5.1. Antimetastatic Activity
Capecitabine and 5'-DFUR given orally were highly antimetastatic in a spontaneous metastasis model with Lewis lung carcinoma (37), a highly metastatic mouse tumor, when given in the neoadjuvant setting. These drugs were only slightly more effective against the inoculated primary tumor than 5-FU in this tumor model (9), whereas they were much more effective against spontaneous metastasis compared to 5-FU. Capecitabine, 5'-DFUR, and 5-FU all inhibited the formation of metastases at, respectively, 53-, 23-, and 4.4-fold lower doses than those needed for inhibiting the growth of the primary tumors. This preferential effect upon the formation of metastases was only weak for UFT and cyclophosphamide and not observed with doxorubicin, nimustine, and mitomycin C (unpublished observation).
The mechanism of this preferential effect of capecitabine and 5'-DFUR upon metastasis may stem from the upregulation of type IV collagenase, a metastatic factor, by intrinsic cytokines (37). IFNy, TNFa, and IL-1a, which are upregulators of dThdPase, increased levels of type IV collagenase by up to 12.2-fold in Lewis lung carcinoma cells, and made the tumor cells 4.6-fold more susceptible to 5'-DFUR in vitro. 5'-DFUR, but not 5-FU, induced lower levels of type IV collagenase at the primary tumor site in mice bearing Lewis lung carcinoma at low doses, which could only show antimetastatic activity. 5'-DFUR and capecitabine may selectively kill tumor cells exposed to intrinsic cytokines or other factors that upregulate dThdPase and a metastatic factor.
Mouse colon 26 causes progressive weight loss and physiological changes associated with cachexia when it grows to a certain size (1-2 g). Capecitabine and 5'-DFUR could reverse this progressive weight loss and improve hypoglycemia, hyperglucocorticism, and hepatic malfunctions, as well as inhibit tumor growth. This mechanism of action has not yet been clarified (38). In contrast, cyclophosphamide, nimustine, and 2'-deoxy-5-fluorouridine (FUdR) were only minimally effective in reversing the weight loss. 5-FU, tegafur, cisplatin, doxorubicin, and mitomycin C were not active in this regard. Reversal of the weight loss was observed within 3 d following the administration of 5'-DFUR to cachectic mice with large tumor burdens even at doses that failed to inhibit tumor growth. The results suggest that 5'-DFUR reverses cachexia independently of its antiproliferative activity. In an additional cachexia model, mice bearing MAC-16 carcinoma, both capecitabine and 5'-DFUR reversed weight loss and lowered the proteolysis inducing factor (39).
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