Effects of 5'-aminothymidine and leucovorin on radiosensitization by iododeoxyuridine in human colon cancer cells
We examined the effects of two biochemical modulators, 5'-aminothymidine (5'-AdThd) and leucovorin (LV), on the in vitro incorporation of iododeoxyuridine (IdUrd) into DNA and its subsequent radiosensitization in two human colon cancer cell lines, HT 29 and HCT 116. 5'-AdThd is a modulator of thymidine kinase activity while LV is an essential cofactor for thymidylate synthase activity. In HT 29 cells, the combination of 5'-AdThd (10 &mgr;m) and IdUrd (1-10 &mgr;m) resulted in a significant increase in IdUrd triphosphate pools and in IdUrd-DNA incorporation. Coadministration of LV (10 &mgr;m) with IdUrd (1-10 &mgr;m) resulted in a significant decrease in thymidine triphosphate pools and a comparable increase in IdUrd-DNA incorporation as the combination of 5'-AdThd + IdUrd. The increase in radiosensitization by clonogenic survival with either combination was a direct linear function with the percentage of IdUrd-DNA incorporation. For HCT 116 cells, however, the results were different. While 5'-AdThd + IdUrd resulted in an increase in IdUrd triphosphate and percentage of IdUrd-DNA incorporation, significant cytotoxicity was noted. The radiosensitivity of HCT 116 cells treated with 5'-AdThd + IdUrd was not a linear function above 25% IdUrd-DNA incorporation. Also, no increase in IdUrd-DNA incorporation or radiosensitization was observed with LV + IdUrd although LV enhanced the decrease in thymidine triphosphate pools by IdUrd treatment. These results indicate heterogeneity in the response of different colon cancer cells to these modulators which may be related to the regulation of deoxynucleotide metabolic enzymes.
Miller
EM
Department of Human Oncology, University of Wisconsin Medical School, Madison, Wisconsin 53792, USA.
Kunugi
KA
Kinsella
TJ