3. Umbruch 4.4..2005 - Online Pot

Potential use of cannabimimetics in the treatment of cancer 175
tions necessary to observe the tumor-suppressing effect [60]. Another
approach for the development of new anti-cancer drugs would be the use of
selective inhibitors of endocannabinoid degradation. These substances would
be devoid of most psychotropic effects as they would preferentially act in those
tissues where the levels of endocannabinoids are pathologically altered [87].
Another possible difficulty for the exploitation of (endo)cannabinoids
against cancer growth is their very low solubility in water and their poor biovailability
when given orally. It seems that Cannabis is more efficient when
smoked, but this administration route presents all the very well known and
unwelcome consequences [88]. A very promising alternative has been recently
proposed by GW Pharmaceuticals with Sativex ® ,a Cannabis extract containing
∆ 9 -THC and cannabidiol that is sprayed sublingually and is now undergoing
clinical trials [89]. Alternatively, the use of water-soluble cannabinoids
such as O-1057 might solve the solubility problems [90, 91], but to date the
intra-tumor application of low doses of cannabinoids seems to represent the
most viable option for those types of tumor that can be treated in this way, as
it results, in animal models, in few if any undesired ‘central’ effects. The safety
and efficacy of such type of administration of ∆ 9 -THC to treat glioma in
humans is currently being assessed in a pre-clinical study in Spain [45].
Probably the greatest advantage offered by the use of cannabimimetics over
other conventional anti-cancer agents might reside in their beneficial effects on
some serious cancer-related disorders in humans, as follows. (1) Cannabinoids
are anti-emetics in animal models of vomiting [92]. Marinol ® and Cesamet ® are
approved to treat nausea and emesis associated with cancer chemoterapy [93,
94]. Modern anti-emetics are selective serotonin 5-HT 3-receptor antagonists,
and, although cannabinoids can block 5-HT 3-receptors [95] they have a very
distinct pharmacological profile. Hence, further studies should be performed to
establish the mechanism of action and what types of cancer chemotherapies are
suitable to cannabinoid anti-emetic treatment [96–99]. It is interesting to note
that the potent TRPV1 agonist resiniferatoxin antagonizes cisplatin-induced
emesis in dogs [100]. (2) ∆ 9 -THC and other cannabinoids reinforce appetite and
increase food intake, seemingly via inhibition of anorexic signals [101–103].
Anorexia and cachexia are, in fact, primary problems in cancer patients.
However, a recent phase III trial has questioned the efficacy of oral ∆ 9 -THC
appetite-stimulating effects in advanced cancer [104]. (3) The neuromodulatory
actions of endocannabinoids in the central, sensory and autonomic nervous
systems result, mostly via CB 1 receptors, in the regulation of pain perception
[105]. Cannabinoids produce spinal, supra-spinal and central analgesia by suppressing
the activity of nociceptive circuits [106]. Peripheral CB 2 might mediate
local analgesia [107] and might be important for cancer pain [108]. At the
moment, cannabinoids seem to be no more potent than codeine (for a review
see [109]), but clinical trials on their use for the treatment of cancer pain are in
progress. Interestingly, the synergic actions of cannabinoid CB 1 receptor agonist
with opioid receptor agonists produces, in animal models, analgesic actions
stronger and longer-lasting (through the avoidance of the development of mor-