02 BOOK OF ABSTRACTS .indd

Effect of immunomodulator biological response modifiers
on murine tumors and metastases
T. A. Korolenko 1 , T. V. Alexeenko 1 , S. Ya. Zhanaeva 1 , A. A. Venediktova, G. Kogan 2 ,
N. N. Besednova 3 , T. A. Kuznetzova 3 , T. N. Zviagintzeva 3 , V. I. Kaledin 4
1
Institute of Physiology RAMS, Novosibirsk, 630099, Russia; 2 Institute of Chemistry, Slovak
Academy of Sciences, Bratislava, Slovakia; 3 Institute of Epidemiology and Microbiology RAMS,
Vladivostok, 690087, Russia; 4 Institute of Cytology and Genetics RAS, Novosibirsk, 630090, Russia
Increased expression, activity and secretion of cysteine, aspartic, metallo- and serine
proteases by tumor cells was shown to connect with tumor growth, invasion and
metastases formation. Biological response modifiers, increasing the host resistance
mechanisms, are perspective in tumor treatment and prevention. The aim: to
study effect of macrophage (Mph) stimulators with different terminal groups and
interaction with Mph glucan or/and fucose receptors in antitumor treatment using
cysteine proteases and their endogenous inhibitor cystatin C as possible markers
of prognosis and efficacy of antitumor therapy. Water-soluble chemically modified
β-1,3-glucans (Institute of Chemistry, Slovak Academy of Sciences, Bratislava) and
polysaccharide fucoidan (Institute of Epidemiology and Microbiology RAMS, Vladivostok,
Russia) have been used. Cathepsins B, L activity and cystatin C concentration (KRKA,
Slovenia) were determined as described (Khalikova et al., 2005). β-1,3-glucans were
shown to increase the positive therapeutic effect of cyclophosphamide (CPA), but did
not reveal antitumor activity themselves (without CPA). Murine tumors (HA-1 hepatoma,
lymphosarcoma LS, Lewis lung carcinoma) were characterized by drastically decreased
cystatin C concentration in tumor cells with significant restoration of cystatin C level in
tumor cells and serum after effective antitumor therapy by CPA or/and β-1,3-glucans.
Cystatin C concentration in tumor tissue and serum can be used as an index of
prognosis of tumor development and efficacy of antitumor therapy. β-1,3-D-glucans are
internalized after binding to specific β-glucan (also to scavenger and dectin) receptors
on Mph and reduced internalization can be responsible for down regulation of
Il-11 and TNF-β secretion (and apoptosis). Fucoidan (alone) was shown to
suppress significantly tumor growth rate and metastases into lung in mice
with Lewis lung carcinoma and did not influence in combination with CPA
(10-100 mg/kg). The most effective was scheme with isolated repeated administration
of small dose of fucoidan (5 mg/kg, 3 times). Fucoidan (5 and 10 mg/kg) decreased
cathepsin L activity (three times) in tumor tissue, but did not change cathepsin B
and D activity, as compare to untreated tumor. Similar results (except cathepsin D)
were obtained in mice treated by combination of CPA + fucoidan. One can conclude
that polysaccharide fucoidan in small repeated doses revealed strong antitumor and
antimetastatic activity acting, possibly, directly on tumor cells and monitoring of tumor
cysteine proteases is useful in control of the efficacy of therapy.
88p17
Supported by INTAS grant 02-0592 and Innovation Grant of Siberian Branch of RAMS,
2005-2006.
References: Khalikova T.A., Zhanaeva S.Ya., Korolenko T.A. et al. Cancer Letters, 223
(2005) 77-83