Skip to main content
SpringerLink
Log in
Book cover

Genetically Engineered Mice for Cancer Research pp 465–476Cite as

Transplanted Tumor Models for Preclinical Drug Testing and the Potential Benefit of Genetically Engineered Mouse Models

  • Chapter
  • First Online:

  • 1329 Accesses

Abstract

Tumor models in rodents have historically served a key role in preclinical anticancer screening programs to evaluate biological activity and to optimize antitumor activity for new compounds. While the role of mouse tumor models in drug development programs has evolved and its predictive capabilities for humans continue to be debated, it is important to note that correlative drug responses have, and continue to demonstrate activity in preclinical mouse models for a majority of the clinically approved chemotherapeutic agents. However, the need for new technologies, strategies, and data analyses that provide greater efficiency in selecting compounds for development, and better predict clinical outcomes, cannot be overstated. Currently, it is predicted that approximately 1.5 million Americans will be diagnosed with cancer annually (American Cancer Society, Cancer facts and figures, 2008). Therefore, discovery of effective treatment strategies is paramount. Advances in the development of novel molecularly targeted agents, more effective use of traditional transplant models, and greater use of genetically engineered mice is expected to improve the accuracy of identifying therapeutic targets and effective compounds (alone or in combination) in the preclinical screening process. This will allow therapeutic agents to be more quickly and safely transitioned into human patients to improve their longevity and quality of life.

This is a preview of subscription content, log in via an institution.

Chapter
USD   29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD   169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

References

  • Alley MC, Hollingshead MG et al (2004) Human tumor xenograft models in NCI drug development. In: Teicher BA, Andrews PA (eds) Anticancer drug development guide: preclinical screening, clinical trials, and approval, 2nd edn. Humana, Totowa, NJ

    Google Scholar 

  • American Cancer Society (2008) Cancer facts and figures. http://www.cancer.org. Accessed 25 Aug 2008

  • Barrett MK (1940) The influence of genetic constitution upon the induction of resistance to transplantable mouse tumors. J Natl Cancer Inst 1:387–393

    CAS  Google Scholar 

  • Beck JA, Lloyd S et al (2000) Genealogies of mouse inbred strains. Nat Genet 24:23–25

    Article  PubMed  CAS  Google Scholar 

  • Bibby MC (2004) Orthotopic models of cancer for preclinical drug evaluation: advantages and disadvantages. Eur J Cancer 40:852–857

    Article  PubMed  CAS  Google Scholar 

  • Biological Testing Branch (2008) http://dtp.nci.nih.gov/branches/btb/btb_index.html. Accessed 25 Aug 2008

  • Bittner JJ (1934) Linkage in transplantable tumours. J Genet 29(1):17–27

    Article  Google Scholar 

  • Borgel SD, Carter JP et al (2003) The impact of tumor location on the activity of 17-DMAG (NSC 707545), a water soluble geldanamycin analog. Clin Cancer Res 9(16):6215S

    Google Scholar 

  • Bosma GC, Custer RP, Bosma MJ (1983) A severe combined immunodeficiency mutation in the mouse. Nature 301(5900):527–530

    Article  PubMed  CAS  Google Scholar 

  • Brown JM (1997) NCI’s anticancer drug screening program may not be selecting for clinically active compounds. Oncol Res 9:213–215

    PubMed  CAS  Google Scholar 

  • Burchill SA (2006) What do, can and should we learn from models to evaluate potential anticancer agents? Future Med 2(2):201–211

    CAS  Google Scholar 

  • Carruthers C, Suntzeff V (1944) Chemical studies on the transformation of mouse epidermis by methylcholanthrene to squamous cell carcinoma. J Biol Chem 155(2):459–464

    CAS  Google Scholar 

  • Céspedes MV, Casanova I et al (2006) Mouse models in oncogenesis and cancer therapy. Clin Transl Oncol 8(5):318–329

    Article  PubMed  Google Scholar 

  • Cloudman AM (1946) A study of the organophilic tendencies of 2 transplantable mouse tumors. Cancer Res 6(9):503

