Long-term persistence and cytokinetics of human tumor cells in vitro following high-dose alkylating agent exposure.
Relapse after high-dose alkylating agent therapy continues to be an important clinical issue. To begin to understand the characteristics of cells surviving alkylating agent exposure human MCF-7 breast carcinoma cells were exposed to a range of concentrations of melphalan or cis-diamminedichloroplatinum(II) and cell survival determined by colony formation over a time course of 4 weeks. When antitumor alkylating agent exposure killed 3-4 logs of cells as determined by surviving fraction after 1 week of colony formation a progressive increase in surviving fraction was evident over the 4-week course of the experiment. Many attached single cells with abnormal morphology were evident in these dishes; however, the colonies which arose over the 4-week observation time were made up of cells morphologically indistinguishable from the control cells. Cell cycle patterns in the cultures exposed to high concentrations of the antitumor alkylating agents indicated a block in G2/M but by 4 weeks post-drug exposure most had returned to a normal exponential growth pattern. When MCF-7 cells or human SW2 small cell lung cancer cells were exposed to a concentration of melphalan or cis-diamminedichloroplatinum(II) that killed 1-2 logs of cells followed by exposure to a concentration range of the same drug for 24 h or 7 days later resistance to the second drug exposure was evident in both cell lines. Using [14C]melphalan the uptake of the drug into MCF-7 cells pre-treated was compared. Decreased drug uptake did not appear to be a factor in resistance to melphalan observed upon re-exposure to the drug. The potential clinical implications of these findings is discussed.
Holden
S A
SA
Dana-Farber Cancer Institute, Boston, MA 02115.
Teicher
B A
BA
Frei
E
E
D001943:Breast Neoplasms / Q000188:drug therapy*; D002453:Cell Cycle; D048429:Cell Size; D002470:Cell Survival; D002945:Cisplatin / Q000627:therapeutic use*; D004351:Drug Resistance; D006801:Humans; D066298:In Vitro Techniques; D008175:Lung Neoplasms / Q000188:drug therapy*; D008558:Melphalan / Q000627:therapeutic use*; D013997:Time Factors; D014407:Tumor Cells, Cultured
D002945:Cisplatin; D008558:Melphalan