Biomedical Engineering Reference
In-Depth Information
in man. This is in line with the Critical Path Initiative of the U.S. Food and Drug Administration
(FDA) that aims at “translating basic scientii c discoveries more rapidly into new and better medi-
cal treatment by creating new tools to i nd answers about how the safety and effectiveness of new
medical products can be demonstrated in faster time frames, with more certainty, at lower cost and
with better information.” The agency is convinced that DDD programs will benei t from the avail-
ability of biomarkers, imaging methods being considered key enabling technologies. The FDA sees
an important role for biomarkers in providing proof-of-principle of a therapeutic intervention, for
stratii cation patient populations, and for the evaluation of therapy response or eventual side effects.
This enthusiasm has to be viewed in relation to the fact that currently only very few biomarkers are
accepted by the FDA as efi cacy readouts (see below), and the development of novel ones seems to
be a major undertaking. Aspects such as specii c versus generic biomarkers, validation, standard-
ization, biomarker proi le versus individual markers, and quantii cation have to be addressed.
As an example, we will discuss two biomarkers for studying the efi cacy of tumor therapy that
are in a fairly advanced stage of development. The measurement of glucose utilization rates via
[
18
F]-2-l uoro-2-deoxyglucose (FDG) PET has evolved as a sensitive diagnostic tool for the charac-
terization of primary tumors and for the detection of metastases. FDG is taken up by cells via the
glucose transporter and phosphorylated by hexokinase to yield FDG-6-phosphate (FDG-6P) and
trapped in the cell (Figure 7.7). The PET activity, hence, rel ects glucose transporter and hexokinase
activity and thus glycolytic activity of the tissue of interest. There is evidence from several clinical
CH
2
OPO
2
6
6
CH
2
OH
6
CH
2
OPO
2-
4
4
Hexokinase
Isomerase
O
O
5
5
4
5
O
HO
HO
OH
HO
1
1
OH
OH
HO
HO
2
2
HO
2
3
OH
3
OH
3
CH
2
OH
(a)
1
6
CH
2
OH
6
CH
2
OPO
2-
4
4
O
5
O
5
HO
HO
1
1
OH
HO
2
OH
HO
2
3
H
3
OH
(b)
6
CH
2
OH
6
CH
2
OPO
2-
4
4
O
5
O
5
HO
HO
1
OH
1
HO
2
OH
HO
2
3
18
F
3
18
F
(c)
FIGURE 7.7
Measurement of tissue glucose utilization using PET and 2-l uoro-2-deoxyglucose. The pri-
mary energy substrate glucose is taken up from the circulation via glucose transporters and is phosphory-
lated within the cells by hexokinase to yield glucose-6-phosphate. The next step in the metabolic cascade
is the isomerization to fructose-6-phosphate, which after further processing enters the citric acid cycle.
By using 2-deoxy-glucose (2DG) as substrate it could be demonstrated that uptake and phosphorylation
are identical as for glucose. Yet, isomerization is not possible due to the lack of the hydroxyl group in the
2-position, and 2DG-6-phosphate is trapped in the cell. Hence, the accumulation of 2DG-6-phosphate,
which is measured using autoradiographic techniques, is considered a surrogate for glucose utilization
by tissue. In the PET version of the 2DG assay the hydrogen at the 2-position is replaced by a l uorine-18
radionuclide (with half-life 110 min) yielding [
18
F]-2-l uoro-2-deoxyglucose (FDG). As glucose and FDG
are different compounds, the rate constants for enzymatic processing of the two substrates differ. This
is accounted for by correcting glucose utilization rates derived from FDG measurements using so-called
lumped constants.
