3+ 4/2002 - Společnost pro pojivové tkáně

ny. After many years of endeavor compounds
were tested by a drug company.
After many years of endeavour the compound
named STI 571 was identified that
appeared to have the desired effect. Today,
after some 3 years of clinical trials, STI 571
appears to induce complete remission in
almost every patient with CML, even at
advanced stages of the disease. There may
even be hope for cure. What lessons does
this story teach us? First, painstaking basic
research is a prerequisite of any progress.
This can best be done by academic
researchers who are free to choose their
projects. Second, drug development
requires enormous resources that are only
available to the industry. Imagination, discipline
and hard core targeting is also
required. Third, to get from gene discovery
to therapy takes a long time. Fourth, the
example shows that the scenario is possibble.
It should start happening more often.
My second example highlights the need
of open – mindedness and imagination.
Another leukemia, acute promyelocytic
leukemia /APLú is often curable today
through the combined use of trans –
retinoic acid and chemotherapy. The disease
occurs as a result of the fusion of the
APL gene with the retinoic acid receptor
alpha – gene. So one might think that the
story resembles that of CML,the knowledge
of the molecular event (in this case one
interfering with the uptake of retinoic acid
hinting that treatment with retinoic acid
may be usefull. Not at all ! Treatment of APL
with retinoic acid preceded the molecular
genetic findings. It was part of Chinese folk
medicine. Imagination, open mindedness
and keen clinical observation are essential.
How about the relatively recently detected
genes that confer susceptibility to common
cancers? BRC and BRCA 2 have been
122
known for approximately 7 years. Their
diagnostic implications are of course huge
in affected families, and testing for mutations
probably leads to better risk awareness
and saved lives. Like in other cancers
showing Mendelian inheritance, a major
benefit is to those at-risk family members
who are found too be mutation negative.
But unfortunately, the BRCA genes have not
yet provided real breakthrougs in our
understanding of pathogenetic mechanisms.
Curative, non-cytotoxic drugs are
but a dream. Colorectal cancer looks somewhat
brighter. Here the mismatch defect
caused by mutations in several genes
occurs not only in the main Mendelian
form of colorectal cancer (HNPCC) but also
in a sizeable proportion (up to 20 %) of sporadic
cancers.These mismatch – repair deficient
colorectal cancer patients have a better
prognosis than others. The basis of this
fenomenon is not yet understood: however,
epigenetic fenomena (methylation, loss of
imprinting) seem to play a role. This gives
hope that drugs and/or procedures may be
forthcoming that interfere with these cancers.
Already mismatch repair deficiency, as
defined by microsatellite instability, is a tool
in the large scale nolecular screening for
HNPCC which in turn facilitates life-saving
clinical surveillance.
In summary, the detection of cancer
related genes is beginning to impact the
clinical handling of subsets of many cancers,
but the road from gene to therapy and
prevention is slow and unpredictable.
GAINS AND LOSSES IN SKULL AND
LIMB DEVELOPMENT
A. Wilkie, Oxford
LOCOMOTOR SYSTEM vol. 9, 2002, No. 3+4
In the diagnosis of syndromes, malformations
of the skull and limbs frequently