You also want an ePaper? Increase the reach of your titles
YUMPU automatically turns print PDFs into web optimized ePapers that Google loves.
NORMOLIFE<br />
Development of new therapeutic<br />
substances and strategies<br />
for treatment of pain in patients<br />
with advanced stages of cancer<br />
Summary<br />
Keywords | <strong>Cancer</strong> pain | analgesic medicines | pain pharmacology |<br />
Prolonging the life expectation of patients with advanced<br />
cancer could be done by modern medicine. However, progressive<br />
pain that is associated with progression of the<br />
disease is the major factor that destructs the last moments<br />
of life. Severe progressive and uncontrolled pain is a major<br />
reason of requesting euthanasia. The applications of oral<br />
(morphine) pills or transdermal patches with lipophilic<br />
analgesic drugs are the most common treatments of cancer<br />
pain. These compounds penetrating into central nervous<br />
system produce side eff ects (respiratory depression, constipation,<br />
tolerance, sedation, etc.) to such extent that pain<br />
treatment is reduced by doctors or refused by the patients.<br />
The discoveries of the last years indicated the changes in<br />
expressions of pro- and antinociceptive receptors in pathologically<br />
changed peripheral tissues as well as in the central<br />
nervous system. The concerted modulation of these receptors<br />
in combination with designed receptor ligands may<br />
block nociceptive signal formation and transmission more<br />
eff ectively than traditional monotherapies. The objective<br />
of this project is to focus on the development of new multitarget<br />
compounds and methods which will interact with<br />
opioid receptors expressed in infl amed and/or pathologically<br />
modifi ed tissues. Partial penetration into the central<br />
nervous system will result in synergistic pain suppression<br />
via interaction between the peripheral and central nervous<br />
system. Alternatively, newly developed compounds could<br />
be applied directly into central nervous system to interact<br />
with the specifi c, pathological set of receptors. The developed<br />
compounds will be screened in vitro in a cell silicon<br />
hybrid biosensor and selected compounds, in vivo in<br />
rodent’s cancer pain models. The project will yield new<br />
basic data on structural requirements of analgesics for<br />
treatment of persistent cancer pain in advanced stages<br />
and will develop new compounds characterized to the<br />
stage that will allow to promote them for further clinical<br />
phase testing.<br />
Problem<br />
The approach in which compounds are designed to interact<br />
with a wide spectrum of targets involved in pain signal formation<br />
and transmission is a new and original therapeutic<br />
strategy, opposite to current strategies that use drugs which<br />
are as receptor-selective as possible. The project’s major<br />
goal is chemical design of new multitarget molecules and<br />
analysis of their pharmacological properties that will result<br />
in the selection of several new compounds for further clinical<br />
evaluation as a new generation of potent analgesics for<br />
multicomponent cancer pain treatment.<br />
Aim<br />
The project will involve three general complementary scientifi<br />
c objectives: chemistry, in vitro biopharmacology and<br />
in vivo pharmacology that will be accomplished by multidisciplinary<br />
teams integrated in the project.<br />
Synthesis of new compounds, designed by theoretical<br />
(SAR) analysis, will be synthesized in chemical laboratories.<br />
Hundred new compounds will be designed and<br />
synthesized on initial stages of the project. These compounds<br />
will be preselected in in vitro tests. The in vitro<br />
tests comprise receptor affi nity evaluation and functional<br />
cell-based assays. The selected (expected 6) compounds<br />
will be fi nally characterized in vivo in an animal model of<br />
cancer pain.<br />
Expected results<br />
The application of a new generation of medicines designed<br />
under the NORMOLIFE project will reduce side eff ects generated<br />
by traditional opioids in central nervous system,<br />
including tolerance, dependence, constipation, euphoria,<br />
etc. The major prospective application of the results will be<br />
a more eff ective treatment of acute as well as chronic, neuropathic<br />
and infl ammatory cancer pain of patients with<br />
advanced stages of the disease. We predict that the project<br />
will be able also to defi ne the diff erences between the spectrum<br />
of pain symptoms and pain progression in progressive<br />
cancer typical for female (ovarian) and male (prostate)<br />
patients. The establishment of such diff erences will help to<br />
propose diff erent pain treatment for women and men.<br />
Potential applications<br />
The experimental preclinical data of the newly-developed<br />
compounds will allow for selection and proposition of new<br />
medicines for further clinical evaluation.<br />
240 CANCER RESEARCH PROJECTS FUNDED UNDER THE SIXTH FRAMEWORK PROGRAMME
Change language