LEUCOVORIN RESCUE OF HUMAN CANCER AND BONE-MARROW CELLS FOLLOWING EDATREXATE OR METHOTREXATE

We have examined the cytotoxic activities of edatrexate (EDX) and meth otrexate (MTX) and their reversal by leucovorin in nine human cancer c ell lines and in human bone marrow CFU-GM cells. EDX was 3.7- to 123-f old more toxic than MTX against the cancer cell lines and 25-fold agai nst the bone marrow cells. Lower EDX concentrates generally were neede d to inhibit cancer cell growth relative to bone marrow cells, however , whereas bone marrow and cancer cell growth were more often susceptib le to the same MTX concentrations. The new antifolate was metabolized to long-chain polyglutamates to a greater extent than MTX in seven cel l lines. Leucovorin at 0.2 mu M rescued two breast cancer and two non- small cell lung cancer cell lines to a lesser extent following EDX tha n MTX, but significant rescue was observed in two head and neck cancer cell lines that formed large amounts of polyglutamates. These cell li nes also accumulated reduced folates to a greater extent than the othe r cell lines following leucovorin exposure. Leucovorin rescued bone ma rrow cells following MTX but only partially following the highest EDX concentrations. EDX may enjoy a better therapeutic index than MTX agai nst some cancer cell lines relative to bone marrow precursor cells, es pecially after leucovorin rescue.