|
|
|
|
|
 |
|
- (Profs. A. Gescher and
W.P. Steward with Drs. T.
Marczylo, R.A.
Sharma, H. Cai,
- D.
Boocock, R.
Tunstall and R.D. Verschoyle)
|
|
|
|
 - CBPG laboratory in the Department of
Oncology
|
|
- In
parallel with the molecular studies, agents undergo preclinical
evaluation in tissue fractions in vitro and in model systems in
vivo. Levels of agent and metabolites are measured in blood,
tissues and excreta, to determine bioavailability and establish the
relationship between pharmacokinetics and dose.
Such information is important in determining the dose range
for clinical trial. The metabolic fate of the agent can be determined
along with its capacity to alter the drug metabolising profile of the target tissue.
The biological activities defined in cell culture are studied in
target organs after administration of agents in vivo, to determine
which are physiologically relevant and which are most useful as
biomarkers of chemopreventive efficacy. To avoid long and costly trials it is essential to develop such surrogate
endpoint biomarkers to confidently predict chemopreventive outcome at an
early stage. Preclinical studies are also important to establish doses which
can be administered safely to patients over long periods of time.
|
|
|
|
|
|
|
|
 |
|
-
-
Even though many putative chemopreventive agents are dietary constituents,
which may have been consumed for hundreds of years, there is
substantial uncertainty regarding the potential for toxicity when
administered as a purified product or clearly defined mixture.
Initially
those already diagnosed with cancer or at particularly high risk,
represent suitable candidates for recruitment to trials.
Agents such as curcumin, resveratrol, genistein,
indole-3-carbinol (I3C) or the brown rice constituent tricin also
possess antiproliferative activity in tumour model systems, so that
pharmacokinetically and pharmacodynamically guided phase I
dose-defining studies can be performed in patients with cancer, thus
obtaining endpoints relevant to chemoprevention as well as detecting
potential anticancer activity. Within the next five years, the diet-derived
substances, curcumin, resveratrol and perhaps tricin will be thoroughly
investigated in this way.
|
|
|
|
|
|
|
- The
final objective of the programme is to take suitable agents into the
clinic. All the preclinical data are used to determine the most suitable target
organ for cancer prevention, set dosing schedules and choice of
biomarkers. Small scale pilot studies are undertaken to detect
potential toxicities, establish a dose and treatment schedule which
is safe and effective, and to verify appropriate biomarkers of
efficacy. This information will contribute to the design of further phase II and
III trials.
- Since
cancer chemopreventive agents are designed for use in healthy
individuals to prevent them from developing cancer, safety is a
prime consideration.
|
|
|
|
