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[I've made a quick attempt at an appropriate new topic for this thread
- db]
Dear colleagues,
it appears that the consensus is that better models are required to
predict responses in tumour tissue (I'd like to focus on tumours in
this post). However, I'd like to throw in a few comments that may be of
interest (and possibly open another can of worms).
A number of you have commented on inter- and intra-tumour
heterogeneity. Obviously, this is an important issue in the clinic. One
feature of tumour physiology is the presence of hypoxic regions. This
is the result of their disorganized vasculature and has direct
consequences for perfusion and drugs reaching target cells (e.g.
hypoxic cells that are distant from blood vessels). In addition,
tumours exhibit fluctuating blood flow, which can lead to acute
(temporal) hypoxia, in contrast to chronic hypoxia. Acute hypoxia,
followed by reperfusion, is similar to ischaemia-reperfusion seen in
other (patho)physiological conditions. In other words, even with
similar plasma PK, tumour concentrations of any given drug will be
different within the same tumour and between tumours. For example, when
radiating tumours in mice the stress that the animals experience can
have profound effects on tumour blood flow ("steal effect") and
actually increase the level of hypoxia, which leads to a demonstrable
reduction in the radiation effect. NB in this context I use oxygen and
radiation as if they were "drugs" with their own corresponding
"efficacy". Nevertheless, they are excellent examples of tumour
heterogeneity, spatial and temporal.
Tumour hypoxia has many profound effects on the responsiveness of
tumour cells to drugs. For example, cell proliferation is decreased
(which attenuates the action of drugs that rely on cell proliferation),
p53 status has changed (which is anti-apoptotic), certain resistance
genes (e.g. for Pgp) are upregulated by hypoxia. In addition, hypoxia
selects for a more aggressive phenotype, increases mutation rates,
increases expression of genes associated with angiogenesis and tumour
invasion, and is associated with a more metastatic phenotype of human
cancers (this is taken from the reference below). Different metastases,
despite from the same primary tumour, may have a different makeup as
they have different clonogenic origin and consequently different
vascularisation (also depending of the site of metastasis) as well as
different intrinsic sensitivity to chemo- and/or radiotherapy.
As I discussed in a recent post we have developed a spatially
distributed PK/PD model that predicts tumour response with the plasma
PK as one of the input parameters. Without knowing the tumour PK at the
macro- and microscopic level this is a way forward and one that works
well in our situation. The model is complex also because it must take
into account the drug diffusion within the extravascular tumour
compartment.
Here is the reference mentioned above, which I highly recommend to
anybody working in the cancer field (and because it has been
co-authored by my boss ;-) ):
Brown JM. Wilson WR. Exploiting tumour hypoxia in cancer treatment.
Nature Reviews. Cancer. 4(6):437-47, 2004 Jun.
HTH
Frederik
--
Frederik B. Pruijn PhD MSc (Senior Research Fellow)
Experimental Oncology Group
Auckland Cancer Society Research Centre
Faculty of Medical and Health Sciences
The University of Auckland
Private Bag 92019
Auckland
New Zealand
Phone: +64-9-3737 599 x86939 or x86090
Fax: +64-9-3737 571
E-mail: f.pruijn.-at-.auckland.ac.nz
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