some animal species are more sensitive than humans are. For example, the mouse is most sensitive to atropine, the cat is less sensitive, and the dog and the rabbit tolerate atropine at doses 100 times higher than does the human.
Species differences in sensitivity can often be explained by differences in metabolism, including quantitative and qualitative differences in the ability to detoxify drugs and also differences in the rates of absorption, transport, distribution, and elimination of chemicals. After oral administration, absorption in laboratory animals is generally considered to be similar to that in humans, although there are quantitative differences for some compounds. For example, species differences in the absorption and action of some compounds are related to differences in the bacterial flora of the gastrointestinal tract. The distribution and storage of drugs are reasonably consistent among mammalian species, including humans, although plasma binding tends to be more extensive in humans than in small mammals. Urinary excretion in different animal species depends to some extent on their different diets, because diet influences urinary pH and thus the extent of ionization of compounds. Biliary excretion is quite variable from species to species and is apparently more extensive in mice and rabbits than in rats and humans. Species differences in response to drugs appear to be related mainly to rates of biotransformation, which are generally more rapid in small laboratory animals than in humans.
27. J.M. Day, P.A. Foster, H.J. Tutill, S.P. Newman, Y.T. Ho, M.P. Leese, B.V.L. Potter, M.J. Potter, A. Purohit. BCRP expression does not result in resistance to STX140 in vivo, despite the increased expression of BCRP in A2780 cells in vitro after long-term STX140 exposure. Br. J. Cancer. 2009; 100:476-86.
26. P.A. Foster, Y.T. Ho, S.P. Newman, M.P. Leese, B.V. Potter, M.J. Reed, A. Purohit. STX140 and STX641 cause apoptosis via the intrinsic mitochondrial pathway and down-regulate surviving and XIAP expression in ovarian and prostate cancer cells. Anticancer Res. 2009; 29:3751-7.
25. J.M. Day, A. Putohit, H.J. Tutill, P.A. Foster, L.W.L. Woo, B.V.L. Potter, M.J. Reed. The development of steroid sulfatase inhibitors for hormone-dependent cancer therapy. Ann N Y Acad Sci. 2009; 1155:80-7.
24. J.M. Day, H.J. Tutill, P.A. Foster, H.V. Bailey, W.B. Heaton, C.M. Sharland, N. Vicker, B.V.L. Potter, A. Purohit, M.J. Reed. Development of hormone-dependent prostate cancer models for the evaluation of inhibitors of 17beta-hydroxysteroid dehydrogenase type 3. Mol. Cell Endocrinol. 2009; 301:251-8.
23. P.A. Foster, S.K. Chander, S.P. Newman, L.W.L. Woo, O.B. Sutcliffe, C. Bubert, D. Zhou, S. Chen, B.V.L. Potter, M.J. Reed, A. Purohit. A new therapeutic strategy against hormone-dependent breast cancer: The pre-clinical development of a dual aromatase and sulfatase inhibitor (DASI). Clin. Cancer Res. 2008; 14: 6469-77.
22. S.L. Tagg, P.A.Foster, M.P.Leese, B.V.L. Potter, M.J. Reed, A. Purohit, S.P. Newman. 2-Methoxyoestradiol-3,17-O,O-bis-sulphamate and 2-deoxy-D-glucose in combination: a potential treatment for breast and prostate cancer. Br. J. Cancer. 2008; 99:1842-8.
21. M.F.C. Parsons, P.A. Foster, S.K. Chander, R. Jhalli, S.P. Newman, M.P. Leese, B.V.L. Potter, A. Purohit, M.J. Reed. The in vivo properties of STX243: a potent angiogenesis inhibitor in breast cancer. Br. J. Cancer. 2008; 99:1433-41.
20. P.A. Foster, M.J.Reed, A. Purohit. Recent developments of steroid sulfatase inhibitors as anti-cancer agents. Anti-cancer Agents in Med. Chem. Review. 2008; 8: 732-8.
19. P.A. Foster, S.K. Chander, M.F.C. Parsons, S.P. Newman, L.W.L.Woo, B.V.L.Potter, M.J. Reed, A. Purohit. Efficacy of three potent steroid sulfatase inhibitors: pre-clinical investigations for their use in the treatment of hormone-dependent breast cancer. Breast Cancer Res. Treat. 2008; 111:129-38.
18. P.A. Foster, Y.T. Ho, S.P. Newman, P.G. Kasprzyk, M.P. Leese, B.V.L.Potter, M.J. Reed, A. Purohit. 2-MeOE2bisMATE and 2-EtE2bisMATE induce cell cycle arrest and apoptosis in breast cancer xenografts as shown by a novel ex vivo technique. Breast Cancer Res. Treat. 2008; 111:251-60.
17. P.A. Foster, L.W. Woo, B.V. Potter, M.J. Reed, A. Purohit. Steroid sulfatase inhibitors block the growth of hormone-dependent endometrial cancer xenografts: A potential new treatment. Endocinology. 2008; 149:4035-42.
