Selection and characterization of L1210 sublines resistant to teniposide (VM-26)

Two spectra of L1210 sublines with gradations of resistance to teniposide (VM-26) were selected by stepwise exposure of cultures to increasing concentrations of the drug. Cultures representing the first spectrum were from 20 times to 1200 times more resistant to VM-26 than were cultures of parental cells. At 24 hr after addition of 22 nM VM-26 to the medium, the growth of cultures of parental cells was inhibited by 50%. Increases in resistance to VM-26 among the sublines coincided with increases in population doubling times. When cells were transferred to drug-free medium, there was a sharp decrease in resistance over the first 10 days; the subsequent decline in resistance, over 2 to 4 months, correlated with a decrease in population doubling times. The second spectrum of resistant sublines arose from the first spectrum after the latter had been maintained for about 1 year on various selective concentrations of VM-26. Resistance to VM-26 by this second group of sublines was from 400 times to over 2000 times greater than that of the parental cell line. Doubling times for these resistant cell populations were similar to the normal rate of the parental cell line. Eight sublines were characterized by two chromosomes with homogeneously staining regions, while the remaining subline had a single chromosome with this anomaly. One of the regions appeared on a submetacentric chromosome in seven of the nine sublines, while the other was on an acrocentric chromosome. These observations indicate that a longer doubling time facilitated selection of increasingly resistant sublines but was not essential for the resistance of sublines in the second spectrum.