    Google Scholar 

  • Corbett TH, Valeriote FA, Baker LH (1987) Is the P388 murine tumor model no longer adequate as a drug discovery model? Invest New Drugs 5:3–20

    Article  PubMed  CAS  Google Scholar 

  • Croy BA, Chapeau C (1990) Evaluation of the pregnancy immunotrophism hypothesis by assessment of the reproductive performance of young adult mice of genotype scid/scid.bg/bg. J Reprod Fertil 88(1):231–239

    Article  PubMed  CAS  Google Scholar 

  • DiMasi JA, Hansen RW, Grabowski HG (2003) The price of innovation: New estimates of drug development costs. J Health Econ 22(20):151–185

    Article  PubMed  Google Scholar 

  • Driscoll JS (1984) The preclinical new drug research program of the National Cancer Institute. Cancer Treat Rep 68(1)

    Google Scholar 

  • Dudkin L, Dilling MB et al (2001) Biochemical correlates of mTOR inhibition by the rapamycin ester CCI-779 and tumor growth inhibition. Clin Cancer Res 7(6):1758–1764

    PubMed  CAS  Google Scholar 

  • Eaton GJ, Outzen HC et al (1975) Husbandry of the “Nude” mouse in conventional and germ-free environments. Lab Anim Sci 5:309–314

    Google Scholar 

  • Fancy Mouse Breeders Club (2008) http://www.nationalmouseclub.co.uk/history.html. Accessed 25 Aug 2008

  • Fidler IJ, Wilmanns C et al (1994) Modulation of tumor cell response to chemotherapy by the organ environment. Cancer Metastasis Rev 13(2):209–222

    Article  PubMed  CAS  Google Scholar 

  • Flaherty KT, O’Dwyer PJ (2004) Conventional design and novel strategies in the era of targeted therapies. In: Teicher BA, Andrews PA (eds) Anticancer drug development guide: preclinical screening, clinical trials, and approval, 2nd edn. Humana, Totowa, NJ

    Google Scholar 

  • Flanagan SP (1966) ‘Nude’, a new hairless gene with pleiotropic effects in the mouse. Genet Res 8:295–309

    Article  PubMed  CAS  Google Scholar 

  • Frei E III (1982) The national cancer chemotherapy program. Science 217:600–606

    Article  PubMed  Google Scholar 

  • Gershwin ME (1977) DiGeorge syndrome: congenital thymic hypoplasia. Animal model: congenitally athymic (nude) mouse. Am J Pathol 89(3):809–812

    PubMed  CAS  Google Scholar 

  • Giovanella BC, Stehlin JS Jr et al (1983) Correlation between response to chemotherapy of human tumors in patients and in nude mice. Cancer 52(7):1146–1152

    Article  PubMed  CAS  Google Scholar 

  • Goldin A, Venditti JM, Carter SK (1977) Screening at the National Cancer Institute. Natl Cancer Inst Monogr 45:37–48

    PubMed  CAS  Google Scholar 

  • Goldin A, Venditti JM et al (1981) Current results of the screening program at the Division of Cancer Treatment, National Cancer Institute. Eur J Cancer 17:129–142

    PubMed  CAS  Google Scholar 

  • Greene HSN, Murphy ED (1945) The heterologous transplantation of mouse and rat tumors. Cancer Res 5(5):269–282

    Google Scholar 

  • Guflino PM, Ediger RD et al (1976) Guide for the care and use of the nude (thymus deficient) mouse in biomedical research. ILAR News 19:M3–M20

    Google Scholar 

  • Hammett FS (1936) Effect of cystine disulfoxide on spontaneous tumors of the mouse. Science 83:108–109

    Article  Google Scholar 

  • Hollingshead MG (2008) Antitumor efficacy testing in rodents. J Natl Cancer Inst 100(21):1500–1510

    Article  PubMed  CAS  Google Scholar 

  • Houghton PJ, Morton CL et al (2007) The pediatric preclinical testing program: description of models and early testing results. Pediatr Blood Cancer 49:928–940

