malignant tumors are a major reason of the enhancement of the disability and mortality rates . according to the world health organization data , there were an estimated 12.4 million new cases of cancer worldwide in 2008 and 7.6 million deaths caused by the disease ( boyle and levin 2008 ) . the available methods at the present for the treatment of tumors are not sufficiently effective . the surgical removal of tumors is not always possible since only a small percentage of onco - patients could be operated and that the risk of postoperative complications is high . chemotherapy is a palliative method of treatment that promotes short - term relief but does not lead to complete recovery . in addition , it is toxic and causes serious violations in the work of many organs , including liver and heart . in this regard , there is a need to develop alternative methods of tumor treatment and to find new substances , which act locally in tumor , causing its destruction . one of the mechanisms of such destruction is the simulation of tumor cells death by necrosis or apoptosis with preserving of normal cell viability . biologically active non - toxic c60 fullerenes ( andrievsky et al . 2005 ; prylutska et al . 2007 ; johnston et al . 2010 ) , which are able to penetrate through the membrane of cells ( foley et al . 2002 ) and have strong antioxidant and antiviral properties ( prylutska et al . 2008 ; cataldo and da ros 2008 ) , could be used for preventing the growth of malignant neoplasms . in fact , some fullerene derivatives have shown promising anticancer or antitumor activity ( freitas 2003 ) . namely , murugesan et al . ( 2007 ) have demonstrated the substantial anti - angiogenic activity of carbon materials such as graphite , multi - walled carbon nanotubes , and c60 fullerenes against either basic fibroblast growth factor- or vascular endothelial growth factor - induced angiogenesis in the chick chorioallantoic membrane model . it is known that an imbalance in the levels of these factors causes many serious diseases including malignant cell growth ( carmeliet 2005 ) . 2010 ) have reported that fullerene derivatives are capable to regulate in low levels simultaneously more than ten angiogenic factors in the mrna level that is further confirmed at the protein level . this result indicates that fullerene - containing materials serve as a potent antiangiogenesis inhibitor that can simultaneously target multiple angiogenic factors . ( 2008 , 2009 ) found that metallofullerene nanoparticles penetrate plasma membrane of tumor cells , effectively inhibit their proliferation , and decrease the activities of those enzymes which are responsible for catalyzing the production of reactive oxygen species in vivo . considering the importance of using fullerenes for the cancer treatment , the purpose of this work was mainly focused on investigating the influence of pristine ( unmodified ) water - soluble c60 fullerenes on the rate of growth of transplanted malignant tumors . the c60 fullerene aqueous solutions ( c60fas ) used for the experiments were prepared as follows ( scharff et al . 2004 ) : a saturated solution of c60 fullerenes ( purity 99.5% ) in toluene was mixed with the same amount of distilled water and the resulted two - phase system was ultrasonicated until the completion of the toluene evaporation . afterwards , the yellow - colored water phase was filtered for removing the c60 fullerenes which were not dissolved . c60fas samples with concentrations of c60 fullerenes in water in the range from 0.1 to 1.0  mg / ml were prepared . the c60fas samples were found to be stable for about 18  months at 4c . theoretical calculations ( prilutsky et al . 1999 ; bulavin et al . 2000 ) showed that c60fas contains both single c60 molecules and their clusters ( with sizes of about 0.74  nm depending of c60 fullerene concentration ) in the hydrated state . moreover , c60 fullerenes structure the water , absorbed by dna molecules ( turov et al . 2010 ) , and thus they can affect the dna functioning in the biosystem . the state of c60 fullerenes in water was examined by using stm technique ( nt - mdt , russia ) . it is important to note that used c60fas does not show a cytotoxic effect with respect to both normal and transformed cells at concentrations below 1.0  mg / ml ( prylutska et al . 