Highly Selective Drug Combinations for Human Colon Cancer Cells Resistant in Vitro to 5-Fluoro-2ˊ-deoxyuridine

In the preceding companion paper, we describe a human colon carcinoma cell line that is resistant in vitro to 5-fluoro-2ˊ-deox-yuridine by virtue of impaired nucleoside transport. Two drug combinations, methotrexate:hypoxanthine:thymidine (dThd) and 5,8-dideazaisofolic acid:dThd, selectively kill these resistant cells with no effect on the sensitive cell population. As little as 0.3 μM dThd was sufficient to completely protect sensitive cells from 5-fluoro-2ˊ-deoxyuridine, and 5,8-dideazaisofolic acid at concentrations that produced over 80% lethality in unprotected cells and the same concentration of dThd in combination with 100 μM hypoxanthine fully protected sensitive cells from >99% metho-trexate-induced cell lethality. In contrast, when resistant cells were exposed to these drugs, they were not protected by dThd, or by the combination dThd:hypoxanthine, in concentrations up to 300 times higher than those necessary to prevent sensitive cell kill. Thus, it may be possible to protect normal renewal tissues while obtaining selective tumor cell kill with these two drug combinations in patients whose colon carcinoma cells are resistant to 5-fluoro-2ˊ-deoxyuridine by virtue of defective transport.