    Article  PubMed  Google Scholar 

  • Johnson JI, Decker S et al (2001) Relationships between drug activity in NCI preclinical in vitro and in vivo models and early clinical trials. Br J Cancer 84(10):1424–1431

    Article  PubMed  CAS  Google Scholar 

  • Kamel-Reid BA, Dick JE (1988) Engraftment of immune-deficient mice with human hematopoietic stem cells. Science 242(4886):1706–1709

    Article  PubMed  CAS  Google Scholar 

  • Kelland LR (2004) “Of mice and men:” values and liabilities of the athymic nude mouse model in anticancer drug development. Eur J Cancer 40:827–836

    Article  PubMed  CAS  Google Scholar 

  • Kerbel RS (2003) Human tumor xenografts as predictive preclinical models for anticancer drug activity in humans: getter than commonly perceived – but they can be improved. Cancer Biol Ther 2(4):S134–S139

    PubMed  CAS  Google Scholar 

  • Killion JJ, Radinsky R, Fidler IJ (1998) Orthotopic models are necessary to predict therapy of transplantable tumors in mice. Cancer Metastasis Rev 17(3):279–284

    Article  PubMed  Google Scholar 

  • Kinders R, Parchment RE et al (2007) Phase 0 clinical trials in cancer drug development: from FDA guidance to clinical practice. Mol Interv 7(6):325–334

    Article  PubMed  CAS  Google Scholar 

  • Kung AL (2007) Practices and pitfalls of mouse cancer models in drug discovery. Adv Cancer Res 96:191–212

    Article  PubMed  CAS  Google Scholar 

  • Liu CN, Lambert JM et al (1996) Cure of multidrug-resistant human B-cell lymphoma xenografts by combinations of anti-B4-blocked ricin and chemotherapeutic drugs. Blood 87(9):3892–3898

    PubMed  CAS  Google Scholar 

  • Lozzio BB, Lozzi CB, Machado E (1976) Human myelogenous (Ph+) leukemia cell line: transplantation into athymic mice. J Natl Cancer Inst 56(3):627–629

    PubMed  CAS  Google Scholar 

  • Ludford RJ (1933) Differences in the growth of transplantable tumours in plasma and serum culture media. Proc R Soc Lond B 112(776):250–263

    Article  CAS  Google Scholar 

  • Manning DD, Reed ND, Shaffer CF (1973) Maintenance of skin xenografts of widely divergent phylogenetic origin on congenitally athymic (nude) mice. J Exp Med 138(2):488–494

    Article  PubMed  CAS  Google Scholar 

  • McCampbell EF (1909) Malignant tumors in mice with a report of a spontaneous adeno-carcinoma in a house mouse (mus musculus). J Med Res 20(113):261–273

    PubMed  CAS  Google Scholar 

  • Monks A, Scudiero D et al (1991) Feasibility of a high-flux anticancer drug screen using a diverse panel of cultured human tumor cell lines. J Natl Cancer Inst 83(11):757–766

    Article  PubMed  CAS  Google Scholar 

  • Mouse Models of Human Cancer Consortium (2008) http://emice.nci.nih.gov. Accessed 25 Aug 2008

  • Murphy JB, Maisin J, Sturm E (1923) Local resistance to spontaneous mouse cancer induced by X-rays. J Exp Med 38:45–653

    Article  Google Scholar 

  • Naito S, Giavazzi R et al (1987) Growth and Metastatic behavior of human tumor cells implanted into nude and beige nude mice. Clin Exp Metastasis 5(2):135–146

    Article  PubMed  CAS  Google Scholar 

  • Nettleship A (1943) Study of a spontaneous mouse rhabdomyosarcoma. J Natl Cancer Inst 3(5):563–568

    Google Scholar 

  • Osieka R (1984) Primary and acquired resistance to antineoplastic chemotherapy. A preclinical and clinical study. Cancer 54(6):1168–1174