2007 ) . the male mice of c57bl/6j line ( 2021  g weight ) were kept in a vivarium on a standard diet . we have to mention that in all experiments performed in the present work , we followed the international principles of european convention for protection of vertebrate animals . tumor transplantation ( lewis lung carcinoma ) was performed by intramuscular injection to the animal s limb ( initial number of tumor cells was equal to 5    10 ; antitumor effect ) or to the pad of animal s limb ( initial number of tumor cells was equal to 1    10 ; antimetastatic effect ) . as is known , the strain of this tumor is characterized by a high degree of lung metastases damage . the c60fas in the volume of 0.1  ml ( the initial concentration of c60 fullerenes in water was 1.0  mg / ml ) was injected intraperitoneal to the animals before the transplantation of tumor ( group 1 ; protective effect ) one time for 5  days with interval through a day . injection of c60fas ( 0.1  ml ) in group 2 ( inhibitive effect ) was started in a day after the transplantation of tumor , which visually appeared on the 10th day . the c60fas was injected one time for 5  days with interval through a day given the fact that c60 fullerenes , introduced intraperitoneal to rats ( dose 500  mg / kg ) , are excreted from the body within 24  days ( gharbi et al . finally , group 0 ( mice with transplanted tumor without c60fas injection ) was used as control . the initial number of animals in each group was 5 in experiment 1 , 7 in experiment 2 ( antitumor effect ) and also 7 in experiment 3 ( antimetastatic effect ) . on the 20th day of experiment 3 , all animals were put to death for the purpose of calculating the number of metastases in the lung of each animal . it is also important to note that these experiments were started in different time periods : experiment 1middle of autumn 2010 ; experiment 2end of winter 2011 ; and experiment 3end of spring 2011 . the antitumor effectiveness of the applied technique was estimated by following quantitative indicators : tumor growth inhibition ( tgi , percent ) : \documentclass[12pt]{minimal } 
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				 \begin{document}$$ k_i^{\text{tgi } } = \frac{{{v_0 } - { v_i}}}{{{v_0 } } } \cdot 100\% $ $ \end{document } , where v0 and vi are the average values of tumor volume in animals of group 0 ( control ) and experimental group i , respectively ; \documentclass[12pt]{minimal } 
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				 \begin{document}$$ v = \frac{{{{(a + b)}^3}}}{{16 } } $ $ \end{document } , where a and b are the length and width ( in millimeters ) of the tumor site;increasing of animal life ( ial , percent ) : \documentclass[12pt]{minimal } 
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				 \begin{document}$$ k_i^{\text{ial } } = \frac{{{t_i } - { t_0}}}{{{t_0 } } } \cdot 100\% $ $ \end{document } , where t0 and ti are the average life span of animals ( in days ) in group 0 ( control ) and experimental group i , respectively;survival of animals of experimental group i compared with control ( \documentclass[12pt]{minimal } 
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				 \begin{document}$$ k_i^{\text{sa } } $ $ \end{document } , percent);metastasis inhibition index ( mii , percent ) : \documentclass[12pt]{minimal } 
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				 \begin{document}$$ k_1^{\text{mii } } = \frac{{{a_0 } \cdot { b_0 } - { a_1 } \cdot { b_1}}}{{{a_0 } \cdot { b_0 } } } \cdot 100\% $ $ \end{document } , where a0 and a1 are frequency of metastasis in the group 0 ( control ) and experimental group 1 , respectively ; b0 and b1 are the average number of metastases in certain organ of animals in group 0 ( control ) and experimental group 1 , respectively . tumor growth inhibition ( tgi , percent ) : \documentclass[12pt]{minimal } 
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				 \begin{document}$$ k_i^{\text{tgi } } = \frac{{{v_0 } - { v_i}}}{{{v_0 } } } \cdot 100\% $ $ \end{document } , where v0 and vi are the average values of tumor volume in animals of group 0 ( control ) and experimental group i , respectively ; \documentclass[12pt]{minimal } 
