Enhancement of cyclophosphamide action
Russ.Chem.Bull., Int.Ed., Vol. 63, No. 5, May, 2014
1191
sume that enzyme inhibition by the formed nitrogen monꢀ
oxide in the first hours after drug administration signifiꢀ
cantly contributes to the enhancement of the chemotherꢀ
apeutic effect of cyclophosphan.
7. S. Mocellin, V. Bronte, D. Nitti, Med. Res. Rev., 2006,
7, 317.
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2. S. S. C. Tam, D. H. S. Lee, E. Y. Wang, D. G. Munree, C. Y.
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k poisku lekarstv [Nitrogen Oxide (NO). A New Way to Search
for Drugs], Vuzovskaya Kniga, Moscow, 2004, 357 pp.
2
8
9
(
The polyfunctional action of DHA•HNO is also
3
[
caused by the hydroxamate group. As already mentioned,
the mechanism of biological action of HAs is mainly reꢀ
lated to the chelation of metalloenzymes. The introducꢀ
tion of the hydroxamate fragment into a molecule of diꢀ
clofenac, which is an inhibitor of cyclooxygenase activity,
results in the appearance of the ability to inactivate the
peroxidase activity of prostaglandin H synthase. The latter
is an unusual enzyme with two types of catalytic activity:
cyclooxygenase (limiting the rate and substrateꢀspecific)
and peroxidase activities (similar to those of other perꢀ
oxidases and contains the heme in the active center). Both
activities can manifest themselves independently of each
1
1
1
(
in Russian).
1
4. Pat. RF 2295517; Byull. Izobr. [Invention Bulletin], 2007, 8
(in Russian).
other. The hydroxamate group of DHA•HNO forms
15. E. M. Treshchalina, O. S. Zhukova, G. K. Gerasimova, N. V.
3
complexes with heme iron of the peroxidase center and
thus prevents redox transformations in this center and the
Andronova, A. M. Garin, Rukovodstvo po eksperimental´nomu
(
doklinicheskomu) izucheniyu novykh farmakologicheskikh
veshchestv: Metodicheskie ukazaniya po izucheniyu protivoꢀ
opukholevoi aktivnosti farmakologicheskikh veshchestv [Guide
on Experimental (Preꢀclinical) Study of New Pharmacological
Substances: Methodical Indications on Studying Antitumor
Activity of Pharmacological Substances], Meditsina, Moscow,
formation of endoperoxide PGH , being a substrate for
2
the consequent enzymes of prostaglandin synthesis. Note
that the administration of hydroxamic acid and a nitro
compound to the mice with lympholeucosis Рꢀ388 resultꢀ
ed in a higher prolongation of the activity of cytochrome
2
005, 637 pp. (in Russian).
2
5
Рꢀ450 than that for the use of one nitrogen oxide donor.
16. M. E. Kudryavtsev, O. N. Dmitrieva, Z. V. Kuropteva, Izv.
Akad. Nauk, Ser. Biol. [Bull. Russ. Acad. Sci., Ser. Biol.],
1996, 453 (in Russian).
7. Eksperimental´naya otsenka protivoopukholevykh preparatov
v SSSR i SShA [Experimental Evaluation of Antitumor Drugs
in the USSR and USA], Ed. Z. P. Sofrina, A. B. Syrkin,
A. Goldin, A. Klein, Meditsina, Moscow, 1980, 293 pp.
Possibly, this is also related to the ability of HAs to chelate
metalloenzymes.
1
Thus, the data obtained in this work showed that the
efficiency of the antitumor action of cyclophosphan can be
enhanced by using it in a combination with compounds of
various mechanism of action. The temporal partial inhibiꢀ
tion of cytochrome Рꢀ450 by NOꢀdonating substances deꢀ
creases the toxicity of the cytostatic and prolongs its action.
The use of cyclophosphan with the hybrid NSAID (DHA•
(
in Russian).
1
8. D. B. Korman, Osnovy protivoopukholevoi khimioterapii [Funꢀ
damentals of Antitumor Chemotherapy], Prakticheskaya Medꢀ
itsina, Moscow, 2008, 503 pp. (in Russian).
•
HNO ), which is a polyfunctional inhibitor of several
19. K. W. Renton, Clin. Biochem., 1986, 19, 72.
3
2
2
0. S. M. Moochhala, Ann. Acad. Med. Singapore, 1991, 20, 13.
1. R. N. Harris, P. J. Basseches, P. L. Appel, A. M. Durski,
G. Powis, Cancer Chemother. Pharmacol., 1984, 12, 164.
2. D. A. Wink, Y. Osawa, J. F. Darbyshire, C. R. Jones, S. C.
Eshenauer, R. W. Nims, Arch. Biochem. Biophys., 1993,
300, 115.
types of activities, can result in the 100% healing of animals.
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6
Received October 31, 2013;
in revised form May 19, 2014
1