The characterization of two human cervical carcinoma HeLa sublines resistant to cisplatin.

Human cervical carcinoma HeLa cells were made resistant to cisplatin by one of two schedules; "acute" (cells repeatedly treated with cisplatin for 1 h in serum-free medium--CA cells) or "continuous" (cells treated repeatedly for 24 h in complete medium--CK cells). The sensitivity of CA and CK sublines to cisplatin and various other antineoplastic drugs was determined by the modified MTT staining procedure. The possible involvement of glutathione (GSH), glutathione S-transferases (GST) and metallothioneins (MT) in cisplatin resistance was examined. The results show that acutely treated CA cells became more resistant to cisplatin than CK cells. The resistance to cisplatin does not involve either glutathione or glutathione transferase. The increased levels of metallothioneins might be involved in the development of resistance. The sensitivity of CA and CK sublines to the selected drugs was different from that of the parent cells. Both sublines became cross-resistant to vincristine and methotrexate, but only CA cells exhibited cross resistance to etoposide doxorubicin and 5-fluorouracil. Thus, the development of resistance to cisplatin is a consequence of numerous intracellular alterations that are reflected in cell response to a variety of anticancer drugs. The response depends on the schedule of resistance development and on the nature of the secondary agent.