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				 \begin{document}$$ v = \frac{{{{(a + b)}^3}}}{{16 } } $ $ \end{document } , where a and b are the length and width ( in millimeters ) of the tumor site ; increasing of animal life ( ial , percent ) : \documentclass[12pt]{minimal } 
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				 \begin{document}$$ k_i^{\text{ial } } = \frac{{{t_i } - { t_0}}}{{{t_0 } } } \cdot 100\% $ $ \end{document } , where t0 and ti are the average life span of animals ( in days ) in group 0 ( control ) and experimental group i , respectively ; survival of animals of experimental group i compared with control ( \documentclass[12pt]{minimal } 
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				 \begin{document}$$ k_i^{\text{sa } } $ $ \end{document } , percent ) ; metastasis inhibition index ( mii , percent ) : \documentclass[12pt]{minimal } 
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				 \begin{document}$$ k_1^{\text{mii } } = \frac{{{a_0 } \cdot { b_0 } - { a_1 } \cdot { b_1}}}{{{a_0 } \cdot { b_0 } } } \cdot 100\% $ $ \end{document } , where a0 and a1 are frequency of metastasis in the group 0 ( control ) and experimental group 1 , respectively ; b0 and b1 are the average number of metastases in certain organ of animals in group 0 ( control ) and experimental group 1 , respectively . within the histological studies , the tumor was fixed in 4% paraformaldehyde solution in phosphate buffer ph  7.4 , dehydrated in alcohols of increasing concentration and poured in paraplast of u.s . the microscopic sections ( thickness of 5  m ) were obtained using the rotary microtome ( leaica rm 21225 rt , germany ) and colored by erlich hematoxylin and eosin . these sections were studied using the light optical microscope ( olympus bx51 , japan ) . the average number of mitotic and apoptotic cells , and the mitotic and apoptotic indices were determined by counting ten regions of view ( each of them contained 500 cells ) with magnification 400. the percentage of area occupied by necrosis was estimated using the  olympus dp - soft  morphometric software . the statistical analysis of obtained results was performed using statistica software package including numerical methods ( gubler 1978 ) . the stm images of submonolayer c60 fullerene film deposited from aqueous solution ( c60 fullerene concentration in water was 1.0  mg / ml ) on au(111 ) surface are shown in fig .  1 . the images reveal almost random arrangement of c60 fullerene clusters with sizes up to 2.8  nm ( the first stable sphere - like cluster consisting of 13 hydrated c60 fullerenes ( prilutsky et al . 1999 ; bulavin et al . 2000 ) ( fig . despite the high mobility of c60 molecules on au(111 ) at the room temperature , images of single c60 molecules were also made ( fig . 1b).fig . 1 
 a large - scale stm image of submonolayer c60 fullerene film deposited from aqueous solution ( c60 fullerene concentration in water was 1  mg / ml ) on au(111 ) surface . some c60 fullerene clusters are aligned along preferential direction < 112>. b single c60 fullerenes . inset : cross - section along line ab . scanning parameters : i 
 t  =  40  pa , u 
 t  =  0.7  v 
 a large - scale stm image of submonolayer c60 fullerene film deposited from aqueous solution ( c60 fullerene concentration in water was 1  mg / ml ) on au(111 ) surface . some c60 fullerene clusters are aligned along preferential direction < 112>. b single c60 fullerenes . inset : cross - section along line ab . scanning parameters : i 
 t  =  40  pa , u 
 t  =  0.7  v the results extracted from experiment 1 ( antitumor effect ) are presented in table  1 . antitumor effect of c60 fullerenes was recorded on the 15th day after transplantation of tumor in group 1 ( protective effect ; 25th day after the introduction of c60 fullerenes ) and in group 2 ( inhibitive effect ) . inhibition of tumor growth in group 1 shows a tendency to decrease from 17.0% ( 15th day ) to 3.1% ( 25th day after tumor transplantation ) . inhibition of tumor growth in group 2 increased from 30.0% ( 15th day ) , reached a maximum of 37.2% ( 18th day ) and then decreased to 16.0% ( 25th day after tumor transplantation ) . the last animal in the control group 0 died on the 32th day of the experiment . the survival of animals in groups 1 and 2 was 20.0% and 40.0% , respectively , compared to the control . finally , the life duration for last animal in group 1 ( protective effect ) and group 2 ( inhibitive effect ) ( 38  days ) was about 1.2 times higher compared to the control ( 31  days).table 1experiment 1 ( antitumor effect)number of days after tumor transplantationgroup 0 ( control)group 1 ( injection of c60fas before tumor transplantation)tumor growth inhibition * , \documentclass[12pt]{minimal } 
