GROWTH-INHIBITORY EFFECTS OF ANTIFOLATES AGAINST AN ADRIAMYCIN-RESISTANT HUMAN SMALL-CELL LUNG-CANCER CELL-LINE

We have established an Adriamycin (ADM) - resistant small cell lung ca ncer (SCLC) cell line, SBC-3/ADM100, which shows multifactorial mechan isms of resistance to ADM, such as overexpression of P-glycoprotein, a n enhanced detoxifying system and a decrease in topoisomerase II activ ity. In the present study, we confirmed that SBC-3/ADM100 showed colla teral sensitivity to methotrexate and TNP-351, a new antifolate, thoug h this cell line showed a typical multidrug resistance (MDR) pattern. We also demonstrated a faster uptake and higher accumulation (1.3-fold ) of TNP-351 in the SBC-3/ADM100 cells than those in the parent SBC-3 cells. These results explain one of the mechanisms for collateral sens itivity in the resistant cells. Furthermore, this cell line was found to have no cross-resistance to edatrexate and minimal cross-resistance to trimetrexate, 254-S (cisplatin analog), 5-fluorouracil and 4-hydro peroxyifosfamide. These drugs will have clinical importance in patient s with SCLC who were previously treated with an ADM-containing regimen . Thus, antifolates, especially TNP-351 and edatrexate, can be expecte d to eradicate residual multidrug resistant SCLC cells selected by ADM .