3. Umbruch 4.4..2005 - Online Pot

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human glioma cell lines [74–76], and inhibits the growth of human glioma
cells subcutaneously implanted in nude mice [76] as well as of human acute
myeloid leukaemia [77], in both cases through induction of apoptosis.
Cannabigerol inhibits the growth of human oral epitheloid carcinoma cells
[78]. The synthetic ajulemic acid (CT3), inhibits glioma cells in vitro and in
vivo [79] and induces apoptosis in human T lymphocytes [80], although the
lack of activity of this compound at CB 1 receptors is still a matter of controversy.
The molecular mechanisms for the anti-cancer effects of most of these
compounds are not yet understood, and are currently under investigation in our
laboratories. TRPV1 receptors, however, do not seem to be involved in the
inhibitory effect of cannabidiol against glioma [76].
Substances targeting the endocannabinoid system in cancer therapy –
pros and cons
The anti-tumor potential of substances that modulate the activity of cannabinoid
receptors or the levels of endocannabinoids, as well as of other possible
targets for the anti-cancer action of these compounds, are still largely unexplored.
It seems that cannabinoids selectively affect tumor cells but not their
non-transformed counterparts and might even protect the latter from cell death
(see above). For example, cannabinoids induce apoptosis of glioma cells in
culture [38, 42, 74, 81], but, by contrast, they protect glial cells from apoptosis
[82, 83], possibly due to a differential ability to synthesize ceramide [81].
Indeed, a general protective role of the endocannabinoid system is emerging
from several recent studies (for a recent review see [84]). Cannabinoids appear
to be well tolerated in animal studies and do not produce the generalized toxic
effects in normal tissues that are a major limitation of most conventional
agents used in chemotherapy, the median lethal dose of ∆ 9 -THC in animals
being of several grams per kilogram of body weight [85]. However, together
with obvious social, political and legal considerations, the therapeutic application
of agonists selective for CB 1 receptors might be limited by the undesired
psychotropic side effects expected from the stimulation of these receptors in
the brain (even though some ‘central’ actions of CB 1 activation may be,
instead, desirable, as discussed below). On the other hand, although devoid of
psychotropic actions, the administration of compounds selective for the CB 2
receptor, as in the treatment of gliomas, skin carcinomas and lymphomas,
might cause the immune-suppressive effects typical of ∆ 9 -THC, and this would
then play against the organism’s own defense against tumor growth. Yet selective
CB 2 receptor agonists appear to be nowadays very efficacious against
some types of pain [86], which could represent an additional benefit of
anti-cancer drugs derived from these compounds. The limitations at least of
CB 1-selective agonists might be overcome by the use of metabolically stable
endocannabinoid analogs in combination with a non-psychotropic substance
like palmitoylethanolamide, which might lower the threshold of concentra-