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				 \begin{document}$$ k_1^{{tgi } } $ $ \end{document } , % group 2 ( injection of c60fas after tumor transplantation)tumor growth inhibition * , \documentclass[12pt]{minimal } 
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				 \begin{document}$$ k_2^{{tgi } } $ $ \end{document } , % 15 
 n  =  5 
 n  =  517.0 
 n  =  530.018 
 n  =  5 
 n  =  54.0 
 n  =  537.220 
 n  =  5 
 n  =  413.0 
 n  =  519.422 
 n  =  4 
 n  =  411.3 
 n  =  513.625 
 n  =  3 
 n  =  33.1 
 n  =  416.027 
 n  =  2 
 n  =  2 
 n  =  232 
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				 \begin{document}$$ ( k_1^{{sa } } = 20.0\% ) $ $ \end{document } 

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				 \begin{document}$$ ( k_2^{{sa } } = 40.0\% ) $ $ \end{document } 
 35 
 n =  1 
 n  =  139 
 n  =  0 
 n  =  0start of c60fas injection before the tumor transplantation12 october 2010 ( group 1 ; protective effect ) . start of c60fas injection after the tumor transplantation24 october 2010 ( group 2 ; inhibitive effect ) . survival of animals ( \documentclass[12pt]{minimal } 
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				 \begin{document}$$ k_i^{{sa } } $ $ \end{document } , percent ) is given in parentheses*p  <  0.05 , the differences are statistically valid compared with the control experiment 1 ( antitumor effect ) start of c60fas injection before the tumor transplantation12 october 2010 ( group 1 ; protective effect ) . start of c60fas injection after the tumor transplantation24 october 2010 ( group 2 ; inhibitive effect ) . survival of animals ( \documentclass[12pt]{minimal } 
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				 \begin{document}$$ k_i^{{sa } } $ $ \end{document } , percent ) is given in parentheses * p  <  0.05 , the differences are statistically valid compared with the control the results obtained from experiment 2 ( antitumor effect ) are presented in table  2 . antitumor effect of c60 fullerenes was recorded on the 13th day after transplantation of tumor in group 1 ( protective effect ; 23th day after the introduction of c60 fullerenes ) and in group 2 ( inhibitive effect ) . inhibition of tumor growth in group 1 shows a tendency to increase ( in contrast to the results of experiment 1 ) from 15.0% ( 13th day ) to the maximum value of 35.0% ( 27th day after tumor transplantation ) . inhibition of tumor growth in group 2 reached a maximum of 25.1% ( 16th day ) and then decreased to 5.0% ( 27th day after tumor transplantation ) . the last animal in the control group 0 died on the 30th day of the experiment . the survival of animals in groups 1 and 2 was 28.6% and 85.7% , respectively , compared to the control . the extension of animal life in group 1 was found to be 30.3% while in group 2 was estimated to be 21.8% compared to the control . finally , the life duration for last animal in group 1 ( 53  days ) ( protective effect ) and group 2 ( 36  days ) ( inhibitive effect ) was accordingly 1.8 and 1.2 times greater compared to the control ( 29  days ) ( this value agrees well with a same for group 2 in experiment 1).table 2experiment 2 ( antitumor effect)number of days after tumor transplantationgroup 0 ( control)group 1 ( injection of c60fas before tumor transplantation)tumor growth inhibition * , \documentclass[12pt]{minimal } 
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				 \begin{document}$$ k_1^{\text{tgi } } $ $ \end{document } , % group 2 ( injection of c60fas after tumor transplantation)tumor growth inhibition * , \documentclass[12pt]{minimal } 