16. P.A. Foster. Steroid metabolism in breast cancer. Minerva Endocrinologica. 2008;33:27-37.
15. P.A. Foster, S.P. Newman, M.P. Leese, S. Bernetiere, J. Camara, B.V. Potter, M.J. Reed, A. Purohit. A new micronised formulation of 2-methoxyestradiol-bis-sulphamate is therapeutically potent against breast cancer. Anti-cancer Res. 2008; 28:577-81.
14. P.A.Foster, C. Stengal, T. Ali, M.P.Leese, B.V.L. Potter, M.J. Reed, A. Purohit, S.P. Newman. A comparison of two orally bioavailable anti-cancer agents, IRC-110160 and STX140. Anti-cancer Res. 2008; 28:1483-91.
13. J.M. Day, P.A. Foster, H.J. Tutill, M.F.C. Parsons, S.K. Chander, G.M. Allan, H.R. Lawrence, N. Vicker, B.V.L. Potter, M.J. Reed, A. Purohit. In vivo inhibition of estrone-stimulated tumor growth by STX1040; a 17b-hydroxysteroid dehydrogenase type 1 inhibitor with therapeutic potential. Int. J. Can. 2008;122:1931-1940.
12. S.P. Newman, P.A. Foster, C. Stengel, J.M. Day, Y.T. Ho, M.P. Leese, B.V.L. Potter, M.J. Reed, A. Purohit. The orally bioavailable microtubule disruptor, STX140, is efficacious in vitro and in vivo in Taxane resistant breast carcinoma cells. Clin. Can. Res. 2008; 14:597-606.
11. M.P. Leese, F.L. Jourdan, K. Gaukroger, M.F. Mahon, S.P. Newman, P.A. Foster, C. Stengal, S. Regis-Lydi, E Ferrandis, A.D. Fiore, G. De Simone, C.T. Supuran, A. Purohit, M.J. Reed, P.V.L. Potter. Structure-activity relationships of C-17 Cyano-substituted estratrienes as anticancer agents. J. Med. Chem. 2008; 51:1295-308.
10. L.W. Woo, D.S. Fischer, C.M. Sharland, M. Trusselle, P.A. Foster, S.K. Chander, A. Di Fiore, C.T. Supuran, G. De Simone, A. Purohit, M.J. Reed, B.V. Potter. Anticancer steroid sulfatase inhibitors: synthesis of a potent fluorinated second-generation agent, in vitro and in vivo activities, molecular modelling, and protein crystallography. Mol. Cancer Ther. 2008; 7: 2435-44.
9. S.P. Newman, P.A. Foster, Y.T. Ho, J.M. Day, B. Raobaikady, P.G. Kasprzyk, M.P. Leese, B.V. Potter, M.J. Reed, A. Purohit. The therapeutic potential of a series of orally bioavailable anti-angiogenic microtubule disruptos as therapy for hormone-independent prostate and breast cancer. Br. J. Cancer. 2007; 97, 1673-82.
8. S.K. Chander, P.A. Foster, M.P. Leese, S.P. Newman, B.V.L. Potter, M.J. Reed, A. Purohit. In vivo inhibition of angiogenesis by sulfamoylated derivatives of 2-methoxyestradiol. Br. J. Cancer. 2007; 96, 1368-76.
7. P.A. Foster, S.P. Newman, S.K. Chander, C. Stengal, R. Jhalli, L.W.L. Woo, B.V.L. Potter, M.J. Reed, A. Purohit. In vivo efficacy of STX213, a second-generation steroid sulfatase inhibitor, for hormone-dependent breast cancer therapy. Clin. Can. Res. 2006; 12, 5543-49.
6. R.S. Scotland, Cohen M, P.A. Foster, M. Lovell, A. Mathur, A. Ahluwalia, A.J. Hobbs. C-type natriuretic peptide inhibits leukocyte recruitment and platelet-leukocyte interactions via suppression of P-selectin expression. PNAS. 2005; 102, 14452-7.
5. A. Ahluwalia, P. Foster, R.A. Scotland, M.G. McLean, A. Mathur, M. Perretti, S. Moncada, A.J. Hobbs. Anti-inflammatory activity of soluble guanalyte cyclase: cyclic GMP-dependent down regulation of P-selectin expression and leukocyte recruitment. PNAS. 2004; 101, 1386-1391.
4. A. Hobbs, P.A. Foster, C. Prescott, R. Scotland, A. Ahluwalia. Natriuretic peptide receptor-C regulates blood flow and prevents myocardial ischemia/reperfusion injury: a novel cardioprotective role for endothelium-derived C-type natiuretic peptide. Circulation 2004; 101, 1231-5.
3. P.A. Foster, S.K.P. Costa, R. Postin, J.R.S. Hoult and S.D. Brain. Endothelial cells play an essential role in the thermal hyperalgesia induced by nerve growth factor. FASEB. 2003; 17, 1703-5.
