Visit our Expo - Redox and Inflammation signaling 2012

Alkylating drugs applied in non-cytotoxic doses as a novel compounds targeting
inflammatory signal pathways
Alexander L. Pukhalsky, Galina V. Shmarina, Vladimir A. Alioshkin and Alex
Sabelnikov
Research Centre for Medical Genetics, Moscow 115478, Gabrichevsky Institute of
Epidemilogy and Microbilogy, Moscow 125212, Russia, East Carolina University,
Greenvill, NC 27858, U.S.A. E-mail: osugariver@medgen.ru
Alkylating drugs (ADs) belonging to the nitrogen mustard family are commonly used as
cytostatic and immunosuppressive agents. Our recent in vitro studies demonstrated that in the
case of gradual dose decrease, the number of targets for alkylation in the cell is also reduced
and the drug switches from crucial cytostatic to cell growth modifier. At doses of 0.3 mkg/ml
and lower, the effects of ADs are no longer associated with DNA damage or altered cytokine
production. Instead, the disruption of signal transduction by the IL-2beta and/or TNF-alpha
cell surface receptors is observed. As a result ADs in the doses 100-fold lower than cytostatic
ones are capable to modify lymphocyte activity including the activity of regulatory T cells.
We hypothesized that ADs may have a beneficial effect in the treatment of inflammatory
diseases. Indeed, the application of non-cytotoxic doses of an AD melphalan (MP) reduces
the severity of murine experimental colitis induced by the replacement of drinking water with
5% solution of dextran sulphate sodium (DSS). Daily administration of MP (0.025 mg/kg
body weight) markedly reduced the severity of DSS-colitis as determined by clinical and
quantitative histological criteria. Moreover, the beneficial effect of MP was also shown in
asthmatic patients. Forty-two patients with moderate and severe asthma were enrolled in
randomized placebo-controlled trial: 21 patients were treated with MP (5 daily inhalation of
the drug in the dose of 0.1 mg) and 21 subjects were inhaled with placebo. Improvement of
exercise tolerance as well as a marked reduction of exacerbation severity and requirement for
inhaled beta2-agonists has been found in MP-treated patients. In 60% of these patients
histological and ultrastructural signs of bronchial epithelium regeneration were also revealed.
Thus, ADs at non-cytotoxic concentrations exert beneficial effect both in acute and chronic
inflammatory diseases. Such anti-inflammatory activity is thought to be due to blocking of
signal transduction through various cytokine surface receptors. Consequently, different steps
of inflammatory cascade turn up inhibited.
List of publications
1. Toptygina AP, Pulhalsky AL, Alioshkin VA. Immunoglobulin G subclass profile of antmeasles
response in vaccinated children and in adults with measles history. Clin Diagn Lab
Immunol, 2005; 12: 845-847.
2. Pukhalsky AL, Shmarina GV, Kapranov NI, Kokarovtseva SN, Pukhalskaya DA,
Kashirskaja NJ Anti-inflammatory and immunomodulating effects of clarithromycin in
patients with cystic fibrosis lung disease. Med Inflam 2004; 13:111-117.
3. Pukhalsky AL, Shmarina GV, Bliakher MS, Fedorova IN, Toptygina AP, Fisenko JJ,
Alioshkin VA Cytokine profile after rubella vaccine inoculation: evidence of
immunosuppressive effect of vaccination. Med Inflam 2003, 12(4): 203-207.
4. Sokolov EI, Pukhalsky AL, Tsyplenkova VG, Shevelev VI. Inhalation of ultra-low
doses of alkylating drugs in the treatment of asthma. Pulmonology 2002; 12(3):82-88
(Russian).
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