    Article  PubMed  CAS  Google Scholar 

  • Osieka R, Houchens DP et al (1977) Chemotherapy of human colon cancer xenografts in athymic nude mice. Cancer 40(5):2640–2650

    Article  PubMed  CAS  Google Scholar 

  • Plowman J, Dykes DJ et al (1997) Human tumor xenograft models in NCI drug development. In: Teicher BA (ed) Anticancer drug development guide: preclinical screening, clinical trials, and approval, 1st edn. Humana, Totowa, NJ

    Google Scholar 

  • Povlsen CO, Visfeldt J et al (1975) Growth patterns and chromosome constitutions of human malignant tumours after long-term serial transplantation in nude mice. Acta Pathol Microbiol Scand 83(6):709–716

    CAS  Google Scholar 

  • Prochazka M, Gaskins HR et al (1992) The nonobese diabetic scid mouse: model for spontaneous thymomagenesis associated with immunodeficiency. Proc Natl Acad Sci USA 89(8):3290–3294

    Article  PubMed  CAS  Google Scholar 

  • Rygaard J (1969) Immunobiology of the mouse mutant “Nude”. Preliminary investigations. Acta Pathol Microbiol Scand 77(4):761–762

    Article  PubMed  CAS  Google Scholar 

  • Rygaard J, Povlsen CO (1969) Heterotransplantation of a human malignant tumour to “Nude” mice. Acta Pathol Microbiol Scand 77(4):758–760

    Article  PubMed  CAS  Google Scholar 

  • Sausville EA, Hollingshead MG (2004) Mouse models in cancer drug discovery and development. In: Figg WD, McLeod HL (eds) Handbook of anticancer pharmacokinetics and pharmacodynamics. Humana, Totowa, NJ

    Google Scholar 

  • Schein PS, Scheffler B (2006) Barriers to efficient development of cancer therapeutics. Clin Cancer Res 12:3243–3248

    Article  PubMed  CAS  Google Scholar 

  • Schepartz SA (1977) Antitumor screening procedures of the National Cancer Institute. Jpn J Antibiot 30:35–40

    PubMed  Google Scholar 

  • Schmidtwolf IGH, Negrin RS et al (1991) Use of a SCID mouse human lymphoma model to evaluate cytokine-induced killer-cells with potent antitumor cell-activity. J Exp Med 174(1):139–149

    Article  CAS  Google Scholar 

  • Schold SC Jr, Bigner DD (1983) Treatment of five subcutaneous human glioma tumor lines in athymic mice with carmustine, procarbazine, and mithramycin. Cancer Treat Rep 67(9):811–819

    PubMed  CAS  Google Scholar 

  • Schuh JC (2004) Trials, tribulations, and trends in tumor modeling in mice. Toxicol Pathol 32:53–66

    Article  PubMed  CAS  Google Scholar 

  • Sharpless NE, Depinho RA (2006) The mighty mouse: genetically engineered mouse models in cancer drug development. Nat Rev Drug Discov 5(9):741–754

    Article  PubMed  CAS  Google Scholar 

  • Shimosato Y, Kameya T et al (1976) Transplantation of human tumors in nude mice. J Natl Cancer Inst 56(6):1251–1260

    PubMed  CAS  Google Scholar 

  • Shultz LD, Lang PA et al (2000) NOD/LtSz-Rag1null mice: an immunodeficient and radioresistant model for engraftment of human hematolymphoid cells, HIV infection, and adoptive transfer of NOD mouse diabetogenic T cells. J Immunol 164(5):2496–2507

    PubMed  CAS  Google Scholar 

  • Singh SK, Hawkins C et al (2004) Identification of human brain tumour initiating cells. Nature 432(7015):396–401

    Article  PubMed  CAS  Google Scholar 

  • Slye M (1915) The incidence and inheritability of spontaneous cancer in mice (third report). J Med Res 32(1):159–200

    PubMed  CAS  Google Scholar 

  • Staats J (1966) The laboratory mouse. In: Green EL (ed) Biology of the laboratory mouse. McGraw-Hill, New York

