Novel Nucleoside Transport Inhibitors of Natural Origin
Part of the
Advances in Experimental Medicine and Biology
book series (AEMB, volume 370)
The salvage pathway of nucleotide biosynthesis is one of the attractive targets for cancer chemotherapy. Dipyridamole, a nucleoside transport inhibitor, may be used for blocking the salvage pathways. Studies have demonstrated that dipyridamole can reduce the rescue effect of exogenous nucleosides and potentiated the cytotoxicity of acivicin, an antimetabolite of de novo pathways of nucleotide biosynthesis, in hepatoma cells1, 2. The inhibitory effect of dipyridamole was cell growth phase -dependent. Cultured hepatoma cells in lag and log phase were highly sensitive to dipyridamole; by contrast, cells in stationary phase were insensitive3, 4. The combination of acivicn and dipyridamole administered in rats bearing s.c. transplanted hepatoma yielded a summation effect, decreasing NTP and dNTP pools5. The synergistic effect of dipyridamole and acivicin was also demonstrated in colon cancer cells6. There have been reports that dipyridamole potentiated the cytotoxicity of several antimetabolites including methotrexate, 5-fluorouracil and N-phosphonacetyl-L-aspartate (PALA)7, 8, 9. In addition to potentiating antimetabolites, dipyridamole was found to enhance the cytotoxicity of doxorubicin, etoposide, vincristine and mitoxantrone10, 11, 12. These synergistic effects of dipyridamole and drugs which are not antimetabolites were due to, at least in part, increased intracellular concentrations of anticancer drugs. Drug sensitivity of multidrug resistant cells may be modulated by dipyridamole13. The use of dipyridamole in cancer chemotherapy has drawn much attention and clinical trials have been underway14, 15. The study of dipyridamole indicates that blocking nucleoside salvage pathways by inhibition of nucleoside transport may be one of the effective ways in chemotherapy. By examination of a series of compounds of natural origin, we have found that green tea polyphenols (GP), antibiotics C3368-A (CA) and C3368-B (CB) are highly active in blocking nucleoside transport in cancer cells. Investigations have demonstrated that GP, CA or CB show synergistic effects with anticancer drugs.
KeywordsSarcoma Doxorubicin Methotrexate Purine Etoposide
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