Abstract
Human tumour xenografts implanted subcutaneously (s.c.) into immunosuppressed mice
have played a significant role in preclinical anticancer drug development for the
past 25 years. Their use as a predictive indicator of probable clinical activity has
been validated for cytotoxics. A retrospective analysis for 39 compounds where both
extensive xenograft testing and Phase II clinical data were available, performed by
the National Cancer Institute (NCI), has shown that 15/33 agents (45%) with activity
in more than one-third of xenografts showed clinical activity (P=0.04). However, with the exception of non-small cell lung cancer, activity within
a particular histological type of the xenograft generally did not predict for clinical
activity in the same tumour. Today, the question (largely unanswered) is how useful
is the xenograft model (particularly the traditional s.c. model) in contemporary cancer
drug discovery? There are many variables when conducting xenograft experiments which
impact on outcome; viz, site of implantation, growth properties of the xenograft and
size when treatment is initiated, agent formulation, scheduling, route of administration
and dose and the selected endpoint for assessing activity. The xenograft model remains
of value in current preclinical cancer drug development, especially when such studies
give due consideration to the above variables and are based on sound mechanistic (e.g.
status of the selected target in the chosen model) and pharmacological (e.g. use of
formulated agent) principles. Dependent upon the drug target, a slowing of xenograft
tumour growth (cytostatic effect) rather than tumour shrinkage might be the major
observed effect. Human tumour xenografts are also particularly useful in determining
pharmacodynamic markers of response for subsequent clinical application. Nevertheless,
it needs to be kept in mind that the use of xenografts is relatively time-consuming
and expensive, raises animal ethical issues and there are instances where the model
is inappropriate as a likely predictor of clinical outcome (e.g. inhibitors of the
metastatic process and anti-angiogenic strategies as the vasculature is of murine
origin).
Keywords
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Article info
Publication history
Accepted:
November 16,
2003
Received:
August 22,
2003
Identification
Copyright
© 2004 Elsevier Ltd. Published by Elsevier Inc. All rights reserved.