    Google Scholar 

  • Staquet MJ, Byar DP et al (1983) Clinical predictivity of transplantable tumor system in the selection of new drugs for solid tumors: rationale for a three-stage strategy. Cancer Treat Rep 67(9):753–765

    PubMed  CAS  Google Scholar 

  • Stephenson RA, Dinney CP et al (1992) Metastatic model for human prostate cancer using orthotopic implantation in nude mice. J Natl Cancer Inst 84(12):951–957

    Article  PubMed  CAS  Google Scholar 

  • Stinson SF, Alley MC et al (1992) Morphological and immunocytochemical characteristics of human tumor cell lines for use in a disease-oriented anticancer drug screen. Anticancer Res 12(4):1035–1053

    PubMed  CAS  Google Scholar 

  • Strong LC (1927) Studies on the effect of potassium alum-hydrochloric acid solutions on the growth and fate of neoplastic tissue. 1. Effect on a slow growing adeno carcinoma of the mouse. Proc Natl Acad Sci USA 13:141–145

    Article  PubMed  CAS  Google Scholar 

  • Suggitt M, Bibby MC (2005) 50 years of preclinical anticancer drug screening: empirical to target-driven approaches. Clin Cancer Res 11:971–981

    PubMed  CAS  Google Scholar 

  • Talmadge JE, Singh RK et al (2007) Murine models to evaluate novel and conventional therapeutic strategies for cancer. Am J Pathol 170(3):793–804

    Article  PubMed  CAS  Google Scholar 

  • Teicher BA (2006) Tumor models for efficacy determination. Mol Cancer Ther 5(10):2435–2443

    Article  PubMed  CAS  Google Scholar 

  • Varticovski L, Hollingshead MG et al (2007) Accelerated preclinical testing using transplanted tumors from genetically engineered mouse breast cancer models. Clin Cancer Res 13(7):2168–2177

    Article  PubMed  CAS  Google Scholar 

  • Venditti JM (1981) Preclinical drug development: rationale and methods. Semin Oncol 8:349–361

    PubMed  CAS  Google Scholar 

  • Voskoglou-Nomikos T, Pater JL, Seymour L (2003) Clinical predictive value of the in vitro cell line, human xenograft and mouse allograft preclinical cancer models. Clin Cancer Res 9:4227–4239

    PubMed  Google Scholar 

  • Weiss B, Shannon K (2004) Preclinical trials in mouse cancer models. In: Holland EC (ed) Mouse models of human cancer. Wiley, Hoboken, NJ

    Google Scholar 

  • Winograd B, Boven E et al (1987) Human tumor xenografts in the nude mouse and their value as test models in anticancer drug development (review). In Vivo 1(1):1–13

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Developmental Therapeutics Program, NCI-Frederick, 1050 Boyles St, Building 1052/239, Frederick, MD, 21702, USA

    Melinda Hollingshead, Michelle Ahalt & Sergio Alcoser

Authors
  1. Melinda Hollingshead
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Michelle Ahalt
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Sergio Alcoser
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Melinda Hollingshead .

Editor information

Editors and Affiliations

  1. , Laboratory Of Cancer Biology and Genetic, National Cancer Institute, Convent Dr. 37, Bethesda, 20892, Maryland, USA

    Jeffrey E. Green

  2. National Cancer Institute, Center for Cancer Research, National Institutes of Health, South Drive 50, Bethesda, 20892, Maryland, USA

    Thomas Ried

Rights and permissions

Reprints and permissions

Copyright information

© 2012 Springer Science+Business Media, LLC

About this chapter

Cite this chapter

Hollingshead, M., Ahalt, M., Alcoser, S. (2012). Transplanted Tumor Models for Preclinical Drug Testing and the Potential Benefit of Genetically Engineered Mouse Models. In: Green, J., Ried, T. (eds) Genetically Engineered Mice for Cancer Research. Springer, New York, NY. https://doi.org/10.1007/978-0-387-69805-2_22

Download citation

Publish with us

Policies and ethics

Search

Navigation