Biomedical Engineering Reference
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adjusted to achieve optimum target inhibition. At least in principle, this appears to be
technically achievable.
7.2.4.5 Monitoring Signal Transduction Inhibitors in Solid Tumors
This is
muchmore challenging due to the difficulties in obtainingmultiple tissue samples and
then disaggregating these for flow cytometry measurements. With accessible lesions,
fine needle aspiration is an alternative to core or incisional biopsy that is less traumatic
and therefore easier to repeat at intervals during treatment. Tumor samples obtained
by fine needle aspiration are dispersed into single cells or small aggregates, and
therefore easier to process for flow cytometry. Alternatively, they can be analyzed
using slide-based cytometry, which has the advantages of allowing morphological
assessment of the cell population and requiring smaller samples. Schwock et al.
recently reported that this approach is technically feasible using human tumor
xenografts, and therefore likely also applicable to human clinical trials [29].
7.3 OTHER TARGETS AND APPLICATIONS
7.3.1 Drug Resistance Mechanisms
The biochemical basis for cellular resistance to anticancer chemotherapy is fairly well
understood in terms of alterations in drug uptake, metabolism, and the initiation of
DNA damage, although the subsequent responses that determine if cell death or
damage repair occurs remain an area of intense research. Although it is clear that drug
resistance is multifactorial and that the relative contribution of the various mechan-
isms differs among tumors, it is likely that some predominate in individual tumors.
Furthermore, the expression levels of some drug resistance mechanisms often
increase during drug exposure resulting in acquired drug resistance. Probably the
best characterized of these in the multidrug resistance (MDR) efflux is pump
P-glycoprotein (Pgp). This is a member of a large family of ATP-dependent
membrane transporters, and is able to actively transport several classes of chemotherapy
agents out of the cell [30, 31]. Examples include anthracyclines, vinca alkaloids, and
taxanes. Increased levels of Pgp occur during exposure to these agents in vitro,and
are implicated in drug resistance in the clinic.
7.3.1.1 P-Glycoprotein Inhibitors
In the 1980s it was recognized that Pgp-
mediated drug resistance could be overcome using pharmacological inhibitors, and
several of these were developed for testing in patients. Given that Pgp also appears to
play a role in protecting normal hematopoietic stem cells from chemotherapy effects
and that Pgp-like molecules are involved in the biliary excretion of some drugs,
combining Pgp inhibitors with chemotherapy has the potential to increase normal host
toxicity; hence, the need for functional markers to monitor pharmacodynamic effects
in patients.
Rubin et al. described an optimized flow cytometry protocol to monitor PD effects
of the potent Pgp inhibitor LY335979 (zosuquidar) that illustrates some important
general principles [32]. These authors exploited the high levels of Pgp expression seen
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