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				 \begin{document}$$ k_2^{\text{tgi } } $ $ \end{document } , % 13 
 n  =  7 
 n  =  715.0 
 n  =  74.016 
 n  =  7 
 n  =  727.2 
 n  =  725.121 
 n  =  7 
 n  =  725.0 
 n  =  75.423 
 n  =  4 
 n  =  723.3 
 n  =  717.027 
 n  =  2 
 n  =  635.0 
 n  =  65.029 
 n  =  2 
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 n  =  630 
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				 \begin{document}$$ ( k_1^{\text{sa } } = 28.6\% ) $ $ \end{document } 

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				 \begin{document}$$ ( k_2^{\text{sa } } = 85.7\% ) $ $ \end{document } 
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 n  =  2 
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				 \begin{document}$$ ( k_2^{\text{ial } } = 21.8\% ) $ $ \end{document}*54 
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				 \begin{document}$$ ( k_1^{\text{ial } } = 30.3\% ) $ $ \end{document}*start of c60fas injection before the tumor transplantation07 february 2011 ( group 1 ; protective effect ) . start of c60fas injection after the tumor transplantation19 february 2011 ( group 2 ; inhibitive effect ) . survival of animals ( \documentclass[12pt]{minimal } 
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				 \begin{document}$$ k_1^{\text{sa } } $ $ \end{document } , % ) and increasing of animal life ( \documentclass[12pt]{minimal } 
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				 \begin{document}$$ k_i^{\text{ial } } $ $ \end{document } , % ) are given in parentheses*p  <  0.05 , the differences are statistically valid compared with the control experiment 2 ( antitumor effect ) start of c60fas injection before the tumor transplantation07 february 2011 ( group 1 ; protective effect ) . start of c60fas injection after the tumor transplantation19 february 2011 ( group 2 ; inhibitive effect ) . survival of animals ( \documentclass[12pt]{minimal } 
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				 \begin{document}$$ k_1^{\text{sa } } $ $ \end{document } , % ) and increasing of animal life ( \documentclass[12pt]{minimal } 
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				 \begin{document}$$ k_i^{\text{ial } } $ $ \end{document } , % ) are given in parentheses * p  <  0.05 , the differences are statistically valid compared with the control for visual comparison of tumor growth , fig . estimations demonstrate that the average tumor volume in experimental group 2 ( inhibitive effect ) is about 1.7 times greater compared to that in group 1 ( protective effect).fig . 2visual comparison of tumor size for animals of group 2 ( inhibitive effect ; a ) and group 1 ( protective effect ; b ) : 34th day after tumor transplantation ( experiment 2 ( antitumor effect ) ) visual comparison of tumor size for animals of group 2 ( inhibitive effect ; a ) and group 1 ( protective effect ; b ) : 34th day after tumor transplantation ( experiment 2 ( antitumor effect ) ) it is also important to note that the visual observation of experimental animals revealed that animals in group 1 ( protective effect ) compared to the animals in group 2 ( inhibitive effect ) have greater mobility and that the color of their hair was more explicit shade . finally , the life duration for last animal in group 1 ( protective effect ) seems to be about 1.5 times greater compared to that of last animals in group 2 ( inhibitive effect ) . the results obtained from experiment 3 ( antimetastatic effect ) clearly demonstrate that the metastasis inhibition index for group 1 ( protective effect ) \documentclass[12pt]{minimal } 
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				 \begin{document}$$ ( k_1^{\text{iim } } = 96\% ) $ $ \end{document } is twice the value of this index for group 2 ( inhibitive effect ) \documentclass[12pt]{minimal } 