2. P.A. Foster, S. Wicks, M. Foster and S.D. Brain. Cellular pathology changes in rat skin following intradermal injection of nerve growth factor (NGF): neutrophil dependent and independent events. J. Pathol. 2002; 197, 245-255.
1. D.Q. Chu, M. Choy, P.A. Foster, T. Cao and S.D. Brain. A comparative study of the ability of calcitonin gene-related peptide and adrenomedullin13-52 to modulate microvascular but not thermal hyperalgesia response. Br. J. Pharmacol. 2000; 130, 1589-1596.
12. P.A. Foster, S.P. Newman, M.P. Leese, B.V.L. Potter, M.J. Reed, A. Purohit. STX140 has a limited haematological and neurotoxicity profile in a xenograft model of breast cancer. AACR, April 2009.
11. P.A. Foster, S.K. Chander, S.P. Newman, R. Jhalli, L.W.L. Woo, C. Bubert, B.V.L. Potter, M.J. Reed, A. Purohit. Use of a dual aromatase-sulfatase inhibitor for the treatment of hormone-dependent breast cancer. ENDO 08.
10. P.A. Foster, S.P. Newman, C. Stengal, Y.T. Ho, J.M. Day, M.P. Leese, B.V.L. Potter, M.J. Reed, A. Purohit. 2-substituted estrogen sulfamates block the growth of MCF-7 breast cancer tumors resistant to paclitaxel. AACR, April 2008.
9. P.A. Foster, S.K. Chander, S.P. Newman, R. Jhalli, L.W.L. Woo, B.V.L. Potter, M.J. Reed, A. Purohit. Use of a sulfatase and aromatase inhibitor in combination for the treatment of human breast cancer. Breast Cancer Res. Tr. 2006; 100, S188-S188.
8. J.M. Day, P.A. Foster, S.K. Chander, H.J. Tutill, M.F.C. Parsons, G.M. Allan, H.R. Lawrence, N. Vicker, B.V.L. Potter, M.J. Reed, A. Purohit. Inhibition of estrone-dependent tumor growth in vivo by the 17 beta-HSD1 inhibitor, 2-ethyl-16 beta-m-pyridylmethylamidomethyl-estrone (2-EtE1-F). Breast Cancer Res. Tr. 2006; 100, S197-S197.
7. P.A. Foster, S.K. Chander, S.P. Newman, L.W.L. Woo, B.V.L. Potter, M.J. Reed, A. Purohit. Inhibition of growth of tumors derived from MCF-7 cells and MCF-7 cells overexpressing steroid sulfatase by STX64 and STX213. AACR, April 2006.
6. S.K. Chander, P.A. Foster, M. Parsons, S.P. Newman, M.P. Leese, A. Purohit, B.V.L. Potter, M.J. Reed. In vivo inhibition of angiogenesis and tumor growth by sulfamoylated derivatives of 2-methoxyestradiol, STX140 and STX641. AACR, April 2006.
5. Y. Ho, P.A. Foster, S.P. Newman, M.P. Leese, B.V.L. Potter, A. Purohit, M.J. Reed. Sulphamoylated derivatives of 2-methoxyestradiol induce apoptosis in breast, ovarian and prostate cancer cell lines throught mitotic arrest via the intrinsic apoptotic pathway. AACR, April, 2006.
4. P.A. Foster, S.K. Chander, S.P. Newman, A. Purohit, L.W.L. Woo, B.V.L. Potter, M.J. Reed. A novel steroid sulfatase inhibitor, 667COUMATE, inhibits the estradiol sulfate stimulated growth of tumors derived from MCF-7 breast cancer cells transfected with steroid sulfatase. AACR, April 2005.
3. P.A. Foster, A. Mathur, A. Ahluwalia. Bradykinin protects against ischemia/reperfusion injury via a KATP channel dependent mechanism: a possible role of nitric oxide. FASEB, 2004. Presented April 2004.
2. P.A. Foster and S.D. Brain. The role of intercellular adhesion molecule (ICAM) in nerve growth factor (NGF)-induced hyperalgesia. Br. J. Pharmacol. Suppl. 2000. 129, 219P.
1. P.A. Foster, A. Ahluwalia, A. Mathur, P.G. McLean, M. Perretti, S. Moncada, A.J. Hobbs. Anti-leukocyte properties of a novel non NO-based soluble guanalyte cyclase activator, BAY 41-2272. FASEB. 2003. 655, C223
P.A. Foster. A review of new therapeutic modalities in breast cancer. Textbook of Gynaecological Oncology. A. Ayhan, M Gultekin, P. Dursun, eds. Günes Publishing 2009. p588-591.
P.A. Foster. Steroid sulfatase inhibitors. Encyclopaedia of Cancer. M. Schwab, eds. Springer. 2009. p467-469.
S.D. Brain and P.A. Foster. Nitric oxide and neurogenic inflammation. In Nitric Oxide and the Peripheral Nervous System. N. Toda, S. Moncada, R. Furchgott and E.A. Higgs, eds. Portland Press. p167-180.