Integrating pharmacology and in vivo cancer models in preclinical and clinical drug development


      Historically, cancer drug development has been a roller coaster. Numerous agents have shown exciting activity in preclinical models and yet have had minimal activity clinically. These disappointments have led to reasonable scepticism about the true value of both syngeneic and xenograft rodent tumour models in accurately identifying agents that will have important clinical utility. Whereas the development of newer techniques, including transgenic mouse models of cancer, offers the potential to develop more predictive models, the role of such mice in cancer drug development is not yet validated. To advance in our understanding of predictive model systems it may be wise to analyse both the successes and the failures of conventional models in order to understand some of their limitations and perhaps to avoid making the same mistakes in the future. Here we review the value and limitations of xenograft models, and the role of integrating preclinical pharmacology in developing new treatments for solid tumours of childhood.


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to European Journal of Cancer
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Johnson J.I.
        • Decker S.
        • Zaharevitz D.
        • et al.
        Relationships between drug activity in NCI preclinical in vitro and in vivo models and early clinical trials.
        Br. J. Cancer. 2001; 84: 1424-1431
      1. Heterotransplantation of human adenocarcinomas of the colon and rectum to the mouse mutant Nude. A study of nine consecutive transplantations.
        Acta Pathol. Microbiol. Scand. [A]. 1971; 79: 159-169
        • Rygaard J.
        • Povlsen C.O.
        Heterotransplantation of a human malignant tumour to “Nude” mice.
        Acta Pathol. Microbiol. Scand. 1969; 77: 758-760
        • Lock R.B.
        • Liem N.
        • Farnsworth M.L.
        • et al.
        The nonobese diabetic/severe combined immunodeficient (NOD/SCID) mouse model of childhood acute lymphoblastic leukemia reveals intrinsic differences in biologic characteristics at diagnosis and relapse.
        Blood. 2002; 99: 4100-4108
        • Houghton J.A.
        • Cook R.L.
        • Lutz P.J.
        • Houghton P.J.
        Childhood rhabdomyosarcoma xenografts.
        Eur. J. Cancer Clin. Oncol. 1984; 20: 955-960
        • Houghton P.J.
        • Horton J.K.
        • Houghton J.A.
        Drug sensitivity and resistance in the xenograft model.
        in: Maurer H.M. Ruyman F.B. Pochedly C. Rhabdomyosarcoma and Related Tumors in Children and Adolescents. CRC Press, Boca Raton1991: 187-202
        • Houghton J.A.
        • Cook R.L.
        • Lutz P.J.
        • Houghton P.J.
        Cancer Treat. Rep. 1985; 69: 91-96
        • Horowitz M.E.
        • Etcubanas E.
        • Christensen M.L.
        • et al.
        Phase II testing of melphalan in children with newly diagnosed rhabdomyosarcoma.
        J. Clin. Oncol. 1988; 6: 308-314
        • Houghton P.J.
        • Cheshire P.J.
        • Hallman 3rd J.C.
        Evaluation of a novel bis-naphthalimide anticancer agent, DMP 840, against human xenografts derived from adult, juvenile, and pediatric cancers.
        Cancer Chemother. Pharmacol. 1994; 33: 265-272
        • Houghton P.J.
        • Cheshire P.J.
        • Hallman 2nd J.D.
        • Houghton J.A.
        Therapeutic efficacy of the cyclopropylpyrroloindole, carzelesin, against xenografts derived from adult and childhood solid tumors.
        Cancer Chemother. Pharmacol. 1995; 36: 45-52
        • Houghton P.J.
        • Houghton J.A.
        • Myers L.
        • Cheshire P.
        • Howbert J.J.
        • Grindey G.B.
        Evaluation of N-(5-indanylsulfonyl)-N′-(4-chlorophenyl)-urea against xenografts of pediatric rhabdomyosarcoma.
        Cancer Chemother. Pharmacol. 1989; 25: 84-88
        • Pappo A.S.
        • Lyden E.
        • Breneman J.
        • et al.
        Up-front window trial of topotecan in previously untreated children and adolescents with metastatic rhabdomyosarcoma.
        J. Clin. Oncol. 2001; 19: 213-219
        • Furman W.L.
        • Stewart C.F.
        • Poquette C.A.
        • et al.
        Direct translation of a protracted irinotecan schedule from a xenograft model to a phase I trial in children.
        J. Clin. Oncol. 1999; 17: 1815-1824
        • Cosetti M.
        • Wexler L.H.
        • Calleja E.
        • et al.
