Rapid development of resistance to antifolates in vitro: possible clinical implication

Within three repeated 7-day incubation periods with either methotrexate (MTX) or trimetrexate (TMTX), human colon adenocarcinoma cells (HCT-8) developed high levels of resistance to these drugs, as evidenced by approximately 20- and 50-fold increases, respectively, in the median effective doses. Similarly, within six short-term exposures (4 hours) to the same drugs, a high degree of resistance developed in the cells. Alternating 4-hour treatment cycles with MTX and TMTX did not delay the onset of resistance to these antimetabolites in the HCT-8 cells. The same strategy produced no better results than giving either MTX or TMTX alone to (C57BL/6 x DBA/2)F1 mice bearing murine leukemia P388 cells. Furthermore, HCT-8 cells resistant to short-term (4-hour) exposure to MTX were cross-resistant to the same drug given for 7 days continuously, and cells resistant to MTX given continuously for 7 days were cross-resistant to the same drug given for 4 hours. Analogous results were obtained with TMTX, indicating that, under these circumstances, changing the schedule of administration of the same agent does not overcome resistance to it. The clinical relevance of these data to prolonged adjuvant chemotherapy, as well as loco-regional and continuous-infusion chemotherapy, is discussed.