Antitumor, antimetastatic and antiangiogenic effect of genistein alone or combined with cyclophosphamide in mouse experimental tumor models

The antitumor, antimetastatic, and antiangiogenic effects of genistein alone, cyclophosphamide alone, and combined therapy with both agents in mice transplanted with B16F-10 melanoma and. Lewis lung cancer (LL2) cells were studied. An influence of the route of tumor cells inoculation on antitumor and antimetastatic effects of these therapeutics was evaluated. The antitumor effect of genistein in mice given B16F-10 cells intradermically and in mice given LL2 cells subcutaneously was observed. In addition, the antimetastatic effect (reduction of number of lung colonies) of genistein in mice inoculated intravenously with B16F-10 cells and in mice inoculated either intravenously or subcutaneously with LL2 cells was observed. No life span prolongation of mice injected intraperitoneally with B16F-10 cells was observed, either after treatment with genistein alone or with cyclophosphamide alone. A synergistic effect of both agents in combined treatment was observed when B16F-10 cells were injected intraperitoneally, intravenously, and intradermically and in a weaker manner when LL2 cells were injected subcutaneously. When LL2 cells were injected intravenously, no additive effect of genistein and cyclophosphamide could be detected. In conclusion, we described experimental mouse tumor models in which the antitumor and antimetastatic effects of genistein alone, cyclophosphamide alone, and genistein and cyclophosphamide combined were dependent on the route of tumor cells implantation. In addition, we applied our own new method allowing quantification of the volume of blood present in tumor tissue, thus the intensity of tumor angiogenesis. In mice bearing transplantable Lewis lung cancer the additive antiangiogenic but not cytostatic effect of genistein combined with cyclophosphamide was observed: treatment with genistein alone reduced tumor blood supply in 35% (tumor weight in 36%), cyclophosphamide alone reduced tumor blood supply in 38% (tumor weight in 70%), and both compounds reduced tumor blood supply in 61% (tumor weight in 75%). In the B16 melanoma model the respective values were 60% and 44% for genistein, 83% and 79% for cyclophosphamide, and 76% and 74% for combined treatment. These results indicate a higher antiangiogenic than cytostatic effect of genistein in both mouse tumor models.