        Irinotecan for pediatric solid tumors.
        J. Pediatr. Hematol. Oncol. 2002; 24: 101-105
        • Santana V.M.
        • Zamboni W.C.
        • Kirstein M.N.
        • et al.
        A pilot study of protracted topotecan dosing using a pharmacokinetically guided dosing approach in children with solid tumors.
        Clin. Cancer Res. 2003; 9: 633-640
        • Zamboni W.C.
        • Stewart C.F.
        • Thompson J.
        • et al.
        Relationship between topotecan systemic exposure and tumor response in human neuroblastoma xenografts.
        J. Natl. Cancer Inst. 1998; 90: 505-511
        • Santana V.M.
        • Zamboni W.C.
        • Gajjar A.
        • et al.
        Pharmacokinetically-guided use of topotecan (TPT), given (daily×5)×2, in children with relapsed solid tumors.
        Proc. Annu. Meet. Am. Soc. Clin. Oncol. 1997; 16: 1839A
        • Leggas M.
        • Stewart C.F.
        • Woo M.H.
        • et al.
        Relation between Irofulven (MGI-114) systemic exposure and tumor response in human solid tumor xenografts.
        Clin. Cancer Res. 2002; 8: 3000-3007
        • Eckhardt S.G.
        • Baker S.D.
        • Britten C.D.
        • et al.
        Phase I and pharmacokinetic study of irofulven, a novel mushroom-derived cytotoxin, administered for five consecutive days every four weeks in patients with advanced solid malignancies.
        J. Clin. Oncol. 2000; 18: 4086-4097
        • Ritschel W.A.
        • Vachharajani N.N.
        • Johnson R.D.
        • Hussain A.S.
        The allometric approach for interspecies scaling of pharmacokinetic parameters.
        Comp. Biochem. Physiol. C. 1992; 103: 249-253
        • Nomura T.
        • Sakurai Y.
        • Inaba M.
        The Nude Mouse and Anticancer Drug Evaluation.
        Japanese Journal of Cancer and Chemotherapy Publishers Inc, Tokyo1996
        • Lave T.
        • Portmann R.
        • Schenker G.
        • et al.
        Interspecies pharmacokinetic comparisons and allometric scaling of napsagatran, a low molecular weight thrombin inhibitor.
        J. Pharm. Pharmacol. 1999; 51: 85-91
        • Luttringer O.
        • Theil F.P.
        • Poulin P.
        • Schmitt-Hoffmann A.H.
        • Guentert T.W.
        • Lave T.
        Physiologically based pharmacokinetic (PBPK) modeling of disposition of epiroprim in humans.
        J. Pharm. Sci. 2003; 92: 1990-2007
        • Poulin P.
        • Theil F.P.
        Prediction of pharmacokinetics prior to in vivo studies. 1. Mechanism-based prediction of volume of distribution.
        J. Pharm. Sci. 2002; 91: 129-156
        • Moody S.E.
        • Sarkisian C.J.
        • Hahn K.T.
        • et al.
        Conditional activation of Neu in the mammary epithelium of transgenic mice results in reversible pulmonary metastasis.
        Cancer Cell. 2002; 2: 451-461
        • Sebolt-Leopold J.S.
        • Dudley D.T.
        • Herrera R.
        • et al.
        Blockade of the MAP kinase pathway suppresses growth of colon tumors in vivo.
        Nat. Med. 1999; 5: 810-816
        • Houghton P.J.
        • Adamson P.C.
        • Blaney S.
        • et al.
        Testing of new agents in childhood cancer preclinical models.
        Clin. Cancer Res. 2002; 8: 3646-3657
        • Weiss W.A.
        • Aldape K.
        • Mohapatra G.
        • Feuerstein B.G.
        • Bishop J.M.
        Targeted expression of MYCN causes neuroblastoma in transgenic mice.
        EMBO J. 1997; 16: 2985-2995
        • Sharp R.
        • Recio J.A.
        • Jhappan C.
        • et al.
        Synergism between INK4a/ARF inactivation and aberrant HGF/SF signaling in rhabdomyosarcomagenesis.
        Nat. Med. 2002; 8: 1276-1280
        • Wetmore C.
        • Eberhart D.E.
        • Curran T.
        Loss of p53 but not ARF accelerates medulloblastoma in mice heterozygous for patched.
        Cancer Res. 2001; 61: 513-516
        • Mordenti J.
        Dosage regimen design for pharmaceutical studies conducted in animals.
        J. Pharm. Sci. 1986; 75: 852-857