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				 \begin{document}$$ ( k_2^{\text{iim } } = 48\% ) $ $ \end{document } on the 20th day after tumor transplantation . figure  3 presents the histological data for the animal tumors of group 0 ( control ; fig . 3c ) on the 20th day after tumor transplantation in experiment 3 ( antimetastatic effect).fig . 3histological sections of lewis lung carcinoma in male mice of c57bl/6j line on the 20th day after tumor transplantation ( experiment 3 ( antimetastatic effect ) : start of tumor transplantation20 may 2011 . start of c60fas injection after tumor transplantation22 may 2011 ) : a ( control)small areas of necrosis of tumor cells , apoptosis ( 200 ) ; b ( group 1 ; protective effect)mitosis and apoptosis of tumor cells ( 400 ) ; c ( group 2 ; inhibitive effect)areas of necrosis of tumor cells ( 200 ) histological sections of lewis lung carcinoma in male mice of c57bl/6j line on the 20th day after tumor transplantation ( experiment 3 ( antimetastatic effect ) : start of tumor transplantation20 may 2011 . start of c60fas injection after tumor transplantation22 may 2011 ) : a ( control)small areas of necrosis of tumor cells , apoptosis ( 200 ) ; b ( group 1 ; protective effect)mitosis and apoptosis of tumor cells ( 400 ) ; c ( group 2 ; inhibitive effect)areas of necrosis of tumor cells ( 200 ) lewis lung carcinoma consists of polymorphic cells , most of which are occupied by the nucleus with large nucleolus , condensed chromatin and light areas of karyoplasm . mitosis , apoptosis and necrosis of tumor cells are observed in all groups ( fig . the isolated lymphocytes are presented in the tumor stroma , and infiltration of polymorphonuclear leukocytes is observed . morphometric studies show the differences in the area of necrosis , mitotic and apoptotic indices between the study group and control , namely : area of necrosis in tumors was 17.7% ( control ) , 12.7% ( group 1 ; protective effect ) and 8.3% ( group 2 ; inhibitive effect ) ; the mitotic index was 1.57 ( control ) , 1.20 ( group 1 ; protective effect ) and 1.82 ( group 2 ; inhibitive effect ) ; the apoptotic index was 2.0 ( control ) , 4.7 ( group 1 ; protective effect ) and 2.9 ( group 2 ; inhibitive effect ) . as can be seen , the area in the tumor necrosis and apoptotic index value for group 1 ( protective effect ) exceed these parameters for group 2 ( inhibitive effect ) . conversely , the value of mitotic index for group 1 ( protective effect ) is less than this parameter for group 2 ( inhibitive effect ) . thus , c60 fullerenes , which were injected to animals before the tumor transplantation ( protective effect ) , activate processes of necrosis and apoptosis of tumor cells , and c60 fullerenes , which are injected to animals after the tumor transplantation ( inhibitive effect ) , activate the process of mitosis of tumor cells . c60fas , without showing direct cytotoxicity , cause at low single therapeutic dose ( 5  mg / kg ) antitumor immune response . specifically , it was observed that a treatment with c60fas inhibits tumor volume of lewis lung carcinoma in male mice of c57bl/6j line . namely , within the study of protective effect of c60fas , it was found that the maximum therapeutic effect was reached 35.0% for the index of tumor growth inhibition . an extension of animal life of about 30.3% was found . within the study of inhibitive effect of c60fas , the treatment purposefully suppresses the growth of this tumor : the maximum therapeutic effect reached 25.1% for the index of tumor growth inhibition ; the survival of animals was 85.7% compared to the control ; and an extension of animal life of about 21.8% was found . the metastasis inhibition index was 96% for protective effect and 48% for inhibitive effect of c60fas . the obtained results can be explained as a result of the high antioxidant activity of c60 fullerenes , neutralizing excess reactive oxygen species in the cell and possibly blocking the specific cell receptors , for example , endothelial growth factor . the proposed treatment with c60fas can be very promising in clinical oncology for the inhibition of tumor growth ( prylutska et al .
growth experiments of transplanted malignant tumors in the presence of water - soluble c60 fullerenes were performed on groups of mice . it was found that c60 fullerenes efficiently inhibit the growth of transplanted malignant tumors . 
 this behavior can be explained through their high antioxidant activity and the blocking of the specific cell receptors ( for example , endothelial growth factor ) . 
 the findings demonstrate the possibility of using c60 fullerenes in anticancer therapy .